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Ismail",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10013.jpg",keywords:"Thermodynamics, Heat Transfer Analyses, Geothermal Power Generation, Economics, Geothermal Systems, Geothermal Heat Pump, Green Energy Buildings, Exploration Methods, Geologic Fundamentals, Geotechnical, Geothermal System Materials, Sustainability",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 29th 2020",dateEndSecondStepPublish:"November 26th 2020",dateEndThirdStepPublish:"January 25th 2021",dateEndFourthStepPublish:"April 15th 2021",dateEndFifthStepPublish:"June 14th 2021",remainingDaysToSecondStep:"2 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Leading research investigator in a collaborative project (2007-2010) with Goldcorp-Musselwhite Canada Ltd. and Engineering of Lakehead University, owner of a Ph.D. degree in Mechanical Engineering from McMaster University, Hamilton, Ontario, Canada and postdoctoral researcher (2004 to 2005) at McMaster University.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"62122",title:"Dr.",name:"Basel",middleName:"I.",surname:"Ismail",slug:"basel-ismail",fullName:"Basel Ismail",profilePictureURL:"https://mts.intechopen.com/storage/users/62122/images/system/62122.jpg",biography:"Dr. B. 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1. Introduction
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The identification of melanoma-associated antigens, the isolation of tumor infiltrating T cells from melanoma lesions, and the significant progress in engineering redirected T cells has favored the development of various strategies in the adoptive immunotherapy of melanoma. Recent trials in adoptive cell therapy (ACT) have achieved spectacular results in inducing remission in advanced stages of the disease, although produced on-target off-tumor toxicities, emphasizing the tremendous potential benefit of harnessing the immune system for fighting the disease. Moreover, the identification of so-called melanoma stem cells along with strategies for selectively eliminating subsets of melanoma cells implies that there is a need for redefining therapeutic targets in melanoma. This review discusses current challenges in the rational design of adoptive cell therapy to target “the beating heart” of melanoma.
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1.1. Advanced stages of melanoma resist conventional therapeutic regimens
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Surgical resection of tumor lesions in early stages of the disease is the curative option for combating melanoma; a 10-year-survival rate of 75 - 85% can be achieved for melanoma in stage I or II. However, melanoma in stage III or IV is still associated with low survival rates of less than 1 year upon diagnosis [1]. Despite the development of novel drugs and major improvements in therapeutic regimens, significant responses were only achieved in predefined groups and of short duration. Treatment with the chemotherapeutic drug dacarbazine (DTIC) and vemurafenib, an inhibitor of mutated BRAF, produced a median progression-free survival of 64% with dacarbazine, respectively 84% with vemurafenib of approximately 6 months [2-4]. The biology of melanoma and the heterogeneity of malignant cells are thought to be responsible for this unsatisfactory situation. First, melanoma cells can persist for long periods of time in a “dormant” stage without any progression in tumor formation [5]. Second, melanoma cells can disseminate early into distant organs including the brain forming micro-metastases, which are small in cell numbers and frequently beyond the detection limit of current imaging procedures [6, 7]. Third, many melanoma cells are notoriously resistant to chemo- and radiation therapy [8-10], making alternative strategies in tumor cell elimination necessary.
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Therefore, in more progressed stages of the disease the recruitment of the cellular immune defense to eliminate cancer cells is thought to be an alternative. Administration of high dose interleukin-2 (IL-2) [11] and anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody [12] as well as interferon (IFN) α-2b prolongs the disease-free survival although at a relatively low response rate and without being curative over time [13, 14]. However, these and other observations imply that activation or modulation of the patient’s immune response may be effective in the treatment of melanoma. A number of approaches for enhancing the immune cell response against melanoma are currently explored with some success. In particular, the adoptive transfer of autologous T cells isolated from melanoma lesions and expanded to large numbers ex vivo has produced encouraging phase II results [15, 16]. The administration of patient’s blood T cells engineered with defined specificity for melanoma-associated antigens are additionally being explored in a number of trials. In this review, we summarize evidence for the potency of adoptive T cell therapy in the treatment of melanoma and discuss current challenges in achieving long-term remission. Upcoming strategies in selective targeting cancer stem cells are also discussed.
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2. Adoptive cell therapy can successfully fight melanoma
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Melanoma can trigger a curative immune response; this conclusion is drawn from the clinical observation of spontaneous and complete melanoma regressions and of the higher frequency of melanomas among immune compromised patients [17, 18]. More direct evidence for the immune cell control of melanoma growth was obtained by the treatment with high dose IL-2, which produces an objective response rate of 16%. Indeed, some of the patients receiving thus treatment exhibit a long-term complete response for years [11, 19]. These observations are remarkable in light of the low and short-lived response rates after chemotherapy and currently drive the development of adoptive T cell therapy for treatment of late stage melanoma.
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The development of adoptive cell therapy (ACT) was further strengthened by upcoming technologies in isolating tumor infiltrating lymphocytes (TIL\'s) from melanoma biopsies (Figure 1). First described in 1969 [20], TIL\'s from melanoma lesions consisted of both effector and helper T cell subsets and can be expanded ex vivo in the presence of IL-2. The expanded cells are then selected for melanoma reactivity. A strong rationale for using these T cells in adoptive therapy is provided by the observation that the infusion of high TIL numbers correlates with better clinical outcome [21, 22] although the prevalence of TIL\'s in primary melanoma lesions and metastases is not a prognostic factor itself.
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Protocols according to GMP standards have been established in several centers to isolate and amplify TIL\'s to numbers appropriate for adoptive therapy. Melanoma reactive T cells are expanded in the presence of IL-2 by culture on feeder cells expressing melanoma antigens [23]. Subsequent to TIL re-infusions, metastases regressed in the majority of patients and a stable disease phase followed. However, only few patients remained in complete remission [21]. The disappointing therapeutic efficacy, despite high numbers of infused TIL\'s is thought to be due to low responsiveness of highly expanded T cells which are unable to execute a productive anti-melanoma attack after administration to the patient. Current TIL protocols therefore attempt to administer so-called “young TIL\'s” (Figure 1), i.e. melanoma infiltrating T cells which underwent short-term culture expansions and therefore passed through fewer cell division cycles prior to re-infusion and thereby exhibit a less differentiated phenotype [24]. Another change in protocols is that TIL\'s are not selected for melanoma reactivity; the rationale behind this is that re-infusion of ex vivo IFN-γ secreting TIL\'s exhibited no major benefit compared to non-responding TIL\'s [16]. Early phase I trials showed improved persistence of young TIL\'s [25] and 50% response rates in a cohort of 20 patients [26], which is just as effective as traditionally grown TIL\'s [27]. Different non-randomized phase II trials at the NCI and at Sheba Medical Center confirmed these early observations (Table 1) [28, 29]. A roadmap describing critical steps for comparative testing the TIL strategy in a randomized multi-center setting was recently published in a White Paper on adoptive cell therapy [30].
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Figure 1.
Adoptive cell therapy for metastatic melanoma. Adoptive cell therapy with tumor infiltrating lymphocytes (TIL´s) makes use of melanoma-specific TIL´s which are isolated from a melanoma biopsy, amplified ex vivo by stimulation with melanoma biopsy cells and propagated to high numbers in the presence of IL-2. In more recent trials, TIL´s are propagated short-term ex vivo without stimulation by melanoma cells and administered as "young" TIL´s.
Adoptive cell therapy trials in patients with metastatic melanoma
\n CHUV, Centre Hospitalier Universitaire Vaudois; DFCI, Dana-Farber Cancer Institute; FHCRC, Fred Hutchinson Cancer Research Center; HMO, Hadassah Medical Organization; LUMC, Leiden University Medical Center; MDACC, M.D. Anderson Cancer Center; MOFFITT, H. Lee Moffitt Cancer Center and Research Institute; NIH, National Institutes of Health; NUH, Nantes University Hospital; PI, principal investigator; SMC, Sheba Medical Center; UC, University of California; UR, University of Regensburg
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3. Adoptive cell therapy with antigen-specific T cells
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The rationale for using melanoma antigen-specific T cells is based on the observation that the success of TIL therapy in some patients correlates with the presence of melanoma-reactive T cells, in particular with those cells specific for Melan-A, MART-1 or gp100 [23, 31]. The median survival of patients treated with Melan-A specific TIL\'s was 53.5 months compared to 3.5 months for patients who received TIL\'s without Melan-A specificity [32]. These observations together with a number of technical obstacles in obtaining TIL\'s from biopsies strengthened efforts to derive melanoma-specific T cell clones from peripheral blood lymphocytes for the use in adoptive cell therapy. The strategy was corroborated by a 50% response rate obtained after transfer of MART-1 or gp100 specific T cell clones isolated and propagated ex vivo from peripheral blood lymphocytes (Table 1) [33]. Melanoma reactive T cell clones in peripheral blood are rare, TIL therapy increases the otherwise low magnitude of the tumor-reactive T cell compartment in vivo, which matches the reactivity in the TIL product [34]. Interestingly, individual TIL products from different patients contain unique patterns of reactivity against shared melanoma-associated antigens [34]. TIL isolation and expansion in vitro, however, is extremely laborious. This limit leads to attempts to engineer patient\'s blood T cells with pre-defined specificity for more specifically redirecting the cytotoxic response toward melanoma. It is therefore assumed that the clinical efficacy of TIL therapy can be improved by application of T cells with more defined tumor-reactivity.
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To engineer specificity for melanoma, T cell receptors (TCR\'s) were cloned from TIL\'s of responding melanoma patients and transferred to peripheral blood T cells of the same patient (Figure 2) [35-38]. The gp100 specific TCR was one of the first TCR’s, cloned from melanoma TIL\'s and introduced ex vivo by retrovirus-mediated gene transfer into blood T cells, which thus obtained redirected specificity for gp100 positive cells. In contrast to their non-modified counterparts, TCR engineered T cells responded to gp100+ melanoma cells by secreting pro-inflammatory cytokines including IFN-γ and by lysing the target cells [45, 46]. Similarly, blood T cells were engineered with recombinant TCR’s with specificity for MART-1 or MAGE-A1. The functional avidity of cloned TCR\'s was improved and engineered T cells were successfully used in subsequent trials [47, 48]. About 30% of patients receiving ACT with MART-1 specific T cells responded with melanoma regression; 19% of patients treated with gp100 specific TCR T cells exhibited objective response, most responses were persistent [38]. TCR engineered T cells also showed efficacy towards brain metastases, which indicates that patients with otherwise incurable metastatic sites may benefit from ACT (Table 1) [115]. In patients with prolonged clinical remission, engineered T cells were present in the circulation for more than a year after initiation of treatment; this indicates that therapeutic efficacy and long-term anti-melanoma immunity may correlate with T cell persistence [49, 50].
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Figure 2.
\n Adoptive cell therapy with redirected T cells. T cells from the peripheral blood of the patient are engineered ex vivo by retro- or lentiviral gene transfer with cDNA coding for a T cell receptor (TCR) with specificity for a melanoma-associated antigen. Alternatively, T cells are engineered with a chimeric antigen receptor (CAR) which recognizes a melanoma-associated antigen by an antibody-derived binding domain. Engineered T cells are expanded ex vivo prior to administration to the patient.
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However, the enthusiasm for adoptive cell therapy with TCR modified T cells has been dampened by several limitations. Tumor cells including those of the melanoma undergo clonal evolution, and some of these evolved cells evade T cell recognition, for instance, as a result of repression of their MHC complex [51], of mutations in their β2 microglobulin chain [52], and of deficiencies in their antigen processing machinery [51, 53]. Each of these alterations renders the melanoma cell invisible to a TCR-mediated T cell attack. A possible safety hazard moreover became apparent when analyzing in more detail the transgenic TCR, which is co-expressed with the physiological TCR in the same T cell. The transgenic TCR turned out to create new but unpredictable specificities by forming hetero-dimers of the recombinant α and β TCR chains with the respective chains of the physiological TCR. Undesirable mispairing of TCR chains may result in loss of specificity and may induce severe auto-reactivity [54, 55]. Tremendous efforts were subsequently made to solve the problem including replacement of TCR constant moieties by the homologous murine domains [56] and creation of additional cysteine bridges [57] to enforce preferential pairing of the recombinant αβ TCR chains in the presence of the physiological TCR.
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These and other technical difficulties promoted the development of an artificial “one-chain-receptor” molecule to redirect T cells in an antigen-restricted manner (Figure 3). In a seminal paper Zelig Eshhar of the Weizmann Institute of Science described a chimeric antigen receptor (CAR), also named immunoreceptor, which is composed in the extracellular part of a single chain antibody for antigen binding and in the intracellular part of the TCR/CD3ζ endodomain for provision of T cell activation [58]. The CAR modified T cell, also known as “T-body”, becomes activated by binding to antigen, and secretes pro-inflammatory cytokines, amplifies and lyses target cells expressing the respective antigen. By using an antibody for binding, the CAR recognizes the target in a MHC-independent fashion and is therefore not affected by loss of HLA molecules, which frequently occurs during neoplastic progression. An additional advantage over transgenic TCR\'s is that CAR\'s can be used independently of the individual HLA subtype. However, the T-body strategy is restricted to antigens expressed on the surface of the target cell; intracellular antigens are not visible to CAR\'s. Due to the broad variety of antibodies available, a nearly unlimited panel of antigens can be targeted with high affinity and specificity, including those which are not classical T cell antigens, e.g. carbohydrates. High affinity CAR\'s activate engineered T cells even after binding to low amounts of target antigen; this not only makes the approach highly sensitive, but also makes the choice of the appropriate melanoma-selective antigen difficult.
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Figure 3.
\n Recombinant receptors to redirect T cells for use in antigen-specific cell therapy. The physiologic T cell receptor (TCR)/CD3 complex consists of the α and β TCR chains, which recognize major histocompatibility complex (MHC)-presented antigen by binding through both variable regions Vα Vβ, and of the CD3 chains. Antigen engagement induces clustering of the TCR complex and the primary signal for T cell activation is generated by the intracellular CD3ζ chain. Recombinant TCR α and β chains can be engineered to T cells in order to provide a new specificity. Alternatively, the V regions of the TCR chains can be combined and fused to the intracellular CD3ζ chain to produce a T cell activation signal upon binding to antigen. The chimeric antigen receptor (CAR) makes use of an antibody binding domain for antigen recognition which is enigneered by fusing the variable (V) regions of the immunoglobulin heavy (H) and light (L) chain. The VH-VL single chain antibody is linked via a spacer to the intracellular CD3ζ chain to produce the primary T cell activation signal upon antigen binding. Intracellular signaling domains of costimulatory molecules like CD28 can be added to provide appropriate costimulation in addition to the primary CD3ζ signal.
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T cells require two signals for full and lasting activation, one provided by the TCR and the other by costimulatory co-receptors; the prototype of which is CD28. The corresponding ligands are usually not present in the tumor micro-environment. Some effector functions including IL-2 secretion require CD28 costimulation along with the primary TCR/CD3ζ signal; this provides a rationale for combining the intracellular CD3ζ with the CD28 signaling domain in one polypeptide chain (Figure 3) [59]. Other costimulatory domains, such as 4-1BB (CD137) and OX40 (CD134), were also linked to CD3ζ; each domain has a different impact on T cell effector functions [60]. Costimulatory domains were furthermore combined in so-called 3rd generation CAR\'s, and a number of additional modifications have been introduced in the last years to improve T cell persistence and activation [61, 62]. CAR\'s with a costimulatory domain clearly demonstrated clinical benefit and improved T cell persistence compared to CAR\'s targeting the same antigen but with only the CD3ζ domain [63-65].
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Various CARs were engineered for targeting melanoma-associated antigens, including HMW-MAA, also known as MCSP [67, 68], melanotransferrin [69], the ganglioside GD2 [70] and GD3 [71]. A clinical trial targeting melanoma cells with CAR engineered T cells is currently recruiting participants [66]. Recent phase I trials using CAR redirected T cells in the treatment of lymphoma/leukemia exhibited spectacular efficacy [72, 73]. However, the enthusiasm was dampened by reports on serious adverse events and even fatalities after CAR T cell therapy [74, 75]. Targeting ErbB2 produced a cytokine storm and respiratory failure in one case [76] which is thought to be due to low levels of antigen on a number of healthy cells which can trigger CAR T cell activation. On the one hand, this event points out that ACT with CAR modified T cells may be a powerful therapy; but, on the other hand, emphasizes the necessity for careful T cell dose escalation studies to balance anti-tumor efficacy and auto-immunity[61, 77, 78].
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4. Challenges and premises in the adoptive cell therapy of melanoma
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To date, approximately half of the melanoma patients treated with TIL ACT benefit from this therapy; genetic modification of T cells may further improve clinical response to melanoma, but this will have to be proven in upcoming trials. However, the strategy has potential challenges which need to be addressed.
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A major challenge of redirected T cells is the tumor selectivity for the target antigen itself, which in most cases is not exclusively expressed on tumor cells but also on healthy cells [79], although almost always at lower levels: for instance MART-1, which is also expressed by melanocytes. When targeting these antigens, vitiligo and inner ear toxicity resulting in a certain degree of deafness are frequently observed side effects [38]. From this perspective it is reasonable to assume that off-target toxicities may be adverse reactions for clinical efficacy in an anti-melanoma response [80]. Since nearly all tumor-associated antigens are self-antigens, strategies will have to be developed to ensure that off-target toxicities are kept to a minimum. Whether T cells with low-avidity TCR or CAR are less prone to induce such undesirable side effects is currently under investigation.
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Melanoma cells, like other cancer cells, down-regulate components of the MHC and become increasingly deficient in antigen processing. As a consequence, TCR engineered T cells can no longer bind to and destroy those melanoma cells. However, they may be visible to a CAR recognizing surface antigens in a MHC independent manner, because of the antibody-derived binding domain (Figure 3). TCR redirected T cells, on the one hand, may also recognize cross-presented targeted antigen, for instance by stroma cells, but this is not the case for CAR engineered T cells. Cross-presented antigen, on the other hand, may help to destroy stroma, which is required to eliminate large tumor lesions [39, 40].
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To avoid mispairing of the recombinant TCR with the physiological TCR chains and the resulting unpredictable auto-immunity, TCR-like single chain antibodies were used as targeting domain in a CAR. Thus combining the MHC-restricted recognition of antigen with the T-body strategy. T cells with TCR-like CAR were redirected towards NY-ESO-1 and MAGE-A1, respectively [41, 42]. The possible advantages of these MHC restricted CAR\'s compared to the use of recombinant TCR\'s still has to be determined in trials.
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The antibody-derived binding domain of a CAR displays extraordinary high affinity compared to a TCR. However, an increase in affinity, for instance, by affinity maturation, does not necessarily improve CAR redirected T cell activation above threshold [41, 43], which is not additionally modulated by CD28 costimulation [44]. A similar effect is also assumed for TCR mediated T cell activation. The TCR or CAR binding avidity probably affects the persistence of engineered T cells at the targeted tumor site. Strong binding to a target antigen may cause the T cells to be trapped and to become fully activated for a cytolytic attack, whereas low avidity interactions may not provide sufficiently long T cell – melanoma cell contacts. In addition to the binding avidity, the amount of target antigen on the cell surface also impacts on the selectivity of redirected T cell activation. In essence, low affinity binding directs the activity of engineered T cells preferentially toward target cells with abundant antigen levels; high affinity binding is likewise effective against low antigen levels on target cells. The optimized affinity to sustain a more selective T cell trafficking to the tumor and activation while avoiding targeting healthy cells that are expressing low quantities of the same antigen, however, still has to be determined.
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A beneficial T cell-to-target cell ratio at the tumor site seems to be required for efficient tumor elimination. Higher numbers of engineered T cells applied per dose will probably increase clinical efficacy; the majority of recent trials have applied up to 1010 cells per dose [27]. These and higher numbers of engineered T cells can be generated by extended expansion protocols; however, cells with a "young" phenotype may not be generated for adoptive transfer under these conditions. Short-term amplification protocols are therefore envisioned for both TIL\'s and engineered blood T cells. However, the majority of recent trials targeting CD19+ leukemia provided evidence for therapeutic efficacy at numbers less than or equal to 105 engineered T cells [73]. This once again raises the question of whether high T cell doses are required for a therapeutic effect.
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The clinical outcome of adoptive cell therapy correlates with the persistence of adoptively transferred T cells [81]. As long as T cells engage their cognate antigen, T cells will expand and persist in detectable numbers; but when the antigen is no longer present, the T cell population will contract to potentially undetectable levels and disappear from circulation. To improve survival of CAR T cells, Epstein-Barr virus (EBV)-specific T cells were engineered with a tumor-specific CAR based on the rationale that T cells recognizing the low amounts of EBV antigens by their physiological TCR will be maintained in a sizable population in circulation and in the process providing enough CAR T cells to recognize and kill melanoma cells in the surrounding tissues. A clinical trial with EBV-specific T cells engineered with an anti-GD2 CAR thus showed benefit over non-virus-specific, CAR engineered T cells in the treatment of neuroblastoma [81].
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Adoptively transferred CD8+ T cell clones may be less persistent than CD4+ T cell clones due to T cell exhaustion after extensive ex vivo amplification and multiple rounds of activation. In addition, CD4+ T cell help is essential for CD8+ T cell persistence in vivo; adoptively transferred pure CD8+ T cell clones may fail to persist [82]. T cell therapy may be combined with antibody therapy to prolong the initiated immune response. For instance, CTLA-4 is upregulated on the surface of activated T cells, where it acts as negative regulator to return the T cell to a resting stage. Co-application of the anti-CTLA-4 blocking antibody, ipilimumab, may prolong the anti-tumor activation of transferred T cells, although it would also affect all the other T cells.
\n
Besides maintaining a high number of T cells in circulation, another challenge is to accumulate significant numbers of effector T cells in the tumor lesion. A tightly controlled network of chemokines controls the migration of cells in the body; adoptively transferred T cells use these networks to accumulate at the tumor site. The expression of specific chemokine receptors controls how cells will migrate against the chemokine gradient into the targeted lesion. Melanoma cells secrete a number of chemokines including CXCL1. However, early imaging studies revealed that melanoma-specific T cells massively infiltrate the lungs, spleen and liver with some accumulation at the tumor site, which clearly represents a minority of the transferred cells, before the cells decline to undetectable levels in circulation [83-85]. Since those T cells do not express CXCR2, the receptor for melanoma secreted CXCL1, TIL\'s were engineered with CXCR2 which generated improved melanoma accumulation and anti-tumor activity in a mouse model [86]. The strategy is currently being explored in an early phase I trial (Table 1) [86].
\n
One of the major hurdles of redirected immunotherapy of cancer in general is the tremendous heterogeneity of cancer cells with respect to the expression of the targeted antigen. Low or lack of antigen expression within the malignant lesions will negatively affect the long-term therapeutic efficacy of the approach. Several reports document relapse of antigen-loss tumor metastases after adoptive therapy with melanoma-reactive T cell clones [87-89] and argue for the use of polyclonal T cells with various melanoma specificities. Melanoma cells expressing the target antigen may successfully be eliminated by redirected T cells, whereas antigen-negative tumor cells will not be recognized. T cell populations modified with different CAR\'s recognizing different antigens expressed by the same tumor may be able to overcome these limitations. However, pro-inflammatory cytokines secreted by redirected T cells into the tumor micro-environment upon activation may attract a second wave of non-antigen restricted effector cells, which in turn may eradiate antigen-negative tumor cells. At least in an animal model, antigen-negative melanoma cells are indeed eliminated when co-inoculated with antibody-targeted cytokines [90]. Moreover, T cells engineered with induced expression of transgenic IL-12 attract innate immune cells including macrophages into the tumor tissue; they eliminate antigen-negative tumor cells in the same lesion [91].
\n
Highly expanded T cells, such as TIL\'s, become hypo-responsive to CD28 costimulation and rapidly enter activation induced cell death, in particular upon IL-2 driven expansion [92]. This may be counteracted by expansion in the presence of IL-15 and IL-21 and/or by co-stimulation via 4-1BB by an agonistic antibody [93].
\n
Metastatic melanoma patients with the B-raf activating mutation V600E transiently benefit from a small molecule drug, PLX4032 or vemurafenib, which inhibits the mitogen-activated protein kinase (MAPK) pathway. Treatment with vemurafenib is accompanied by increased T cell infiltrations in the melanoma lesions [94, 95]. Combination of B-raf inhibition with melanoma-specific ACT may provide an option to prolong the clinical response.
\n
Although the TCR downstream signaling machinery is used by the prototype CAR, monocytes, macrophages as well as NK cells can also be redirected by CAR\'s in an antigen-specific fashion [96, 97]. Whether redirected non-T cells are advantageous in tumor elimination to cancer patients in general and to melanoma patients in particular has to be explored in clinical trials.
\n
\n
\n
5. Does targeting "melanoma stem cells" provide hope for long-term remission from melanoma?
\n
Observations that a number of malignant lesions display a tremendous cellular and phenotypic heterogeneity and contain pluripotent stem cells led to the hypothesis that cancer is initiated and maintained by so-called cancer stem cells (CSC’s). Low abundance, induction of tumors upon transplantation under limiting conditions, radiation and chemo-resistance, self-renewal and a-symmetric differentiation into a variety of cell types are properties postulated for CSC’s. The concept was sustained by deciphering the hierarchical organization in hematological malignancies [98], and subsequently in solid cancers including mammary, prostate, pancreatic, colon carcinoma and glioma [99-103]. Transplantation of melanoma cell subsets under limiting dilution conditions showed that a subset of cancer cells can induce tumors of the same histological phenotype as the parental tumor [99, 104, 105]. A first study using the limiting dilution transplantation assay identified a melanoma cell subset which exhibits stem-like capacities and expresses CD20 [106]. A conclusion drawn from these and other experiments was that melanoma is organized in a hierarchical manner originating from an initiator cell. In this context, several phenomena in melanoma biology which have been clinically observed but not well understood are described by the CSC model, for instance, metastatic relapse more than a decade after surgical treatment of the primary lesion. Residual CSC’s are thought to drive cancer relapse even after years of “dormancy” [107]. Moreover, melanoma initiating cells were identified as expressing either the transporter protein ABCB5 [104] or the nerve growth factor receptor CD271; the latter occurs in melanoma in a frequency of approximately 1/2000 cells [108].
\n
However, transplantation under more rigorous conditions, i.e., ideally of one isolated melanoma cell, revealed that nearly every fourth randomly taken melanoma cell (1/2 - 1/15) can induce tumors and raising the question of the validity the stem cell paradigm for melanoma [109, 110]. From these and subsequent studies, it has been concluded that the potential of melanoma induction is not closely associated with a particular phenotype and that the number of potential CSC’s in melanoma may not necessarily be low. This resulted in a further conclusion that nearly every melanoma cell is capable to re-program to a tumor initiating cell under certain experimental conditions of xeno-transplantation irrespectively which particular marker phenotype the cell expressed at the time of isolation from a melanoma lesion.
\n
Once the tumor is established, a minor subset seems to take over control of melanoma progression. Evidence is provided by recent observations from a pre-clinical model [69], which addressed the question of whether specific elimination of defined melanoma cells from an established xeno-transplanted lesion causes tumor regression by adoptive transfer of antigen-specific cytotoxic T cell. The rationale is that, if there is a clearly defined hierarchy of cancer cells in an established tumor, specific ablation of the melanoma sustaining cells from the established tumor tissue must inevitably lead to a decay of the tumor lesion independently of targeting the cancer cell mass. However, the melanoma sustaining cell may, but must not, be identical to CSC’s identified by the transplantation assay. Targeted elimination of a minor subset of CD20+ melanoma cells completely eradicated transplanted melanoma lesions, whereas targeted elimination of any random melanoma cell population in the same lesion did not. CD20+ melanoma cells are rare, i.e. approximately 1-2%, in melanoma, independently of the histological type and the transplanted tumor tissue. A caveat is that in approximately 20% of melanoma samples, no CD20+ melanoma cells could be detected by histological screening. When these tumors were transplanted, adoptive transfer of CD20-specific CAR T cells did not induce tumor regression. Interestingly, CD20 re-expression in a random subpopulation of those tumor cells did not render the tumor lesion sensitive for complete eradication with CD20-specific T cells. This indicates that CD20 expression per se is not dominant in maintaining melanoma progression. However, the phenotype of CD20+ melanoma cells may be flexible and associated with additional capabilities which mediate the dominant effect.
\n
The first clinical evidence confirming this concept was recently provided by a case report [111]. A patient with stage III/IV metastatic melanoma, which harbored CD20+ melanoma cells at a frequency of 2%, received intra-lesional injections of the anti-CD20 therapeutic antibody rituximab and concomitant dacarbazine treatment. Dacarbazine as mono-therapy had already proved to be ineffective. This treatment produced lasting complete and partial remission accompanied by a decline of the melanoma serum marker S-100 to physiological levels, a switch of a T helper-2 to a more pro-inflammatory T helper-1 response, all without treatment related grade 3/4 toxicity. Although anecdotic, this data provides the first clinical evidence that targeting the subset of CD20+ melanoma sustaining cells can produce regression of chemotherapy-refractory melanoma. Moreover, the report highlights the potency of selective cancer cell targeting in the treatment of melanoma.
\n
These observations although so far based on a pre-clinical model and a clinical observation which will have to be reproduced in larger cohorts have major impact on the future development of melanoma therapy.
\n
First, the melanoma maintaining cells may be more resistant to current therapy regimens than the bulk of melanoma cells. Standard therapy strategies attempt to eliminated all cancer cells in a tumor lesion; elimination of any other cancer cells than the tumor progressing cells will rapidly de-bulk the tumor lesion. The melanoma will inevitably relapse, driven by the remaining melanoma sustaining cells, which are extraordinary resistant to chemotherapeutics. This resistance is probably due to transporter molecules like ABCB5, which are highly expressed by a number of CSC’s including melanoma [104] and therefore efficiently counteract chemotherapy. Melanoma maintaining cells like other CSC’s are merely in a "dormant" state and replicate less frequently than the majority of cancer cells in the same lesion, which reduces the efficacy of anti-proliferative drugs. Low proliferative capacities together with the efficient export of chemotherapeutics contribute to CSC resistance toward a variety of therapeutic drugs. As a consequence, alternative strategies that specifically induce cell death of those cells are required. Moreover, the situation is exacerbated by the fact that the melanoma maintaining cells in the lesion are rare and unlikely to be eliminated by the random targeting provided by most therapeutic agents. Specific targeting by cytotoxic T cells redirected towards CD20 or by CD20-specific therapeutic antibodies like Rituxan™ (rituximab) or Arzerra™ (ofatumumab), probably as adjunct to a tumor de-bulking strategy, may improve the situation.
\n
Second, whether the prevalence of CD20+ melanoma maintaining cells in a tumor lesion may correlate with clinical progression or relapse has to be addressed. If so, the frequency of CD20+ melanoma cells may serve as a surrogate marker for therapeutic efficacy and/or prognosis. Chemotherapy and/or radiation may induce amplification of these cells thus contributing to their accumulation during tumor progression and metastasis.
\n
Third, melanoma maintaining cells may exhibit an extraordinary functional and phenotypic plasticity. As a consequence, continuous presence of targeting therapeutic agents will be required to eliminate those cells, which exhibit newly acquired melanoma initiating and/or maintaining capacities. In their pre-clinical model, Schmidt and colleagues [69] used CAR engineered T cells which penetrate tissues, scan for targets and persist for long-term acting as an antigen-specific guardian. These T cells are present in the targeted lesion as long as cells expressing the target antigen appear. Repetitive restimulation of these T cells, for instance by engaging their TCR with EBV-specific antigens [63, 81], may sustain persistence of CAR T cells in sufficient numbers over long periods of time. In this constellation, cellular therapy has a major advantage compared to pharmaceutical drugs, which are present in therapeutic levels for short periods; in the case of melanoma the required period for screening for re-appearance of such melanoma initiating cells may be many years. The development of an antigen-specific memory by adoptively transferred CAR T cells, as recently shown in a pre-clinical model [112], may be of benefit to patients in preventing a melanoma relapse.
\n
\n
\n
Acknowledgements
\n
Work in the author\'s laboratory was supported by the Deutsche Krebshilfe, Bonn and Ziel 2. NRW Programm of the Ministerium für Innovation, Wissenschaft, Forschung und Technologie des Landes Nordrhein-Westfalen and of the European Union.
\n
\n
Abbreviations
\n
\n ACT, adoptive cell therapy; CAR, chimeric antigen receptor; CTLA-4, anti-cytotoxic T-lymphocyte-associated antigen-4; CSC, cancer stem cell; EBV, Epstein-Barr virus; GMP, Good Manufacturing Practice; IFN, interferon; IL, interleukin; TCR, T cell receptor; TIL, tumor infiltrating lymphocyte
\n
\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/42380.pdf",chapterXML:"https://mts.intechopen.com/source/xml/42380.xml",downloadPdfUrl:"/chapter/pdf-download/42380",previewPdfUrl:"/chapter/pdf-preview/42380",totalDownloads:1900,totalViews:353,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,dateSubmitted:"April 19th 2012",dateReviewed:"September 20th 2012",datePrePublished:null,datePublished:"January 30th 2013",dateFinished:null,readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/42380",risUrl:"/chapter/ris/42380",book:{slug:"melanoma-from-early-detection-to-treatment"},signatures:"Jennifer Makalowski and Hinrich Abken",authors:[{id:"39699",title:"Prof.",name:"Hinrich",middleName:null,surname:"Abken",fullName:"Hinrich Abken",slug:"hinrich-abken",email:"hinrich.abken@uk-koeln.de",position:null,institution:null},{id:"155920",title:"MSc.",name:"Jennifer",middleName:null,surname:"Makalowski",fullName:"Jennifer Makalowski",slug:"jennifer-makalowski",email:"jennifer.makalowski@uk-koeln.de",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_1_2",title:"1.1. Advanced stages of melanoma resist conventional therapeutic regimens",level:"2"},{id:"sec_3",title:"2. Adoptive cell therapy can successfully fight melanoma",level:"1"},{id:"sec_4",title:"3. Adoptive cell therapy with antigen-specific T cells",level:"1"},{id:"sec_5",title:"4. Challenges and premises in the adoptive cell therapy of melanoma",level:"1"},{id:"sec_6",title:'5. Does targeting "melanoma stem cells" provide hope for long-term remission from melanoma?',level:"1"},{id:"sec_7",title:"Acknowledgements",level:"1"},{id:"sec_8",title:"Abbreviations",level:"1"}],chapterReferences:[{id:"B1",body:'\n Garbe C, Peris K, Hauschild A, Saiag P, Middleton M, Spatz A, Grob J-J, Malvehy J, Newton-Bishop J, Stratigos A, Pehamberger H, Eggermont A. Diagnosis and treatment of melanoma: European consensus-based interdisciplinary guideline. 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Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
Dept. I Internal Medicine, University Hospital Cologne, Cologne, Germany
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
Dept. I Internal Medicine, University Hospital Cologne, Cologne, Germany
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1. Introduction
The new-millennium has witnessed the appearance of an infinite number of developments in strategic administration-thinking as a result of the “information technology revolution”, and the appearance of the term “knowledge economy”, which looks at the institution’s excellence not only in terms of quantitative or qualitative productivity, but also in terms of the quality of knowledge that exists in its human assets, represented as talent. Therefore, management as a contemporary science has changed its language to focus on mental abilities where talented individuals institute a strategic resource in an institution [1]. Talent is a primary source of competitive advantage for institutions [2, 3, 4, 5, 6]. As a result, there are many practical benefits for institutions that focus on talents [5, 6, 7, 8, 9]. For example, talent assists in increasing rankings and profits of higher education institutions [8, 9]. To explain, universities’ rankings are aligned with the talent of high-performing employees [8, 9, 10, 11, 12]. These talented individuals contribute significantly to a university’s performance by attracting new students, conducting high-quality teaching and learning, conducting high-level research and securing funds for further research [8, 9, 10, 11, 12].
Over the past two decades, there has been a dramatic increase in TM studies [13]. TM has become a common term since the McKinsey group first mentioned it in their 1997 report ‘The War for Talent’ [14, 15, 16, 17, 18, 19, 20, 21]. Then, Michaels et al. [22] discussed TM in more detail in their book [19, 23, 24]. Since then, the topic has attracted enthusiastic interest from scholars in various fields and sectors [17, 21]. In the higher education sector as an industry, TM as a primary component of strategic human resource management can improve a university’s performance over the long term by advancing its strategy and enact it through its talented individuals [12, 25, 26]. Thus, TM is a key for institutional success by making it possible for institutional systems to achieve higher goals [27, 28, 29, 30]. Consequently, it is considered a core resource of innovation and social development [12, 21].
Nonetheless, new research in the strategic human resource area is urgently needed and rapidly expanding, as institutions have encountered significant challenges associated with TM [21, 26, 31]. These key challenges are faced by higher education institutions which need to give high-quality assurance in their technical expertise and activities [32, 33, 34, 35, 36] and their ability to be a leading exporter of international education [35, 36, 37, 38]. Bradley [12] has suggested that a key solution to meet these challenges in Australian higher education could be the application of TM programmes. Such programmes include processes such as attraction, development and retention of talent, which are keys to growth and success of higher education institutions within their industry [12, 26, 39, 40, 41].
The review of the chapter is covered into five sections. The introduction of the chapter is provided in Section 1. Next, the TM theory and a brief explanation of this concept are provided. It discusses the conceptual identity and intellectual frameworks of TM. Talent management practices (TMPs) are reviewed and addressed in Section 3. Here, the practices that are included in the review are attraction, development and retention of talent. Section 4 discusses the innovations of TM in higher education. Finally, Section 5 concludes this chapter.
2. Method
The authors adopted both theoretical and practical approaches. Theoretically, a systematic review that includes empirical and theoretical studies on TM which have been published between 2007 and 2017 in scholarly research has been adopted. A total of 35 academic works were involved in the review [42]. Practically, the authors carried out an empirical qualitative study in six Australian universities to understand the best processes that are currently used in managing talent in the higher education sector [43, 44]. It comprised qualitative multi-method studies including (i) a brainstorming session to develop sets of questions, (ii) a focus group session to define the scope of individual interviews and (iii) individual interviews to obtain an in-depth understanding on the subject [45, 46, 47]. Qualitative methods were enough to comprehend the best practices of innovation that are currently utilised in managing talent in the higher education environment. The sample consisted of 6 participants for brainstorming, 11 in the focus group session and 6 individual interviews.
3. The conception of talent management
In today’s business world, talents are considered strategic resources for meeting institutional demand for increased competitiveness [4, 5, 6, 7, 8, 9, 41, 48, 49]. Prior to reviewing TM, it is essential to describe the term talent [21, 50]. Iles et al. [14], Barron [51], Blass [52], Li and Devos [53], Cannon and McGee [54], Tansley et al. [55], Festing and Schäfer [56] and Naim et al. [57] all introduce talent as high-performing employees who have been considered to have significantly contributed to the progress of an organisation and its future development. Others like Rudhumbu and Maphosa [39], Harstad [58] and Sparrow and Makram [59] consider these as employees who are capable to add value by increasing organisational production. Having experience, mastery, knowledge, the skills, ability and the potential for development are all considered by Silzer and Church [60], Gümüş et al. [61], Beardwell and Thompson [62], Silzer and Dowell [63] and D’Annunzio-Green [64] as indications of talent.
Similarly, Baublyte [65] and Macfarlane et al. [66] have defined talent as those who exhibit leadership qualities that play a pivotal function within the organisation and show superior behaviour. Some other characteristics ascribed to the talent of human capital are that it is beneficial, unique [67, 68] and a major institutional resource [69, 70]. According to Scaringella and Malaeb [31], Ross [71] and Butter et al. [72], talent is an innate ability to learn things in an effortless and skilful manner inherent in these intelligent and creative individuals. Other researchers, such as Murongazvombo [73], Chuai [74], Kravtsova [75], Kramer et al. [76] and Kaliannan et al. [77], have defined talent as an essential driver and success element for an institution both short and long term [21].
As a concept, in the higher education environment, TM as a primary component of the strategic human resource management can improve a university’s performance over the long term by understanding the strategy enacted through its talented individuals [12, 25, 26]. This is a key for institutional success by making it possible for institutional systems to achieve higher goals [27, 28, 29, 30]. In the literature, there are six common perspectives on TM, which are [21] (1) process, (2) strategic, (3) developmental, (4) cultural, (5) competitive and (6) human resource planning perspectives [53, 65, 78].
4. The process perspective
This was defined by Iles et al. [14], Blass [52] and Cappelli [79], for whom TM appears as a complex set of processes that operate in large institutions so that the institutions and individuals within them can meet current and future needs with overall benefits for the institution. In a similar vein, Dessler [80], Tansley et al. [81], Blackman and Kennedy [82] and Ali et al. [83] portray the TM process as needing full integration, in order to become a standard practice to attract individuals who have high potential for creative development and to retain them in order to generate a unique value to the institution. In other words, it is a specific method for attracting and retaining abilities and essential knowledge for the future [80, 81, 82, 83].
5. The strategic perspective
TM is a strategy to attract the right talent and provide workers with potential contributions via strategic workforce planning and high-quality development experiences that build institutional capabilities [59, 84]. In the same way, it is a strategic function for identifying talent gaps and managing succession planning, along with attracting [85], selecting, motivating, developing and maintaining highly qualified individuals [86, 87]. TM can be useful in empowering employees to understand their essential capabilities and to produce an effective climate which professionally empowers them to underpin, capture and develop these talents into individual productivity [59, 71]. Therefore, TM should inform the selection of high-performance incumbents to fill positions [88, 89].
6. The developmental perspective
TM is a strategic priority for business institutions and is perceived as a crucial driver in developing institutional performance [90, 91]. Similarly, Cannon and McGee [54], Silzer and Dowell [63] and Moczydłowska [92] explain TM as a set of procedures, programmes and activities applied to highly qualified employees who are characterised by high potential in their development in order to achieve an institution’s goals now and in the future. The reason for this is that, if an institution fails to provide talented development and training, it may lose available talent [93].
7. The competitive perspective
As perceived by Beamond et al. [94], Tomany [95] and Meyers and Van Woerkom [96], TM is an engine of sustainable competitive advantage, which is tricky to simulate, is rare and valuable and cannot be replaced by competitors. From the same perspective, Iles et al. [14], Al Haidari [50], Gelens et al. [68], Collings and Mellahi [88], Waheed et al. [97] and Yap [98] define it as activities, processes and development of skills which require individuals to achieve a sustainable competitive advantage and institutional success by providing competent and highly qualified individuals who are more capable than competitors in other institutions.
8. The human resource planning perspective
Cui et al. [17], Beardwell and Thompson [62], Cappelli [79], Nissler [99] and Lewis and Heckman [100] introduce TM as a tool of human resource planning to develop a plan to meet institutional human resource needs, in order to attract employees with the appropriate skills in the appropriate areas of work. This involves a number of procedures designed to attract, develop and retain extremely talented staff to meet institutional needs. In other words, TM anticipates the necessity for human resources and then builds a strategy to meet it.
9. The cultural perspective
According to this perspective, TM focuses on social and cultural contexts of available human resources within a range of qualities [101]. These qualities include innate ability, intelligence and creative skills [31, 71, 72, 102]. Proponents of this perspective propose that individuals are successful only when they have sufficient talent and believe that the success of institutional work will be followed by their own success [101, 103]. Table 1 shows a summary of perspectives on TM.
The TMPs according to the opinions of authors and researchers.
Source: Prepared by the researcher based on the above sources.
To conclude this section, the scope of TM is restricted to the strategic perspective for three reasons. First of all, the strategic perspective includes all the perspectives above [104]. Secondly, this perspective outlines how an institution can efficiently implement TMPs [104, 105]. Finally, TM is a function of attraction, development and retention processes which contribute strategically to an institution’s success [105, 106, 107].
10. Talent management practices: a critical review
In the twenty-first century, TM has become more important and has received attention from institutions that seek a foothold in the institutional map of excellence. High-performing institutions are identifiable by their talented individuals who are able to show initiative, creativity and excellence in performance [27, 28, 29]. In higher education environments where high-performing organisations are identifiable by their talented individuals who are able to show initiative, creativity and excellence in performance. TMPs assist higher education institutions regarding such as the development of the talent pool, improvement of the productivity of individuals, support for effective planning and improvement of human resource management [40, 41]. Besides, attraction, development and retention of talent are strategically the keys to growth and success of higher education institutions [12]. The reason for this is that competitive advantage can be maintained by attracting, developing and retaining highly qualified individuals in key positions [3, 41, 49, 108]. Therefore, a majority of institutions have started to rethink their procedures and policies to achieve better acquisition and retention of individual talents. It is obvious that there is a strong competition between institutions in a technology-driven modern era, which has caused an increase in knowledge workers along with vast market changes [27, 28, 29]. In the scope of TM literature, several studies through the period 2007–2017 have shown in Table 1.
As shown in Table 1, it is obvious that many scholars have focused their empirical and theoretical attention on attraction, retention, and development of talent. Of all articles reviewed, talent retention is the dominant process with 25 articles (68.5%) of TMPs research have concentrated on, followed by both talent attraction and development with 68.5 per cent (24 articles), and talent attraction with 22 articles (73.3%). The least attention was paid to the TMPs of leadership development, talent acquisition, skills gap analysis, workforce and talent planning and performance management with two or three articles each.
Overall, as mentioned in the method section of this chapter, the authors carried out an empirical qualitative study in six Australian universities to understand the best processes that are currently used in managing talent in the higher education sector [43, 44]. This study explored the best TMPs of innovation in the aforementioned sector. (1) Talent attraction (social domain and institutional excellence), (2) talent development (performance management, coaching talent and leadership development) and (3) talent retention (benchmarking, job satisfaction, nonmonetary rewards, employee empowerment and employee motivation) were selected as best processes of TM in the higher education sector.
10.1 Talent attraction
In modern knowledge-based institutions, talent attraction is one of the most essential success elements [105, 136, 137]. Higher education institutions, for example, are strongly based on the attraction of experienced staff to fill key positions [9, 12, 36]. They primarily aim to attract talented candidates from the internal or external labour market [130]. However, there are some difficulties and challenges in attracting qualified staff to higher education institutions [9, 36]. These issues include safety and security, workloads [36] and conflicting opinions [9]. To meet these challenges, Beardwell and Thompson [62] highlight the following approaches that have been identified as effective for attracting talent:
The job-based approach: this includes writing a comprehensive description of a job which is filled by an employee, and then creates the desired person specification, which is based on that job description. However, this approach is inflexible because the changes that can occur in the main tasks or list of responsibilities of the main job are not taken into consideration.
The person-based approach: this focuses on identifying individual attitudes sought by an institution. It can be adopted in order to recruit individuals to fill a vacant job and participate in achieving the broader business targets of the institution.
The competency-based approach: this tries to recruit people by, for example, specifications, knowledge, experiences, skills and personal values that are attached to a job and used as a guide for an individual. However, this approach can encounter practical implementation difficulties and therefore may not achieve the institution’s goals.
Talent attraction can be divided into two sub-variables: (1) social domain and (2) institutional excellence. Throughout the chapter, the term ‘social domain’ is used to refer to support in difficult times, social innovation and work-life balance. An institution can attract more talented employees by providing them with social support in critical areas, for example, motherhood and monetary difficulties [138]. In regard to work-life balance, the last decade has seen a growing trend towards family-friendly workplaces [139]. Thompson [137] defines work-life balance as a personal perspective that is related to compatibility for talented employees inside and outside their workplace. Socialising with colleagues, lifestyle opportunities or appropriate locations are determinant factors for attracting new talented individuals, because they add work-life balance to institutions, which in turn contributes increasingly to their productivity [98, 136, 137, 139].
In the literature, the term ‘institutional excellence’ is generally understood to mean a strong tool and a key driver that assists institutions to achieve their strategic and operational aims [140, 141]. Excellent institutions adopt managerial attitudes that focus on total quality in all internal processes to attract high-quality individuals [53, 142]. As previously stated, the qualitative study explores a number of excellence-related factors that contribute to attracting new talents to higher education institutions. These factors include talent branding, the reputation of an institutions, institutional culture, institutional climate and work environment.
Talent branding as a key element of talent attraction enables institutions to manage talent of employees through an institutions’ identity, loyalty and culture, as a means of attracting high-potential individuals [53, 142, 143, 144, 145]. Institutional branding depends on the available resources for employees’ recruitment. In order to achieve financial and time goals, institutions have to consider particular resources in terms of where to obtain the profile required. In order to be excellent and successful in attracting talent, institutions need to follow appropriate strategies, adopt ethical principles in each phase of their current practices and build a strong and distinctive reputation in the labour market to be competitive [74, 123]. There are two different strategies for recruiting talent to an institution [53, 80, 146, 147]:
(1) Internal brands: An institution relies on its candidates. This will decrease the risks connected with the recruitment process and will save costs. An institution may know or can observe a candidate’s strengths and weaknesses as well as the fact that current employees are possibly more committed to the institution. In particular, avoiding external advertisements enables institutions to save costs of external channels. However, Dessler [80] argues that rejected applicants may become discontented, and it can also waste time since often the manager already knows whom they want to hire.
(2) External brands: Institutions cannot always get all the employees they need from their current staff and therefore need to tap into external sources to find candidates [53, 80]. However, online recruitment channels may encourage excessive numbers of applications to reach a limited audience (online job search), or the process is seen as too impersonal, discouraging some candidates [62, 80]. Therefore, institutions should develop a strong and distinguishable employer brand, which links institutional values to the employee management strategy and the institution’s brand [62, 121]. This can attract the best possible talent by promoting a unique combination of mental and practical benefits in the work place [62, 121].
Indeed, an institution that has excellence in its activities builds a good reputation, which then allows it to attract the best talents [125, 145, 148, 149]. This view is supported by Horseman [10] and Cruz-Castro et al. [150] who write that reputation and university ranking are key elements of institutional excellence to attract talented individuals. Furthermore, a desirable institutional climate is a determinant of attracting new talented employees [125, 137, 151]. Similarly, a supportive institutional culture with innovation can be an excellence-related factor for attracting qualified employees [140]. In regard to consideration of the work environment, this is a driving force for attracting talent [98, 125]. Working environment factors such as improved health, stress reduction, autonomy, job security and satisfaction within an institution are considered determining aspects for attracting talent to the institution [136, 137, 139, 151].
In summary, it has been demonstrated in this review that talent attraction is a basic factor of innovation and success in various sectors in general and in the higher education sector specifically, because of the key role that talent attraction plays in the functioning of higher education institutions. Thus, talent attraction in educational institutions is a function of social domain and institutional excellence.
10.2 Talent development
In a perfect business world, because of strong competition, institutions should develop their talented employees to enable them to become productive more rapidly [152]. Hence, the talent development process needs to be embedded within staffing progress and be regarded as a successful measure for institutions to improve the skills of their highly qualified individual staff members [40, 74, 142, 153]. Talent development is considered a critical resource of differentiation and sustainable competitive advantage [62, 153]. It is strategically important for an institution’s success [ 108, 153, 154]. For instance, the development of talent working within higher education institution also assists in retaining talented employees [153], which in turn assists in increasing university rankings and profits [8, 9]. University rankings are aligned with the talent of high-performing employees, and these talented individuals contribute significantly to a university’s performance by recruiting new students, conducting professional teaching, conducting high-level research and securing research funding [8, 9, 10, 11, 12].
The development process of talent involves three elements: (1) performance management, (2) coaching talent and (3) leadership development.
Performance management—As one of the key processes of talent development, this assists in filling the gap between the current and planned performances of highly qualified employees [153, 154, 155, 156]. It evaluates the current performance of talents to assist them in identifying their competency level and then developing their capabilities [125, 130]. Through this process, training needs can be identified to develop talent [156, 157]. Institutions should offer their experienced staff appropriate development strategies to improve their strong points and hence improve their total performance, including particular competencies, strengthening their motivation and boosting their career development [40, 158, 159].
Coaching talent—This is the second sub-variable of talent development. The existing literature on coaching talent is extensive and focuses on learning and development of talent [160, 161]. Even though coaching talent can be a significant tool for achieving high talent development through learning skills and creating knowledge, the difficulty in transforming these skills from outside an institution has been a disadvantage [142, 162]. Coaching talent through internal job rotation can develop individual knowledge and experience from different departments and divisions within an institution [163, 164, 165]. Training and mentoring programmes are valuable tools for developing talent [160, 166, 167]. These programmes can be offered online [130] and can also include face-to-face learning and teaching courses for academic staff [168] to gain required knowledge and skills [130, 168]. In addition, leading institutions provide their talented employees with career development opportunities [98, 104, 161, 169].
Leadership development—This is a key process of talent development [153]. It assists institutions in achieving overall institutional sustainability [160, 169, 170]. Effective and developed leadership is a key element of institutional sustainability [171]. Institutional sustainability through leadership assists institutions to strategically generate intrinsic values and wellbeing for all stakeholders [171]. The leadership development process includes ‘coaching, multi-source feedback, stretch assignments, mentoring, international job assignments and formal development programmes’ [169], as well as succession planning [164, 172, 173]. In academic institutions, high-level leadership provides talented individuals with sufficient opportunities in regard to functional planning programmes [12, 154]. Conversely, a lack of formalised institutional leadership training could negatively affect employees from achieving their advancement potential [166]. Therefore, the leadership development process enables leaders to obtain the skills and competencies necessary to be effective through role assignment leadership programmes [169, 170].
In brief, it has been shown in this review that talent development is a critical source of innovation and sustainable competitive priority in various sectors in general and in the higher education sector specifically. It assists in retaining highly qualified employees and increasing university rankings and profits. Thus, talent development in academic institutions is a function of performance management, coaching talent and leadership development.
10.3 Talent retention
Talent retention becomes a progressively worthwhile process of building an institution’s ability to acquire and maintain a competitive advantage [118, 174, 175]. It is focused on retaining talent among an institution’s staff so they remain with an institution [130]. Due to fierce competition to attract talent among leading institutions in all sectors in general and particularly in the higher education sector, the retention of talented staff in higher education institutions is problematic [12, 166, 176, 177]. This is partly due to constant growth in the economy that makes job opportunities for academic talent almost unlimited [12, 177]. Retention of talented individuals is mainly aimed at enabling an institution to keep a high-value workforce and to build a unique source of competitive advantage, which can lead to institutional growth and success [124, 178]. Talent retention is constructed using five sub-variables: (1) benchmarking, (2) job satisfaction, (3) nonfinancial rewards, (4) employee empowerment and (5) employee motivation.
First of all, benchmarking can broadly be defined as a key tool for setting aims by utilising learning and external standards from other institutions, which can act as the best practice for performance [10]. This tool has received considerable attention within Australian institutions [179]. It is seen as a beneficial way of retaining talented staff within higher education institutions through assessing the current strategies of talent retention from the best performing institutions [10, 180]. There are several types of benchmarking within the higher education sector [10]: internal benchmarking compares performance to other divisions of the university, competitive benchmarking compares performance against a chosen group of peer universities, sector benchmarking is a comparison with all universities in the same country and strategic benchmarking involves a comparison with overseas universities. Competitive compensation is considered as an essential element of success towards retaining highly qualified individuals within an institution that seeks to achieve a competitive advantage [181, 182]. Thus, institutions should have a competitive benchmarking system, which is a determining factor for retaining their highly qualified staff [125, 142, 182]. The second sub-variable of talent retention is job satisfaction. It was not until the late 1930s that historians began to consider job satisfaction as worthy of scholarly attention [183]. Job satisfaction involves a positive emotional attitude in workplaces to assist higher education institutions to retain experienced staff and achieve a competitive advantage [11, 166, 184, 185, 186]. It can be understood in terms of work environments, work conditions, relationships with supervisors and career opportunities [177, 184, 186]. Existing high-quality working environments and conditions promote job satisfaction, which assists the improvement of performance at both individual and institutional levels [166, 177, 184]. Therefore, high job satisfaction of talented individuals in academic workplaces is a reflection of existing effective retention strategies [166, 177].
Thirdly, nonfinancial rewards can play a crucial role in assisting an institution in retaining its talented staff through increasing productive time and engagement among individuals and consequently improving their overall productivity [125, 158, 187, 188, 189]. Nonmonetary rewards improve retention rates of highly qualified employees working in higher education institutions [176]. Those rewards involve certification, genuine appreciation and recognition [158]. Likewise, Hina et al. [188] hold the view that nonfinancial rewards include personal growth, interesting work, participation, flexibility, acknowledgement, significance of a role and achievement. Nonfinancial rewards in higher education institutions constitute funding external education, promotion and participation [190]. Employee empowerment is the fourth element of the talent retention construct. A large and growing body of literature about ‘human relations movement’ has been developed since the 1990s [175, 191, 192]. Employee empowerment practices are an essential element of motivating and retaining highly qualified employees for a long time within an institution [83, 193, 194]. Employee empowerment in academic workplaces assists in retaining talented staff, both academic and professional [192, 193]. It improves the satisfaction levels of an institution’s employees through granting them self-efficacy in their workplaces [195, 196]. Successful institutions that seek to increase their productivity should empower employees through encouraging creative ideas and involvement in decision-making [175, 189, 194, 197]. Thus, employee empowerment is a process which values employees by providing them with sufficient responsibility and authority to manage their work professionally [194]. The fifth and final sub-variable of talent retention is employee motivation. Motivational and valued work, professional advancement and supportive learning environments are seen as the key to retaining talented employees [11, 123]. In higher education environments, employee motivation plays a key role in retaining valued staff [11, 166, 177, 198]. An institution should offer proper financial rewards to its employees to ensure employee motivation [159, 199]. Career advancement is a creation of opportunities for highly qualified individuals that could lead them to improve and develop their career paths [137, 152]. These created opportunities are essential for retaining talented individuals [98, 104, 161, 169].
In summary, it has been shown in this review that talent retention is a main area of interest within the field of TM. It is a key source for innovation and sustaining competitive advantage in various institutions in general and educational institutions specifically. Thus, talent retention is a function of benchmarking, job satisfaction, employee empowerment, employee motivation and nonfinancial rewards.
To conclude this section, a review of the TM literature identifies a number of processes in various sectors and institutions. The most common practices of TM are attraction, development and retention. This view is supported by the outcomes of the qualitative study that has been conducted in a case of the higher education sector in Queensland, Australia [43].
11. Discussion
TM is considered a form of investment because talented individuals are viewed as the core source of innovation and social development [12]. The practices of TM are positively associated with improving innovation of institutional performance [200, 201, 202]. These practices play an essential role in nurturing the appropriate conditions for channelling and motivating employees towards the improvement of innovation activities [202]. Consequently, when an organisation fails to redefine its staff value proposition, it will continually have issues in attracting, developing and retaining talent [39]. Thus, TM can provide considerable benefits to an institution [5, 6, 7, 8, 9]. For example, it improves the institution’s overall performance, its ethos, its competitiveness and talent retention, which in turn prevent risks to the institution [203]. TM assists development of the talent pool, improvement of the productivity of individuals, support for effective planning and improvement of human resources management [40, 41]. Furthermore, attraction, development and retention as key practices of TM are strategically the keys of innovation to growth and success of the higher education industry [12], as a competitive advantage can be maintained by attracting, developing and retaining highly qualified individuals in key positions [3, 41, 49, 108].
TM can affect and adjust the behaviours and abilities of individuals to innovate [202]. Talented individuals have become a competitive weapon and resource of innovation for institutions in obtaining a sustainable competitive advantage [204, 205, 206]. A majority of higher education organisations have realised that talented individuals are strategic assets because they play a key role in the success, innovation and growth of the higher education institutions over the long term [9, 12, 39, 40]. These individuals assist higher education organisations with cultural adaption through identifying the challenges of public perception and the development of active learning environments [26, 89, 207]. Highly qualified employees constitute a critical resource of creativity, innovation and therefore future revenues for institutions [12, 106]. In addition, increase in the strategic importance of human resources management for competitive advantage can be achieved by talented individuals [206, 208, 209]. As a result, innovation is a complicated task, which requires high professional ability in knowledge-intensive positions [202]. Hence, talented individuals play a significant role in an institution’s survival and innovation in a dynamic environment [201, 208, 210, 211].
This study provides a clear and inclusive outline of the extant scholarly research from the period 2007–2017. Reviews in this period provide an opportunity to learn from prior experiences in TM. Most importantly, this empirical research is one of the first few studies that extended the previous investigation of TMPs in various sectors to the higher education sector. Both empirical qualitative research represented by the case study in the higher education sector and previous research of TM confirm that the key practices of TM are considered as attraction, development and retention of talent. Looking to Table 1, it is apparent that the vast majority of research is outside the higher education sector; the few studies from within are in non-Australian contexts. This finding is supported by the previous studies. For example, Paisey and Paisey [25] find that TM studies in the higher education sector are limited. The majority of TM studies focus on theoretical frameworks with little focus on pragmatic studies [95, 212, 213, 214]. Furthermore, practical studies on TM are either quantitative or qualitative [20, 213]. On the other side, the findings of Table 1 is supported by the previous research that TMPs ‘can be grouped into five core groups: (i) recruitment, attraction and selection; (ii) training and development; (iii) retention; (iv) identification and (v) performance management of talent’ [21, 53, 116, 126, 213].
Observing at Table 1, many scholars have given empirical attention on retention, development and attraction of talent [121, 131, 205, 206, 213, 215, 216, 217, 218]. One of the key reasons behind this attention is that talent attraction, retention and development are strategically very essential in today’s ephemeral knowledge economy, as they firstly assist an institution to achieve strategic business goals and meet basic business requirements and they form the foundation for the implementation of business strategies [21, 97, 106, 165, 172, 218, 219, 220]. Secondly, institutions that establish their principal competence in talent attraction, talent development and talent retention guarantee their own steadiness and growth among other competitive institutions in the same business sector [21, 107, 108, 221]. Finally, attraction, development and retention of talent are essential for growth and success of higher education institutions over the long term by enacting their strategy through their highly qualified employees [12, 21, 39, 40]. In addition, Table 1 shows that the least attention was paid to the TMPs of acquisition, leadership development, skills gap analysis, workforce and talent planning with one or two articles each.
In general, the results of the three core themes of TM above are in line with Bradley [12], Kamal [26], Rudhumbu and Maphosa [39] and Wu et al. [40] who emphasise that attraction, development and retention of talent are strategically essential for educational success and growth. This view is supported by Waheed et al. [97], Kim et al. [106], Tatoglu et al. [165], Hejase et al. [172], Ford [218], Rothwell [219] and Rothwell et al. [220] who point out that ‘attraction, development, and retention of talent are strategically more important in today’s volatile knowledge economy; because they help an institution achieve strategic business aims, meet basic business requirements, and form the foundation to implement business strategy’ [21]. Similarly, van den Broek et al. [107], Mwangi et al. [108], Xue [127] and Kataike [221] state that an institution ‘that established its core competence in attraction, development, and retention of talent guarantees its own stability and success among other competitors in the industry’ [21].
Overall, although the findings of our case study are consistent with some of the prior studies, there are major variances. This study is one of the first studies that examine TMPs in Australian higher education. The consistency with the previous research was partially conceptual, theoretical or regarding methodological matters. In conclusion, this section has attempted to provide a discussion of both an empirical case study and literature relating to the innovations of TM in the higher education sector. TM is a strategic source for sustaining competitive advantage in all kinds of institutions. Therefore, talent is an essential management for innovative institutions [21, 222, 223, 224].
12. Conclusion
This chapter has attempted to provide a clear explanation of the literature relating to TM. It aims to improve the theoretical and practical understanding of TM research in the higher education sector. The principal conclusion of the empirical study is that higher education institutions are aware of innovation sources that are currently used in managing talent in their divisions and faculties. These were (1) talent attraction (social domain and organisational excellence), (2) talent development (performance management, coaching talent and leadership development) and (3) talent retention (benchmarking, employee motivation, employee empowerment, nonmonetary rewards and job satisfaction). As a result, those individuals contribute significantly to a university’s performance by attracting new students and securing funds for further research. These themes are positively associated with innovation speed of the higher education institutions. TM is an integrated management system that starts with the practices of attracting, developing and retaining talents. So that institutions can benefit from this in the form of products (commodities/services) that have difficult characteristics of imitation and competition. This is because of the expertise and knowledge possessed by their efficient human resources. Although the scholars and researchers differ in determining a unified concept of talent, the specialised literature produces two trends in its definition, some of which are traditionally based on high intelligence, while the modern trend is based on excellent performance, mental ability, technical and dynamic skills, creative thinking and leadership abilities. In addition, the review of literature included various views of talent, but all the scholars and researchers agree that talent is a valuable resource of innovation for all institutions. The literature also identified six common perspectives on TM. From the literature, the strategic perspective was identified as most relevant to achieving the research objectives.
The generalisability of these findings is limited to the Australian university sector in Queensland. This study recommends that there is further research to be done in the higher education area, especially in relation to talent using empirical methodologies. More specifically, mixed method research should be used to fill the gap in the TM literature. As the least attention was paid to the practices of leadership development, talent acquisition, skills gap analysis, workforce and talent planning, and performance management with two or three articles each. This requires more attention in the future research to fill the gap in the TM literature. It would be useful to investigate the current methodology and topic of this research in other countries in order to generalise the findings within the global context.
\n',keywords:"talent management, talent attraction, talent development, talent retention, higher education",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/64542.pdf",chapterXML:"https://mts.intechopen.com/source/xml/64542.xml",downloadPdfUrl:"/chapter/pdf-download/64542",previewPdfUrl:"/chapter/pdf-preview/64542",totalDownloads:711,totalViews:0,totalCrossrefCites:0,dateSubmitted:"May 28th 2018",dateReviewed:"September 7th 2018",datePrePublished:"November 27th 2018",datePublished:"June 24th 2020",dateFinished:null,readingETA:"0",abstract:"In the new millennium, talent management (TM) has become more important and has received attention from institutions that seek a foundation on the map institutions of excellence. Higher education institutions are represented by their possession of highly qualified employees who are able to show initiative, creativity and excellence in performance. Those individuals are the core resources of innovation and social development. It is apparent that there is a great competition among institutions in this modern technology era, driving an increase in knowledgeable employees along with vast market changes. Consequently, academic institutions have started to rethink their procedures and policies to achieve better attraction, development and retention of those employees. Therefore, this chapter aims to improve the theoretical and pragmatic comprehension of TM as an essential source of innovative and educational development. Through pragmatic use of elements of previous research approaches combined with a comprehensive qualitative study, this study concludes that higher education institutions are aware of innovation sources that are currently used in managing talent in their divisions and faculties. These were talent attraction, talent development, and talent retention. Both empirical research represented by the case study in the higher education sector and previous research confirm that the best practices of TM are considered as attraction, development and retention of talent.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/64542",risUrl:"/chapter/ris/64542",signatures:"Atheer Abdullah Mohammed, Abdul Hafeez-Baig and Raj Gururajan",book:{id:"8283",title:"Innovations in Higher Education",subtitle:"Cases on Transforming and Advancing Practice",fullTitle:"Innovations in Higher Education - Cases on Transforming and Advancing Practice",slug:"innovations-in-higher-education-cases-on-transforming-and-advancing-practice",publishedDate:"June 24th 2020",bookSignature:"Dominique Parrish and Joanne Joyce-McCoach",coverURL:"https://cdn.intechopen.com/books/images_new/8283.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"197795",title:"Associate Prof.",name:"Dominique",middleName:null,surname:"Parrish",slug:"dominique-parrish",fullName:"Dominique Parrish"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"260495",title:"Ph.D. Student",name:"Atheer Abdullah",middleName:null,surname:"Mohammed",fullName:"Atheer Abdullah Mohammed",slug:"atheer-abdullah-mohammed",email:"atheerabdullahmohammed.mohammed@usq.edu.au",position:null,institution:null},{id:"260498",title:"Dr.",name:"Abdul Hafeez",middleName:null,surname:"Baig",fullName:"Abdul Hafeez Baig",slug:"abdul-hafeez-baig",email:"abdul.hafeez-baig@usq.edu.au",position:null,institution:{name:"University of Southern Queensland",institutionURL:null,country:{name:"Australia"}}},{id:"260499",title:"Prof.",name:"Raj",middleName:null,surname:"Gururajan",fullName:"Raj Gururajan",slug:"raj-gururajan",email:"raj.gururajan@usq.edu.au",position:null,institution:{name:"University of Southern Queensland",institutionURL:null,country:{name:"Australia"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Method",level:"1"},{id:"sec_3",title:"3. The conception of talent management",level:"1"},{id:"sec_4",title:"4. The process perspective",level:"1"},{id:"sec_5",title:"5. The strategic perspective",level:"1"},{id:"sec_6",title:"6. The developmental perspective",level:"1"},{id:"sec_7",title:"7. The competitive perspective",level:"1"},{id:"sec_8",title:"8. The human resource planning perspective",level:"1"},{id:"sec_9",title:"9. The cultural perspective",level:"1"},{id:"sec_10",title:"10. Talent management practices: a critical review",level:"1"},{id:"sec_10_2",title:"10.1 Talent attraction",level:"2"},{id:"sec_11_2",title:"10.2 Talent development",level:"2"},{id:"sec_12_2",title:"10.3 Talent retention",level:"2"},{id:"sec_14",title:"11. Discussion",level:"1"},{id:"sec_15",title:"12. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Allal-Chérif O, Makhlouf M. Using serious games to manage knowledge: The SECI model perspective. 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School of Management and Enterprise, University of Southern Queensland, Australia
The Industrial Management Department College of Administration and Economic University of Baghdad, Baghdad, Iraq
School of Management and Enterprise, University of Southern Queensland, Australia
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IntechOpen’s Academic Editors and Authors have received funding for their work through many well-known funders, including: the European Commission, Bill and Melinda Gates Foundation, Wellcome Trust, Chinese Academy of Sciences, Natural Science Foundation of China (NSFC), CGIAR Consortium of International Agricultural Research Centers, National Institute of Health (NIH), National Science Foundation (NSF), National Aeronautics and Space Administration (NASA), National Institute of Standards and Technology (NIST), German Research Foundation (DFG), Research Councils United Kingdom (RCUK), Oswaldo Cruz Foundation, Austrian Science Fund (FWF), Foundation for Science and Technology (FCT), Australian Research Council (ARC).
Open Access publication costs can often be designated directly in the grants or in specific budgets allocated for that purpose. Many of the most important funding organisations encourage, and even request, that the projects they fund are made available at no cost to the wider public. IntechOpen strives to maintain excellent relationships with these funders and ensures compliance with mandates.
\\n\\n
In order to help Authors identify appropriate funding agencies and institutions, we have created a list, based on extensive research on various OA resources (including ROARMAP and SHERPA/JULIET) of organizations that have funds available. Before consulting our list we encourage you to petition your own institution or organization for Open Access funds or check the specifications of your grant with your funder to ascertain if publication costs are included. Where you are in receipt of a grant you should clarify:
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Does your institution already have a budget for covering Open Access publication costs?
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Does your grant list Open Access publication fees as legitimate direct/indirect costs?
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If you are associated with any of the institutions in our list below, you can apply to receive OA publication funds by following the instructions provided in the links. Please consult the Open Access policies or grant Terms and Conditions of any institution with which you are linked to explore ways to cover your publication costs (also accessible by clicking on the link in their title).
\\n\\n
Please note that this list is not a definitive one and is updated regularly. To suggest possible modifications or the inclusion of your institution/funder, please contact us at oapf@intechopen.com
\\n\\n
Please be aware that you must be a member, or grantee, of the institutions/funders listed in order to apply for their Open Access publication funds.
Open Access publication costs can often be designated directly in the grants or in specific budgets allocated for that purpose. Many of the most important funding organisations encourage, and even request, that the projects they fund are made available at no cost to the wider public. IntechOpen strives to maintain excellent relationships with these funders and ensures compliance with mandates.
\n\n
In order to help Authors identify appropriate funding agencies and institutions, we have created a list, based on extensive research on various OA resources (including ROARMAP and SHERPA/JULIET) of organizations that have funds available. Before consulting our list we encourage you to petition your own institution or organization for Open Access funds or check the specifications of your grant with your funder to ascertain if publication costs are included. Where you are in receipt of a grant you should clarify:
\n\n
\n\t
Does your institution already have a budget for covering Open Access publication costs?
\n\t
Does your grant list Open Access publication fees as legitimate direct/indirect costs?
\n
\n\n
If you are associated with any of the institutions in our list below, you can apply to receive OA publication funds by following the instructions provided in the links. Please consult the Open Access policies or grant Terms and Conditions of any institution with which you are linked to explore ways to cover your publication costs (also accessible by clicking on the link in their title).
\n\n
Please note that this list is not a definitive one and is updated regularly. To suggest possible modifications or the inclusion of your institution/funder, please contact us at oapf@intechopen.com
\n\n
Please be aware that you must be a member, or grantee, of the institutions/funders listed in order to apply for their Open Access publication funds.
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