\r\n\tThe Japanese were revolutionizing quality improvement. As a result, Japan adopted a "total quality" approach to its strategies. In the United States, Total Quality Management (TQM) encompasses not only statistics but also approaches that encompass the entire organization. There were several subsequent quality-management initiatives. \r\n\tIn 1986, Motorola developed Six Sigma to improve its business processes by minimizing defects. A philosophy that views all work as a process, which can be identified, measured, analyzed, improved, and controlled. Generally, "Six Sigma quality" is an indicator that a process is well controlled.
\r\n
\r\n\tLean manufacturing (1988), also known as just-in-time manufacturing, derives from Toyota's 1930 operating model "The Toyota Way." Lean describes a set of management practices that reduce waste and increase productivity. \r\n\tThe ISO 9000 series of quality-control standards appeared in 1987. ISO 9001 integrates a process-oriented approach into enterprise management based on the plan-do-check-act method. The quality movement has matured as we enter the 21st century. ISO 9000 was revised in 2000 to emphasize customer satisfaction. The fifth edition of ISO 9001, published in 2015, emphasizes risk-based thinking to improve the application of the process approach. In addition to the manufacturing sector, quality has moved into service, healthcare, education, and government. For example, through standards such as ISO/IEC 17025 for testing and calibration laboratories and ISO 15189 for medical laboratories. \r\n\tMore recently, it has been recognized that the Fourth Industrial Revolution, Industry 4.0, best defines the present industry model. As its part, "Quality 4.0" refers to the future of quality and organizational excellence.
\r\n
\r\n\tThe book will aim to introduce a comprehensive overview of the up-to-date models used in quality management systems by experts in the field.
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He has over 20 years of experience as a consultant and auditor of quality management systems, and over 16 years of experience as a quality manager. He has been recruited as a quality and laboratory expert for seminars and professional laboratory meetings throughout Europe, Africa, and South America. Currently, he is the head of the R&D Department at the Portuguese Institute of Blood and Transplantation; a CLSI and EURACHEM fellow.",coeditorOneBiosketch:"Dr. Xavier received her Ph.D. from the University of Lisbon, Portugal. 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1. Introduction
Incidence rates for melanoma continue to rise between 2-3% each year in the United States [1]. Although melanoma accounts for 5% of new cancer cases, the disease is responsible for most deaths resulting from skin cancer. Five-year survival rates for localized disease have historically been greater than 95% after successfully excising tumors that are less than 1 mm thick [2]. Yet, despite intense efforts in the field, the ability to improve patient survival with invasive forms of the disease has changed little over the past two decades. Current five-year prognostic rates for regional and metastatic melanoma are approximately 66% and 15%, respectfully [1].
FDA-approved agents dacarbazine (DTIC), interferon-α, and high-dose IL-2 have long been employed as palliative therapies in advanced-stage melanoma patients (albeit with significant adverse side effects) [3]. Recent exciting data from large multicenter clinical trials has helped usher in the FDA approval of two new therapies that significantly improve upon the efficacy of existing first-line treatments such as DTIC. Ipilimumab is a humanized monoclonal antibody that functionally blocks the CTLA-4 molecule involved in suppressing T cell activation. In a randomized, double-blind phase III study, metastatic melanoma patients with unresectable stage III or IV disease were administered ipilimumab, ipilimumab plus a peptide vaccine specific to the melanosomal antigen gp100, or gp100 vaccine alone [4]. Ipilimumab therapy resulted in at least a 10 month median overall survival compared to 6.4 months for the gp100 vaccine treatment arm, but no statistical differences were observed between the ipilimumab treatment groups. In a follow-up phase III trial, patients with treatment-naive stage III or IV melanoma received DTIC alone or combined ipilimumab and DTIC therapy [5]. Although there was an improvement to median overall survival (9.1 versus 11.2 months, respectively), treatment with ipilimumab/DTIC significantly improved survival rates in patients at 3 years of follow-up. Vemurafenib is a small molecule drug that inhibits the activity of mutant BRAF (BRAF V600E) molecules in melanoma cells that constitutively signal via the MAPK pathway, promoting tumor cell proliferation and preventing cancer cell apoptosis [6]. Patients with previously untreated metastatic melanoma were first screened for the BRAF V600E mutation and then randomized to receive vemurafenib or DTIC in a phase III clinical trial [7]. At 6 months post therapy, vemurafenib resulted in an improved overall survival rate of 84% relative to 64% for DTIC treatment. Objective responses were also observed in 48% of vemurafenib-treated patients compared to 5% confirmed responses in the DTIC treatment arm. Although these preliminary findings are promising, the follow-up time of the study was inadequate to address the final objective and evaluation of progression-free survival rates for these patients is currently ongoing [8]. In a similarly structured phase II trial, vemurafenib administration in previously-treated BRAF V600E-selected melanoma patients led to a median overall survival of 15.9 months, which exceeds that previously observed for standard first-line treatments in patients with metastatic melanoma [9]. Unfortunately, the current level of care for metastatic melanoma remains far below the general expectations of wide-spread durable responses since most patients relapse from the above mentioned therapeutic interventions and eventually succumb to disease.
2. Supposed barriers to effective treatment
Improving tumor stage classification, candidate drug/therapy selection, and prediction of a patient’s outcome to treatment could result from defining molecular events involved in the transformation of normal melanocytes into melanomas [2]. The delineation of these molecular patterns has proven difficult, however, since melanoma contains high frequencies of dissimilar gene mutations, deletions, duplications, and translocations across the range of patients evaluated [10]. A number of inherited events have been illuminated (transmissible through genetic or epigenetic means) that appear directly involved in initiating a melanocyte’s pathway to malignancy by first inducing the clonal selection and outgrowth of cells [11]. Examples include alterations in the kinases BRAF and KIT and the tumor suppressor protein PTEN. The activating BRAF (BRAF-V600E) point mutation occurs in approximately 50% of melanomas (more commonly in cutaneous melanomas) and constitutively drives the MAPK pathway - without upstream RAS activation - leading to cell proliferation and survival [12]. The frequency of BRAF mutations is also preserved among primary and metastatic melanoma lesions, supporting the hypothesis that genetic disruption of BRAF is an early event that does not drive metastasis alone [12, 13]. KIT alterations account for up to 25% of acral and mucosal melanoma subtypes [6, 14]. The most common genetic change in KIT is an activating point mutation that stimulates the MAPK and PI3K-AKT signaling pathways, promoting cell growth and migration and preventing apoptosis [15]. Additional common melanoma defects are cells disrupted/deficient in the gene encoding PTEN. Under normal physiologic conditions, growth factors bind their respective cell surface receptor tyrosine kinase (RTK) and induce PI3K activity. PTEN serves to block PI3K function by preventing phosphorylation of PIP2 to PIP3, which ultimately drives signaling events through the PI3K-AKT pathway. In the absence of the phosphatase activity of PTEN, the AKT signaling cascade is unrestrained, driving the cell into a pro-survival mode. Simultaneous PTEN and BRAF alterations are two of the more widely documented correlative markers in late-stage melanoma patients and highlight the importance of the overlapping and non-overlapping functions of the AKT and MAPK pathways, respectively, in maintaining a malignant state. The common melanoma genetic aberrations (e.g., BRAF, KIT, PTEN) are not currently utilized for clinical diagnosis or prognosis, though, considering the seemingly paradoxical instances where gene markers do not correlate with independent classifiers of tumorigenesis [2]. For example, PTEN expression profiles have been reported to predict more aggressive forms of melanoma in cases of PTEN gene disruption [16] or activation [17] alongside clinico-pathological results. Drug-candidate discovery and testing has instead flourished with the improved knowledge of recurring primary genetic aberrations that appear to induce melanoma, as highlighted above for the FDA-approved BRAF inhibitor vemurafenib. Many other potential therapies have entered into clinical trials and have been well-described in a recent review [6]. One such promising drug is the RTK inhibitor dasatinib. With regard to melanoma, dasatinib targets KIT (and a limited range of alternate RTKs), leading to the disruption of the MAPK and PI3K signaling pathways. In a recently completed phase I trial, unselected patients with stage III or IV metastatic melanoma were administered dasatinib along with DTIC [18]. Combined treatment resulted in an objective response rate of 13.8% and median progression free survival of 13.4 weeks and appeared to be more active than either agent applied alone based on historical controls. Although these results are promising and support follow-up studies with this TKI, clinical evidence suggests that dasatinib preferably inhibits mutated KIT (occurring at exon 11 or 13) versus overexpressed wild-type KIT in melanoma patients [19-21]. It will, therefore, be of interest to closely monitor the differential anti-tumor efficacy of dasatinib treatment in melanoma patients harboring KIT mutations in future trials in order to select the most suitable patient population for clinical trial accrual.
Monotherapeutic use of drugs specific to the more commonly disrupted signaling pathways in melanoma has several drawbacks. At best, known drug/molecular target combinations are available for no more than 50% of melanoma patients (as in the case with vemurafenib and mutated BRAF), which severely limits treatment options for excluded patients. Drug resistance also presents a major concern in melanoma patients treated under these regimes. Tumor cells are capable of thwarting the benefits of targeted molecular approaches based on a number of innate and acquired mechanisms that include utilizing compensatory cell signaling pathways [22] and survival signals provided by the supportive TME [23]. In the instance of vemurafenib treatment, most BRAF-V600E-selected patients respond to therapy in the short-term (~80%) but fail to maintain durable responses [24]. Such clinical observations are not specific to melanoma but describe a wider phenomenon of eventually developing resistance to molecularly-targeted approaches in solid tumors [25, 26]. It has been hypothesized that therapy administration actually promotes the natural selection of a resistant tumor mass in the host [27]. These problematic corollaries will have to be overcome through the prudent use of combinational strategies that coordinately attack tumor cells and/or the tumor stroma at multiple, non-redundant levels. As one example, tyrosine kinase inhibitor (TKI) drugs (e.g., sunitinib, axitinib, dasatinib) remain attractive front-line agents to improve the efficacy of other co-applied strategies such as immunotherapy since these small molecule inhibitors may enable heightened responses to immune intervention based on the removal of suppression pathways inherent in the TME (as discussed in subsequent sections).
The initial driver mutations occurring in a melanocyte (e.g., BRAF, KIT, PTEN) are directly implicated in arresting cell cycle control points and promoting the clonal selection and expansion of cells that may disseminate systemically [11]. These primary genetic aberrations also induce an array of secondary events – all of which may contribute to molecular intra- and inter-patient heterogeneity. The pattern of tumor growth typically follows a course, whereby, melanomas transition from a benign radial phase in the epidermis (i.e., nevus) to vertical growth into the dermis and eventual systemic spread [28]. Upon reaching a size of 1-2 mm, a primary tumor nodule is growth-limited based on the need to develop a blood supply capable of providing sufficient nutrients to cells and effectively discharging metabolic waste [29]. To progress beyond this 1-2 mm limit, molecular signals in the tumor must be initiated to promote neovascularization. Hypoxia serves as one stimulus to initiate the expression of vascular endothelial growth factor (VEGF) by melanoma cells [30]. VEGF secretion by tumor cells can also result from inflammatory cytokines derived from infiltrating immunosuppressive cell populations such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). In general terms, locoregional VEGF production recruits endothelial precursor cells by binding its cognate high affinity receptor VEGFR2 [29, 30]. Endothelial cells in turn promote pericyte trafficking and coverage via elaboration of platelet-derived growth factor (PDGF). The effects of angiogenic pathways induced under conditions of tumor growth, however, do not resemble normal physiologic conditions. There is no hierarchical structure of arterioles to venules to capillaries. Instead, the tumor blood supply consists of a chaotic distribution of immature and mature endothelial cells, which are partly due to continued VEGF signaling by melanoma and endothelial cells and pericytes. Chronic VEGF expression serves to antagonize the interaction of endothelial cells and pericytes (by inhibiting PDGF/PDGFR binding) as well as to promote an ongoing cycle of endothelial cell recruitment and proliferation. The end-results are blood vessels comprised of loosely connected endothelial cells with little-to-no pericyte coverage. Consequently, blood flow is severely restricted in areas of the tumor while fluid build-up (e.g., plasma protein extravasation) occurs in the tumor interstitium, all of which contributes to heightened hypoxia, acidosis, and interstitial pressure. These TME dynamics in late-stage disease may help account for melanoma’s intrinsic resistance to chemo/radiotherapies [31]. First, the delivery of anti-tumor strategies is impaired due to deficiencies in the tumor-derived blood supply and increased interstitial pressure. The hypoxic environment also directly contributes to a reduced efficacy of drug function such as in the case of radiotherapies. Lastly, conventional strategies that incorporate cytotoxic drugs have a diminished effect on tumor cells selected for growth under hypoxic and acidic conditions.
3. Improving treatment strategies
3.1. Vascular reconditioning hypothesis
Correcting deficiencies in the tumor vasculature could potentially circumvent many of the problems that serve to limit the effective treatment of late-stage metastatic melanoma patients as outlined above. Historically, vasculature disruption was hypothesized to starve tumors, leading to apoptosis/necrosis and lesional regression. In reality, anti-vasculature measures appear to primarily modulate the overall tumor blood vessel architecture through actions on immature endothelial cells [32]. These effects lead to transient improvements in blood flow (thereby, diminishing hypoxia and acidosis) and reduced interstitial pressure in the tumor mass [31]. In phase II clinical trials, patients with either metastatic melanoma or colorectal cancer have experienced improved response rates when bevacizumab (an anti-VEGF monoclonal antibody therapy) was combined with a standard of care treatment such as chemotherapy [33-37]. Although bevacizumab monotherapy exhibits minimal clinical impact [38], the antibody appears to exert a helper action by improving the bioavailability/activity of co-delivered cytotoxic drugs via its disruption of the melanoma-associated vasculature. This overarching paradigm has been formally tested in a number of preclinical models showing the improved distribution and efficacy of anti-tumor agents subsequent to tumor blood vessel “normalization” [29]. One caveat to this strategy is the need to consider the optimal schedule for application of each modality to yield superior anti-tumor efficacy. Our laboratory has recently reported that delayed TKI administration in a therapeutic melanoma mouse model negated protection from a dendritic cell (DC) vaccine based on subcutaneous tumor growth kinetics [39]. These studies and others indicate a window of therapeutic opportunity where anti-vasculature measures are highly effective in enhancing co-administered anti-tumor therapies. Melanomas, however, would be expected to become refractory to the action of anti-vascular drugs based on the selection of mature blood vessels that are effectively stabilized by pericytes [32]. As noted with molecular targeting strategies, tumor cells are also likely selected based on their ability to induce angiogenesis via alternate signaling pathways that do not overlap those sensitive to the originally-administered agents. In the absence of an effective second line strategy, increased tumor growth following anti-vasculature monotherapy may instead occur [40].
3.2. Immunotherapy and melanoma
The immune system provides a promising platform for consideration of inclusion in combined anti-melanoma therapies as it holds many theoretical advantages over standard treatment options such as chemotherapy or bulk cytokine (biologic modifier) administration. Namely, immunotherapies can be tailored to specifically target and kill tumor cells while leaving the surrounding normal tissue intact. Immune memory (recall) can also aid in sustained therapeutic action as a result of active vaccination, allowing for the maintenance of sub-clinical residual disease (in the adjuvant setting) or the prevention of recurrent tumor variants (i.e., through mechanisms of immune cross-priming and epitope spreading in the protective T cell repertoire). Several clinical studies have highlighted the proof-of-principle for immunotherapy in mediating objective clinical responses in melanoma patients. Therapies incorporating ipilimumab and bevacizumab have been discussed in preceding sections. Impressive clinical results have also been obtained using ex vivo expanded tumor infiltrating lymphocytes (TIL; T cells) in combination with rhIL-2 and non-lethal irradiation therapy, although this is a highly specialized process limited to a few locations worldwide [41, 42]. Durable complete responses (CR) (RECIST) have been observed in 22% of patients undergoing this form of treatment and most responses have been durable for > 3 years irrespective of prior treatments. Not all patients are suited to this approach, however, due to the technical constraints of resecting and culturing TIL (approximately 45% of patients are eligible at this stage) and severe toxicities associated with IL-2 administration and lymphodepletion.
The general failure of immunotherapeutic strategies to date likely involves a number of issues. As noted, melanoma is a vascularized cancer that maintains an aberrant blood vessel system. Immunologic strategies that rely on the anti-tumor properties of effector cells such as CD8+ T cells or antibodies may be unable to penetrate areas of the tumor based on the abnormal dynamics of blood flow and high interstitial pressure. Other melanoma characteristics such as reduced oxygen content and low pH serve to further reduce the function of cytotoxic CD8+ T cells if they should even be recruited into the TME. First-line strategies that recondition the melanoma-associated vasculature would be expected to overcome such obstacles and allow for the improved delivery and cytotoxic action of immunotherapeutic moieties.
Melanoma is an inherently immunogenic tumor, given the anti-tumor properties of resected TIL in vitro [43] and clinical observations that patients with higher frequencies of TIL have improved overall survival [43, 44]. However, the late-stage TME is also quite immunosuppressive. Due in part to the hypoxic nature of the TME, immunosuppressive cells such as regulatory T cells (Tregs), TAMs, and MDSCs become enriched within the tumor and reinforce their own survival/function while coordinately opposing the survival/function of protective T effector cells and Type-1 polarized DCs via soluble mediators and direct cell-to-cell contact [45, 46]. Elaboration of cytokines such as IL-10 and TGF-β sustain Tregs and inhibit T cell Type-1 polarization and DC maturation [47-49]. T cells are further suppressed by MDSC secretion of reactive oxygen and nitrogen species, TGF-β, VEGF, and arginase (i.e., through L-arginine depletion) [50]. Additionally, melanoma cells can express inhibitory molecules such as PD-L1 on their cell surface that interacts with T cell-expressed PD1, leading to T cell dysfunction and death [51]. Melanoma cells might also prevent DC processing/presentation or T cell targeting through defects in the antigen presenting machinery and/or antigen loss. Therefore, combined immunotherapies must counteract the suppressive TME at some level (e.g., ipilimumab’s anti-CTLA-4 mode of action). By reversing the balance of immunosuppression toward inflammatory Type-1 immunity, one can envision improved clinical benefits for coordinately-applied cancer vaccines. Yet, the optimization of the vaccine sub-component of such regimens remains an area of intense study [52].
3.3. Focus on dendritic cell vaccination
DCs provide a theoretical advantage over other vaccine types since they potently stimulate antigen-specific de novo and memory recall T cell responses [47]. Under steady-state conditions, a mature DC first migrates out of the periphery and into the TME where antigen is sampled and processed/presented in the form of MHC class I/II-peptide complexes [53]. After upregulating CCR7 expression, antigen-loaded DC become competent to migrate to tissue-draining lymph nodes, where it may provide an antigenic target, costimulation (e.g., DC CD80/86 binding the T cell receptor CD28), and cytokines to allow for the activation of antigen-specific CD4+ and/or CD8+ T cells. These educated effector T cells then return to the blood circulation where a portion of these cells may enter the tumor and perform anti-tumor activities.
Effective vaccination against melanoma antigens (many of which are non-mutated and expressed by normal melanocytes) presents a formidable challenge. Indeed, most tumor-associated antigens are on the whole less immunogenic than tumor specific antigens that arise as a result of viral infection (e.g., HPV induced cervical cancer). Assuming that host central and peripheral tolerance mechanisms have not deleted the appropriate T cell repertoire, the maturation status of the DC may be key to whether specific anti-melanoma T cell responses can be invoked at all. For example, improperly matured DCs may engage responder T cells and induce either anergy or death rather than T cell activation, expansion, and differentiation into effector cells. In addition, the immunosuppressive TME can adversely condition both endogenous DC and T cell survival/function. Immuno-oncologists have attempted to tackle these confounding issues by adoptive transfer of ex vivo manipulated DCs (and T cells) that exhibit preferred (normal) bioactivity. In the case of DCs, these cells may be harvested as blood precursors from cancer patients and subsequently polarized to a Type-1 phenotype through genetic manipulation or exposure to a cocktail of inflammatory-prone soluble mediators in culture. After further loading with target antigens associated with tumor cell growth and progression, this cellular vaccine may be reinfused back into the patient. Fully-mature DCs generated in this fashion are able to efficiently home to draining lymph nodes and activate/instruct resident effector-prone T cells while remaining functionally-resistant to TME inhibitory factors such as IL-10, TGF-β, VEGF, IL-6, and PGE2 [54]. The framework for the autologous DC delivery strategy in cancer patients has been validated to some degree with the FDA-approved cellular immunotherapy designated sipuleucel-T. In this protocol, peripheral blood mononuclear cells (PBMCs) are harvested from men with castration-resistant prostate cancer and incubated with a fusion protein containing prostatic acid phosphatase and GM-CSF, a cytokine important for DC maturation [55, 56]. The stimulated PBMCs are then delivered back into patients every two weeks for a total of three injections. In a phase III double-blind multicenter trial, sipuleucel-T resulted in a median survival advantage of 4.1 months in 22% of individuals versus the placebo group [55]. Sipuleucel-T promoted heightened Type-I T cell and antibody responses against the vaccine fusion protein in a majority of patients presumably due to the enhanced maturation state of infused activated DCs [56]. Overall survival correlated with improved specific immunity in responding patients suggesting that sipuleucel-T’s mechanism of action includes immune targeting of prostate carcinoma cells by vaccine-induced T cells.
Many clinical studies have highlighted the ability of DC-based adoptive therapy to boost resident anti-tumor T cell responses and to mediate corollary clinical activity in patients with melanoma [57-65]. In one of the first reported DC-based therapy trials in the melanoma setting, DCs were harvested from patients (regardless of their HLA type), cultured in the presence of rhGM-CSF and rhIL-4 for one week, and pulsed with melanoma-associated peptides (e.g., HLA-A2 restricted gp100, tyrosinase, and Melan-A/MART1 peptides) or autologous tumor lysates [59]. The cellular vaccines were delivered into tumor uninvolved inguinal lymph nodes at least 4 times at weekly intervals. Eleven out of 16 (69%) enrolled patients developed DTH reactions to intradermal injections of DCs loaded with either vaccine-derived peptides or tumor lysates following DC vaccine therapy. Subsequent analysis of infiltrating T cells in representative biopsied DTH sites revealed peptide-specific reactivity to antigenic components of the vaccine. Overall, 2 CR and 3 PR were observed with these same patients also exhibiting vaccine-specific reactivity as evidenced in DTH testing. In a separate phase I clinical trial reported by Ribas and colleagues, GM-CSF/IL-4 ex vivo cultured DCs were loaded with a Melan-A/MART1 peptide and delivered intradermally into metastatic melanoma patients a total of 3 times every 2 weeks alongside tremelimumab (anti-CTLA-4) treatment [66]. Tetramer and ELISPOT analysis revealed increases in the frequency of peripheral Melan-A/MART1-reactive CD8+ T cells as a consequence of specific vaccination in 9 of 15 (60%) individuals, although tremelimumab therapy did not appear to enhance Melan-A/MART1 T cell frequency and function. Four vaccinated patients experienced objective clinical responses (2 CR, 2 PR) with 3 individuals also displaying an improved MART-1 T cell response post-DC vaccination. Although such studies provide proof-of principle, major improvements are still needed in order to achieve durable clinical responses and prolonged survival rates in a majority of patients undergoing autologous DC therapy. A potential improvement to DC activity in vivo may reside with how DCs are manipulated ex vivo following leukopheresis. In cases where DCs are stimulated to an underwhelmed (use of GM-CSF/IL-4) or exhausted (use of PGE2) Type-1 state, effector T cells suffer from an inability to effectively mediate anti-tumor responses [49]. One promising DC polarizing method incorporates IL-1β, TNF-α, IFN-α, IFN-γ, and poly-I:C in the ex vivo culturing phase to effectively mature DCs (designated α-DC1). Twenty-two patients with recurrent malignant glioma were administered up to 4 vaccinations intranodally of α-DC1 loaded with glioma associated antigens at 2 week intervals [67]. At the conclusion of the immunization cycle, 58% of evaluable patients demonstrated a response to at least one antigenic component of the vaccine based on PBMC specific activity through IFN-γ ELISPOT or tetramer analysis. Upregulated gene expression profiles of Type-1 cytokines (e.g., IFN-α, IFN-γ) and chemokines (e.g., CXCL10) were also observed in PBMCs from α-DC1 treated patients, suggesting that the vaccine therapy enhanced the cytolytic activity and trafficking ability of immune cells. Progression free survival was extended to 12 months in 9 of 22 patients receiving the α-DC1 vaccine. The ability of α-DC1 to produce IL-12 (and, hence, stimulate CD4+ and CD8+ T cell function) correlated to prolonged progression free survival. Based on the safety profile and relative success of this trial, the α-DC1 generation protocol is currently being evaluated in a phase I trial in patients with metastatic melanoma (NCT00390338).
Another way to improve the immunogenicity of autologous DC-based therapy involves the choice of antigenic target for presentation to T cells (i.e., therapeutic selection of the responding anti-tumor T cell repertoire for expansion). Most DC-based vaccine trials have incorporated melanoma-associated antigens such as gp100, tyrosinase, Melan-A/MART1 and MAGE in the vaccine formulation. Despite the surprisingly high immunogenic nature of these “self” antigens in vaccinated patients, tumor cells can continue to grow progressively by evading the effector T cell system via various well-described mechanisms [46, 48, 53]. For instance, the tumor mass is composed of a heterogeneous mixture of cancer cells that exhibit a range of defects/deficiencies in the antigen presentation machinery that limits effective presentation of tumor antigen-derived peptides in MHC complexes and leads to poor recognition by the immune system. As such, a fraction of tumor cells may become “invisible” to the adaptive immune system, resulting in the negative selection of treatment-resistant tumor cells in progressor lesions [68]. This scenario can be avoided in part by the use of vaccines incorporating antigens that represent proteins required for maintenance of the transformed state, progressive growth, or metastasis. Alternatively, one may consider the inclusion of antigens expressed not by tumor cells themselves but by the supportive stromal cells (whose phenotype is uniquely modified by the TME) that enable the formation of large bulk tumors. We hypothesize that peptides associated with tumor angiogenesis (summarized in Table 1) may provide an ideal source of targets for DC/peptide vaccine design. In effect, targeting the underlying tumor stroma (e.g., vascular cells, pericytes) would disrupt melanoma growth and promote tumor-specific immunity and protection. Our laboratory has previously demonstrated the ability to successfully treat HLA-A2+ transgenic mice bearing established colon carcinoma or melanomas using DC-based vaccines containing antigens differentially associated with the tumor vasculature [69]. Animals administered peptide-loaded DC vaccines displayed enhanced protection from established tumor growth and ability, in instances of complete regression, to provide durable protection from dormant disease. Interestingly, active vaccination against tumor stromal antigens led to the corollary cross-priming of T cell responses directed against alternate vascular-associated antigens that were not originally comprised in the vaccine therapy as well as bona fide tumor cell-associated antigens. Normal donors and melanoma patients also exhibited immune reactivity to many of the stromal antigens upon in vitro sensitization, indicating that operational tolerance to such “self” antigens may be broken using a DC/peptide-based vaccination approach [70]. Importantly, this vaccine strategy appears safe in treated mice since we have not observed deleterious immunologic responses against the normal tissue vasculature, disruptions to the normal cutaneous wound healing process, or aberrations in the fertility/litter size of pre-vaccinated female animals [69, 70].
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t\tStromal antigen\n\t\t\t
\n\t\t\t
\n\t\t\t\tCell expression\n\t\t\t
\n\t\t\t
\n\t\t\t\tAA positions\n\t\t\t
\n\t\t\t
\n\t\t\t\tPeptide sequence\n\t\t\t
\n\t\t\t
\n\t\t\t\tCD8+ T cell response\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t\tHLA-A2+ transgenic mice\n\t\t\t
\n\t\t\t
\n\t\t\t\tHLA-A2+ normal donors\n\t\t\t
\n\t\t\t
\n\t\t\t\tHLA-A2+ melanoma patients\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
DLK1
\n\t\t\t
P
\n\t\t\t
269-277
\n\t\t\t
RLTPGVHEL
\n\t\t\t
++
\n\t\t\t
+
\n\t\t\t
++
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t
\n\t\t\t
310-318
\n\t\t\t
ILGVLTSLV
\n\t\t\t
++
\n\t\t\t
+
\n\t\t\t
++
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t
\n\t\t\t
328-336
\n\t\t\t
FLNKCETWV
\n\t\t\t
+++
\n\t\t\t
+
\n\t\t\t
++
\n\t\t
\n\t\t
\n\t\t\t
EphA2
\n\t\t\t
VEC
\n\t\t\t
883-891
\n\t\t\t
TLADFDPRV
\n\t\t\t
+++
\n\t\t\t
+
\n\t\t\t
++
\n\t\t
\n\t\t
\n\t\t\t
HBB
\n\t\t\t
P
\n\t\t\t
31-39
\n\t\t\t
RLLVVYPWT
\n\t\t\t
+
\n\t\t\t
+
\n\t\t\t
++
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t
\n\t\t\t
105-114
\n\t\t\t
RLLGNVLVCV
\n\t\t\t
+
\n\t\t\t
+
\n\t\t\t
+
\n\t\t
\n\t\t
\n\t\t\t
NG2
\n\t\t\t
P
\n\t\t\t
770-778
\n\t\t\t
TLSNLSFPV
\n\t\t\t
-
\n\t\t\t
-
\n\t\t\t
++
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t
\n\t\t\t
2238-2246
\n\t\t\t
LILPLLFYL
\n\t\t\t
+
\n\t\t\t
-
\n\t\t\t
++
\n\t\t
\n\t\t
\n\t\t\t
NP1
\n\t\t\t
P
\n\t\t\t
331-339
\n\t\t\t
GLLRFVTAV
\n\t\t\t
+
\n\t\t\t
+
\n\t\t\t
+++
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t
\n\t\t\t
433-441
\n\t\t\t
GMLGMVSGL
\n\t\t\t
++
\n\t\t\t
+
\n\t\t\t
+++
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t
\n\t\t\t
869-877
\n\t\t\t
VLLGAVCGV
\n\t\t\t
+++
\n\t\t\t
+
\n\t\t\t
+
\n\t\t
\n\t\t
\n\t\t\t
NP2
\n\t\t\t
P
\n\t\t\t
214-222
\n\t\t\t
DIWDGIPHV
\n\t\t\t
-
\n\t\t\t
-
\n\t\t\t
++
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t
\n\t\t\t
328-336
\n\t\t\t
YLQVDLRFL
\n\t\t\t
-
\n\t\t\t
-
\n\t\t\t
++
\n\t\t
\n\t\t
\n\t\t\t
PDGFRβ
\n\t\t\t
P
\n\t\t\t
890-898
\n\t\t\t
ILLWEIFTL
\n\t\t\t
+++
\n\t\t\t
+
\n\t\t\t
+
\n\t\t
\n\t\t
\n\t\t\t
PSMA
\n\t\t\t
VEC
\n\t\t\t
441-450
\n\t\t\t
LLQERGVAYI
\n\t\t\t
+
\n\t\t\t
-
\n\t\t\t
+
\n\t\t
\n\t\t
\n\t\t\t
RGS5
\n\t\t\t
P
\n\t\t\t
5-13
\n\t\t\t
LAALPHSCL
\n\t\t\t
+
\n\t\t\t
-
\n\t\t\t
++
\n\t\t
\n\t\t
\n\t\t\t
TEM1
\n\t\t\t
VEC/P
\n\t\t\t
691-700
\n\t\t\t
LLVPTCVFLV
\n\t\t\t
+
\n\t\t\t
++
\n\t\t\t
++
\n\t\t
\n\t\t
\n\t\t\t
VEGFR1
\n\t\t\t
VEC/P
\n\t\t\t
770-778
\n\t\t\t
TLFWLLLTL
\n\t\t\t
++
\n\t\t\t
+
\n\t\t\t
+
\n\t\t
\n\t
Table 1.
Candidate melanoma-associated vascular peptides for DC vaccine design. CD8+ T cell response summaries are provided from previous work by our laboratory [69, 70]. Naïve HLA-A2+ transgenic mice were vaccinated bi-weekly with DCs pre-pulsed with the appropriate antigen-derived peptide. One week following the second DC vaccine, splenic CD8+ T cells were harvested and co-cultured 48 hours with the HLA-A2+ T2 cell line pulsed with the relevant peptide. CD8+ T cell elaboration of IFN-γ (as a read-out for Type-1 activity) was then determined through ELISA. Human CD8+ T cell responses to stromal peptides were determined by first isolating PBMCs and stimulating cells in the presence of antigen-loaded autologous DCs for 1 week. Normal donor samples underwent 2 rounds of IVS while PBMCs obtained from melanoma patients were subjected to 1 round of IVS. CD8+ T cell IFN-γ expression was assessed as similarly described for HLA-A2+ transgenic mice. Abbreviations used: AA, amino acid; P, pericyte; VEC, vascular endothelial cell; -, No observed activity; +, low activity; ++, medium activity; +++, high activity; IVS, in vitro sensitization
3.4. Combining small molecule drugs with DC vaccination
In addition to empirically improving DC vaccine design (e.g., via the ex vivo conditioning of the APC and a rationale selection of the included antigenic targets), the effectiveness of such treatments would be expected to improve by mitigating the functional constraints on vaccine-induced T effector cells imposed by the generally suppressive TME. As previously mentioned, the aberrant dynamics of the tumor vascular architecture and enrichment of regulatory cell populations (e.g., MDSC, Treg) in the TME consort to diminish the recruitment, vitality, and tumoricidal activity of immune cells in situ. Therefore, the conditional abrogation of the negative attributes of the TME would be predicted to improve infiltration and function of vaccine-expanded T cell populations, leading to more durable objective clinical responses in melanoma patients as diagramed in Figure 1. What follows are examples of three FDA-approved TKI drugs that could be utilized in DC-based vaccine combination immunotherapies to achieve this goal.
Figure 1.
Paradigm for effective combination treatment of melanoma. Established vascularized cancers such as melanoma are entrenched with a chaotic blood vessel network and immunosuppressive cell populations. These TME properties serve to prevent the intratumoral delivery and function of single-agent cytotoxic therapies, including specific active vaccination. In cases of combined therapeutic strategies where the melanoma-associated vasculature is first modulated through TKI drug sensitization, for example, immature blood vessels (i.e., endothelial cells loosely decorated by or absent in pericyte coverage) may be disrupted, resulting in a normoxic TME with reduced interstitial pressure and acidity. Frequencies of MDSC and Treg cells are also minimized through mechanisms that are not entirely clear. Consequently, vaccine-initiated effector T cells can better traffick into tumors and exert their anti-tumor functions. Mature DCs are also able to infiltrate the tumor lesion and sample material from dying cells or necrotic tissue for cross-presentation purposes to unknown/untargeted tumor associated antigens, leading to activation of a broad T cell repertoire that is competent to promote durable anti-tumor immunity. Abbreviations used: TKI, tyrosine kinase inhibitor; MDSC, myeloid-derived suppressor cell; Treg, regulatory T cell; DC, dendritic cell; TME, tumor microenvironment
Sunitinib binds to and inhibits a range of tyrosine kinases including the vascular associated molecules VEGFR and PDGFR. The drug is approved for use in patients with metastatic renal cell carcinoma (mRCC) or gastrointestinal stromal tumors, where most patients respond favorably to treatment in the short-term [71, 72]. In one recently reported phase I trial, metastatic melanoma patients harboring KIT mutations were administered sunitinib using the FDA-approved regimen of 50 mg/day for 4 weeks followed by 2 weeks off drug [73]. Out of 10 evaluable patients, 1 individual had a CR that lasted 15 months while 2 PR endured between 1-7 months. A separate clinical study, reported on the ability of sunitinib to work in concert with docetaxel therapy in patients with solid tumors including melanoma [74]. Two PR were confirmed in a total of 12 metastatic melanoma patients treated with the combination regimen, supporting a potential tumor vascular “reconditioning” role of sunitinib in improving the delivery and function of cytotoxic therapies within the TME. Our own animal studies support a similar paradigm for combination immunotherapies [39]. Protection from established melanoma progression (based on tumor growth kinetics and survival) were enhanced in mice receiving both sunitinib and DC/peptide-based vaccination versus either agent administered as a monotherapy. Sunitinib co-treatment facilitated the recruitment of DC-“primed” Type-1 CD8+ T cells into melanoma lesions based in part on the upregulated expression of VCAM-1 (on vascular endothelial cells) and CXCR3 ligand chemokines (e.g., CXCL9, CXCL10, CXCL11) within the TME. This TKI also reduced frequencies of immunosuppressive cell populations such as MDSC and Tregs in the tumor and tumor draining lymph node (TDLN), which was associated with increased cytotoxic potential mediated by vaccine-induced CD8+ T cells. Sunitinib therapy has similarly been reported to prevent the peripheral accumulations of MDSCs and Tregs in mRCC patients [75-77]. Although the molecular mechanism underlying these alterations remains an open question, sunitinib inhibits STAT3 activation (via inhibition of upstream tyrosine kinases) which may prove core to its perceived anti-tumor actions [39, 75].
Axitinib is a potent TKI targeting VEGFRs (VEGFR1, 2, and 3) that support tumor angiogenesis [30, 78]. Following the completion of a recent phase III trial [79], axitinib was granted approval by the FDA as a second-line therapy for mRCC patients refractory to first-line treatment options including sunitinib. Axitinib has also been used to treat patients with melanoma. Pre-clinical studies have supported a role for axitinib monotherapy to disrupt angiogenesis and tumor formation in xenograft melanoma models [80]. A multicenter phase II trial also justified the continued use of axitinib-based treatment in metastatic melanoma patients [81]. Individuals receiving this TKI experienced reductions of VEGFR2 and VEGFR3 and increased levels of soluble VEGF in their plasma. Treatment with axitinib was associated with an overall objective response rate of 18.8%, which is comparable to historical response rates for chemotherapy and IL-2-based therapies. Given the relative clinical success for axitinib monotherapy, we assessed the impact of axitinib on DC/peptide-based vaccination on established melanoma growth in murine models [82]. Melanoma-bearing mice administered axitinib and specific vaccines were protected from tumor growth and displayed enhanced survival for up to 80 days following melanoma implantation. Axitinib-sensitization improved the trafficking and retention of vaccine-induced CD8+ T cells in the TME, with the Type-1 functionality (as assessed by IFNγ expression) of CD8+ T cells elevated in both the tumor site and the TDLN. Similar to our observations with sunitinib [39], axitinib reduced systemic frequencies of MDSCs and Tregs and promoted a Type-1 TME, as evidenced by the upregulated expression of Tbet, IFN-γ, CXCR3, and CXCL10 gene transcripts.
Dasatinib has already been reported to selectively abrogate mutated KIT activity in human melanomas [19, 83]. This TKI also inhibits other tyrosine kinases such as the Src family of kinases (impacting PI3K-AKT signaling) involved in melanoma adhesion, motility, and invasion [84, 85]. As a monotherapy, dasatinib was well-tolerated in melanoma patients, yielding an objective response rate comparable to alternate current first-line treatment options [18]. Dasatinib diminishes tumor angiogenesis by inhibiting the tyrosine kinases EphA2 and PDGFR that play significant roles in endothelial and pericyte biology, respectively [84]. In unpublished results from our laboratory, dasatinib mediates anti-TME effects that are similar to sunitinib and axitinib in melanoma-bearing mice [39, 82]. Animals treated with dasatinib undergo a restructuring of the tumor vasculature in association with reduced hypoxia and MDSC/Treg frequencies and increased accumulation of T effector cells in the TME, particularly when combined with a DC/peptide-based vaccine. The combined therapy also yielded greatest objective clinical benefit when compared with either monotherapeutic approach. Overall, these studies have supported the design of a pilot phase II trial (dasatinib + DC/tumor stromal antigen-based vaccine) at the University of Pittsburgh planned to begin enrolling patients in Q4 2012. In this trial, HLA-A2+ patients with advanced-stage melanoma will be administered dasatinib and an autologous αDC1/peptide vaccine, with frequencies of antigen-specific T cells monitored in patient blood and tumor biopsies over time along with objective clinical responses.
4. Conclusions
The emergence of ipilimumab and vemurafenib as treatment alternatives to the long-standing DTIC-, IL-2-, and IFN-α-based therapies attests to progress made in treating patients with metastatic melanoma. Although the genetic heterogeneity of melanoma cells has confounded high-throughput sequencing technologies, patterns of molecular aberrations are becoming clearer and help support the clinical application of FDA-approved small molecule drugs (such as TKIs) as therapeutic options in eligible patients. Select TKIs (e.g., sunitinib, axitinib, dasatinib) not only directly inhibit melanoma growth and progression by specifically disrupting cell intrinsic signaling pathways, but these drugs indirectly perturb tumorigenesis based on their “normalizing” effects on the TME. Central to this therapeutic paradigm is the ability of the drugs to recondition the chaotic architecture and fluid dynamics of the blood vasculature in the TME. The short-term consequences of TKI sensitization are impressive and include a reversal of hypoxia, acidosis, and interstitial pressure in the TME, which allows for a corollary improvement in the accumulation and action of co-applied cytotoxic therapies (including immunotherapies).
Combinational immunotherapies hold great promise in minimizing/preventing the emergence and progression of (same) therapy-resistant melanoma populations, as has typically been observed in cases of single-agent treatment strategies. These approaches also have potential to result in a state of perpetual disease dormancy which may extend patient overall survival [69]. The current challenge to the field is to determine the best combination (dosing and scheduling) of agents to best affect a state of durable clinical benefit in the advance-stage disease setting. From our work, and that of many others, immunotherapy represents one promising component of such combined treatment strategies, particularly when integrated with agents that act as immune adjuvants, inhibitors of immune regulatory cells, and “normalizers” of the TME. Preclinical studies have clearly justified the combined strategy of TKI drug therapy alongside specific DC/peptide-based vaccination. In particular, TKI administration essentially serves as an “immune adjuvant” by reversing the inherent immunosuppression of the TME upon diminishing frequencies of suppressive cell populations and physically manipulating the tumor vasculature architecture. Vaccine-initiated effector T cells are then able to more effectively infiltrate a tumor lesion in order to perform their clinically-beneficial cytolytic functions. Prospective clinical trials will test the validity of this operational biologic paradigm on patient outcome and define a series of safe and effective combination treatment options for melanoma patients.
Acknowledgments
This work was supported by NIH grants P01 CA100327, R01 CA114071, R01 CA140375 and P50 CA121973 (to W.J.S.) and the University of Pittsburgh Cancer Center Support Grant (CCSG; P30 CA047904). D.B.L. was supported by a Postdoctoral Fellowship (PF-11-151-01-LIB) from the American Cancer Society.
\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/42292.pdf",chapterXML:"https://mts.intechopen.com/source/xml/42292.xml",downloadPdfUrl:"/chapter/pdf-download/42292",previewPdfUrl:"/chapter/pdf-preview/42292",totalDownloads:1650,totalViews:108,totalCrossrefCites:0,totalDimensionsCites:0,totalAltmetricsMentions:0,impactScore:0,impactScorePercentile:3,impactScoreQuartile:1,hasAltmetrics:0,dateSubmitted:"May 16th 2012",dateReviewed:"September 20th 2012",datePrePublished:null,datePublished:"January 30th 2013",dateFinished:"January 24th 2013",readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/42292",risUrl:"/chapter/ris/42292",book:{id:"3543",slug:"melanoma-from-early-detection-to-treatment"},signatures:"Devin B. Lowe, Jennifer L. Taylor and Walter J. Storkus",authors:[{id:"160106",title:"Dr",name:null,middleName:null,surname:"Storkus",fullName:"Storkus",slug:"storkus",email:"storkuswj@upmc.edu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Supposed barriers to effective treatment",level:"1"},{id:"sec_3",title:"3. Improving treatment strategies",level:"1"},{id:"sec_3_2",title:"3.1. Vascular reconditioning hypothesis",level:"2"},{id:"sec_4_2",title:"3.2. Immunotherapy and melanoma",level:"2"},{id:"sec_5_2",title:"3.3. Focus on dendritic cell vaccination",level:"2"},{id:"sec_6_2",title:"3.4. Combining small molecule drugs with DC vaccination",level:"2"},{id:"sec_8",title:"4. Conclusions",level:"1"},{id:"sec_9",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'American Cancer Society. http://www.cancer.org/Research/CancerFactsFigures/CancerFactsFigures/cancer-facts-figures-2012 (accessed 14 August 2012).'},{id:"B2",body:'Tremante E, Ginebri A, Lo Monaco E, Frascione P, Di Filippo F, Terrenato I, et al. Melanoma molecular classes and prognosis in the postgenomic era. Lancet Oncol. 2012;13(5) e205-11.'},{id:"B3",body:'Lacy KE, Karagiannis SN, Nestle FO. Advances in the treatment of melanoma. Clin Med. 2012;12(2) 168-71.'},{id:"B4",body:'Hodi FS, O\'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8) 711-23.'},{id:"B5",body:'Robert C, Thomas L, Bondarenko I, O\'Day S, M DJ, Garbe C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. 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Durable complete clinical responses in a phase I/II trial using an autologous melanoma cell/dendritic cell vaccine. Cancer Immunol Immunother. 2003;52(6) 387-95.'},{id:"B59",body:'Nestle FO, Alijagic S, Gilliet M, Sun Y, Grabbe S, Dummer R, et al. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med. 1998;4(3) 328-32.'},{id:"B60",body:'Thurner B, Haendle I, Roder C, Dieckmann D, Keikavoussi P, Jonuleit H, et al. Vaccination with mage-3A1 peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma. J Exp Med. 1999;190(11) 1669-78.'},{id:"B61",body:'Salcedo M, Bercovici N, Taylor R, Vereecken P, Massicard S, Duriau D, et al. Vaccination of melanoma patients using dendritic cells loaded with an allogeneic tumor cell lysate. 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Multicenter phase II study of matured dendritic cells pulsed with melanoma cell line lysates in patients with advanced melanoma. J Transl Med. 2010;8 89.'},{id:"B66",body:'Ribas A, Comin-Anduix B, Chmielowski B, Jalil J, de la Rocha P, McCannel TA, et al. Dendritic cell vaccination combined with CTLA4 blockade in patients with metastatic melanoma. Clin Cancer Res. 2009;15(19) 6267-76.'},{id:"B67",body:'Okada H, Kalinski P, Ueda R, Hoji A, Kohanbash G, Donegan TE, et al. Induction of CD8+ T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with {alpha}-type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in patients with recurrent malignant glioma. J Clin Oncol. 2011;29(3) 330-6.'},{id:"B68",body:'Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity\'s roles in cancer suppression and promotion. 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Clin Cancer Res. 2008;14(20) 6674-82.'},{id:"B78",body:'Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L. VEGF receptor signalling - in control of vascular function. Nat Rev Mol Cell Biol. 2006;7(5) 359-71.'},{id:"B79",body:'Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807) 1931-9.'},{id:"B80",body:'Hu-Lowe DD, Zou HY, Grazzini ML, Hallin ME, Wickman GR, Amundson K, et al. Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res. 2008;14(22) 7272-83.'},{id:"B81",body:'Fruehauf J, Lutzky J, McDermott D, Brown CK, Meric JB, Rosbrook B, et al. Multicenter, phase II study of axitinib, a selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, in patients with metastatic melanoma. Clin Cancer Res. 2011;17(23) 7462-9.'},{id:"B82",body:'Bose A, Lowe DB, Rao A, Storkus WJ. Combined vaccine+axitinib therapy yields superior antitumor efficacy in a murine melanoma model. Melanoma Res. 2012;22(3) 236-43.'},{id:"B83",body:'Antonescu CR, Busam KJ, Francone TD, Wong GC, Guo T, Agaram NP, et al. L576P KIT mutation in anal melanomas correlates with KIT protein expression and is sensitive to specific kinase inhibition. Int J Cancer. 2007;121(2) 257-64.'},{id:"B84",body:'Buettner R, Mesa T, Vultur A, Lee F, Jove R. Inhibition of Src family kinases with dasatinib blocks migration and invasion of human melanoma cells. Mol Cancer Res. 2008;6(11) 1766-74.'},{id:"B85",body:'Jilaveanu LB, Zito CR, Aziz SA, Chakraborty A, Davies MA, Camp RL, et al. In vitro studies of dasatinib, its targets and predictors of sensitivity. Pigment Cell Melanoma Res. 2011;24(2) 386-9. '}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Devin B. Lowe",address:null,affiliation:'
Dermatology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
'},{corresp:null,contributorFullName:"Jennifer L. Taylor",address:null,affiliation:'
Dermatology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
'},{corresp:"yes",contributorFullName:"Walter J. Storkus",address:"storkuswj@upmc.edu",affiliation:'
Dermatology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
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1. Introduction
Herbal medicine is the use of only plants for medicinal and therapeutic purpose to treat the diseases and to improve human health [1, 2, 3, 4]. Herbal medicine is the most commonly used complementary and alternative medicine (CAM) [5]. World Health Organization (WHO) has defined herbal medicines as last labeled medicinal product that contain an active ingredient, aerial, or underground parts of the plant or other plant material or combinations [4, 6]. Herbal medicine is classified into three groups: 1) herbal drugs have proven efficacies and known active compounds and doses, 2) have expected efficacies, active compound needs to be standardized, and 3) uncertain efficacies [4, 6].
Herbal medicine includes herbs, herbal materials, and last herbal products. In some countries, herbal medicine may contain natural organic or inorganic active ingredients [7]. The number of medicinal plants as medicine is around 20.000 and they are also used for adding taste, odor and color to food since the ancient times [8].
In the 21st century, herbal medicine has been considered as a promising future medicine for people health [4]. During long time before the modern medicine, herbs had been the mainstream remedies for nearly all illness [1, 4]. People had commonly diagnosed illnesses themselves, prepared and prescribed their own herbal medicines for thousand years ago [1]. Herbal remedies, nowadays, it still plays an important role in the health care and most of people rely on herbal medicine for their primary health care [9, 10].
Herbal plants for medicine are easily obtainable without prescription or prescribed by herbal practitioners. Due to drug resistance and difficulties in finding accessible and reliable drugs, herbal medicines have become an alternative option in our healthcare system [11].
Herbal medicines have been used either alone or in combination with conventional medicines [11]. But even though herbal products are frequently used and regarded as ‘natural’, they can also cause adverse drug reactions [9, 12, 13] as well as adverse interactions with other medicines [9, 14, 15].
Herbal remedies are generally considered as safe, though their efficacies are unclear and their adverse effects may vary from human to human [2]. Despite of increasing popularity of herbal medicine, their safety and effectiveness have not been scientifically proven [1]. According to their wide use, many herbal products used frequently have not undergone complex scientific analyses via clinical experiments [9]. Though its reported that some of these plants have medicinal properties in the literature it has also been showed that other plants could be not safe for consumption as being toxic and adverse effects in the human body [4, 16]. Therefore, the aim of this review is to understand the current status of the herbal medicine used on the children and adolescents.
2. Prevalence of herbal medicinal product use
The use of herbal remedies has increased in recent years. It is predicted that this rate will be greater for the COVID-19 pandemic process. WHO has been reported nearly ~80% of the world’s population uses and trust herbal products for treatment [17, 18, 19, 20].
About 2.9 million American children and teenagers have used herbs or their supplements [21]. In China, the use of herbal medicine is about changing from 30–50% of the total drug consumption. It is estimated that in other developed countries, more than 50% of the population use herbal products at least once in their life. The herbal medicines account for 60% of treatment at home in developing countries [4, 22]. In the children with a chronic illness or among inpatients and outpatients are higher use of the herbal medicine [9, 23].
The using herbal drugs among children are 85.5% in Germany [23]. Children with neuropsychiatric diseases use herbal medicine about 35.4% [24]. The elementary school-age children in South Korea have epileptic problems ~17.2% and they use herbal medicine at high range varying from 65.2% to 67.8% [25]. In Turkey, the prevalence of pediatric use of herbal drugs was 58.6% [26]. Bülbül et al. [27] reported that 27% of parents, who used herbal products for their children within 1 year, used them without a doctor’s recommendation [27].
3. Areas of herbal medicinal product use
The use of at least one herbal or food product has been commonplace during episodes of acute illness among African American communities [28]. Families with children who have chronic medical conditions, such as autism, cystic fibrosis, rheumatoid arthritis, respiratory tract infections or asthma use to herbal remedies as part of their treatment [1, 10, 29, 30, 31]. The majority of herbal remedies are used to treat coughs, colds, and intestinal disorders [9].
The herbal medicine use in children with respiratory illnesses was 59.3% [32]. Parents of children with asthma reported using a range of herbal products (12.8%) for self-care [33]. The most common used herbal medicine for pediatric asthmatic patients were linden (21.6%) and ginger (21.2%) [34]. Herbal medicine has traditionally been used in the treatment of symptoms for nocturnal enuresis or urinary incontinence [35, 36, 37].
The ginger, chamomile, mint, cardamom, garlic and onion were used to prevent and treat nausea caused by chemotherapy [38]. It has been reported some herbal products are effective in the management of ear pain in Otitis Media [2]. Children with Attention Deficit Hyperactivity Disorder and Anxiety of Depression take herbal products a part of their treatments. The use of CAM in children with medical comorbidities, excessive sleep problems or insomnia is 1.8 times higher than children without such difficulties [39]. It is reported that herbs significantly decreasing body temperature, cough and breathing difficulties, and improving absorption of pulmonary infiltration and quality of life on the severe acute respiratory syndrome (SARS) [40]. The herbal formula (Ma Xin Shi Gan Tang) was claimed to antiviral effect on which inhibits the entry of influenza virus and have potential in managing seasonal pandemics of influenza infection [41].
4. Toxicity of herbs
Herbal products were used mainly because of hearsay recommendation, dissatisfaction with conventional medicine, and fear of adverse-effects of drugs [30]. It is important to understand that mothers consider herbs to be ‘natural and safe’ and are therefore more willing to try herbal remedies such as herbs, olive oil, and food for their babies’ health. This is no different to any other country, where the local ‘health food shop’ and vitamin bars in pharmacies are well frequented by concerned parents. For some participants, decisions regarding use of traditional practices are usually made by an extended family member or through advice from virtual support groups and social media [42].
The herbal medicines have been obtainable without prescription and professional advices. This practice could lead to harm in children. Because of the variability in herbal product ingredients, the actual dose of active ingredients being consumed is often variable and unknown. When compared with adults, since children have smaller sizes and their immature systems they may be particularly susceptible to the effects of such dosage variations [29]. For this reason, before the administration of any therapeutic agents into children’s body, the mothers must be taken into attention to consider the anatomy and physiology of them. The development level of organs such as brain, liver, and kidney affect rate of the absorption, distribution, metabolism and excretion of drugs. The inappropriate doses could lead to the accumulation of drugs in the body and finally cause the toxic effects. The unstandardized preparation of herbal medicines by manufacturer and contaminants (metals, chemical drugs, etc.) create a risk for children’s health [29, 43]. Herbal products are widespread usages in children; professionals should be aware of this and be alert for possible side-effects/interactions [30].
Herbal medicines have some drawbacks such as contamination with chemicals. One of the most contaminants is pesticide on the herbal products [44]. The wide spread use of pesticides in agriculture has caused severe environmental pollution and possible health hazards including severe acute and chronic poisonings. WHO estimates that the incidence of pesticide poisonings in developing countries has doubled during the past decade [45, 46].
Herbal products can also produce adverse side effects that range from mild one to fatal ones. For example; herbs believed to have an effect on blood-clotting abilities may cause serious side effects for patients with certain blood-related conditions such as hemophilia. Some herbs may increase the effects of anticoagulant medications, and then it may be creating the risk of bleeding [1].
5. Advice to parents
Health care practitioners might be considered some practical points, when parents come to counsel about herbal medicine. Parents should realize that all herbal medicine is not safe [30]. Parents have to be informed about the potential risk or adverse effects of the long-term use of herbal products [47]. When parents are informed about herbal products it maybe prevents the negative interactions [30, 48]. Parents have to be understood that natural is not equal to safe [29].
Unless parents must have the essential knowledge on herbal products, they do not give the herbal remedies to their children [18, 43]. It is important for clinicians to ask the question to find out the beliefs and alternative therapies of the parents, and it is necessity to understand whether they give the herbal remedies in their children [29]. Lack of information about taken herbal remedies by child can prolong a hospital stay or hamper the clinician’s approach to diagnosis and management [29].
6. Herbal medicine for the treatment COVID-19
On these days, herbal medicine plays a major role in the prevention and treatment of many diseases also as the novel coronavirus. Chinese medicine is the pioneer of herbal medicine among all of the countries [49]. There was wide usage of traditional Chinese medicine through the last SARS-COV outbreak. The five most famous applied herbs were Astragali Radix (Huangqi), Saposhnikoviae Radix (Fangfeng), Glycyrrhizae Radix Et Rhizoma (Gancio), Atractylodis Macrocephalae Rhizoma (Baizhu), and Lonicerae Japonicae Flo [50].
Du et al. [51] have summarized the theoretical foundation, potential effect of Chinese herbs on COVID-19 patients, and Yang et al. compared the evidence of current applications of traditional Chinese’s herbs in the treatment of COVID-19 patients [52]. Todays, many guidelines related to herbal medicine have been issued for the prevention and treatment of COVID-19 [50, 53]. The herbs were commonly recommended in some symptoms, like fatigue, fever, chills, heavy limbs, and gastrointestinal symptoms in these guidelines [54]. Recent clinical evidence have also showed the therapeutic effectiveness of traditional medicine in treating different stages of COVID-19 [55, 56, 57, 58, 59]. Wang et al. [60] investigated effect of traditional Chinese medicine on hospitalized patients with COVID-19. They suggested that patients should receive Kaletra early and should be treated by a combination of Western and Chinese medicines [60]. Li et al. [61] were reported that Lianhua Qingwen had antiviral and anti-inflammatory activity against SARS-CoV-2 in their experimental study. Traditional Chinese Medicine has suggested to prescribe the herbs that are likely to be effective in the diagnosis and treatment plan of COVID-19 [62]. Notably, the usage frequency of Armeniacae Semen was highest among the herbal formulae recommended for the treatment of pediatric COVID-19 [63]. The herbal products’ diversity for the recommended treatment of pediatric COVID-19 is lower compared to the adults. This might be due to the difference in the spectrum of diseases between the children and the adults [64].
7. Nurses’s role
Overall, the type of herbal products changes all of the worlds. Besides it can be changes in the different societies at one country. Their usage is high prevalence among most traditional society [42]. In Taiwan, about 60% of participants reported that use folk remedies during their child’s hospitalization, and the 72% of them would not inform healthcare providers about usage of folk remedies to their children [65]. This illustrates that it is important health practitioners, including nurses, are aware of the use of folk remedies within the community, and investigate about the use of folk remedies or traditional healing practices in a non-judgemental manner [42].
The growing trend of herbal products’ uses is a major challenge to health system, children and families. To ensure the quality and safety of nursing interventions to child and mothers, it is important to learn the mothers’ knowledge on beliefs and barriers to health care in their living. In addition, nurses need to be open to listening to patients and admitting their practice of traditional remedies while evaluating risks to create a nursing care plan [66]. The nurses have regular contact with parents within the healthcare centers or family health services [67]. Nurses are required to be have sufficient understanding and knowledge about CAM therapies [68]. Therefore, nurses can be credible sources for parents who need the accurate and trust information on herbal medicinal products. Nurses have to ask to parents what methods they used to understand if the parents have any qualms or difficulty obtaining prescription medications for their child [69].
8. Conclusion
The usage of herbal medicines increases day by day. People usually choose the herbal products instead of medical drugs [46]. The use of medical plant species in the treatment of children diseases is a part of traditional knowledge that is handed down by hearsay advices [20].
Herbal medicine can be unconsciously used as though these products are harmless [70, 71]. The use of herbal products in children is a concern, because a few information is available on their benefits and risks at these population [72, 73]. This creates a serious problem in the treatment of children, and it can be occurred a serious hazard in clinical care [74]. Since herbal products are available not only in pharmacies, but also in food stores and supermarkets there is a serious risk to users and remains a major concern about the herbal drug safety issue [18].
As the global use of herbal products continues to increase and many more new products are introduced into the market the risk will be greater for public health day by day [75]. The risk increases because of compromised by lack of suitable quality controls, inadequate labeling, and the absence of appropriate patient information [76].
Most herbal medicines have not been subjected to rigorous clinical trials As a result, it still continues the lack of evidence-based information about the efficacy and safety of herbal products in children [1, 77]. Despite of the high prevalence of herbal remedies’ uses, there is a communication problem between CAM users and healthcare professionals. Healthcare professions both have to ask about herbal remedies’ uses and inform to their patients or their parents about herbal medicine. Also, parents have to inform to their physicians on herbal remedies’ uses to their children during conventional treatment [78]. Health professionals must recommend to parents the correct use of herbal medicine in children, assist in herbal therapeutic decisions, and monitor for adverse effects and interactions [1, 77]. Finally, herbal products or folk remedies may be inherently unsafe. Owing to the possibility of serious health complications arising from the use of herbal products, it is mandatory to understand their use in the general population in order for appropriate measures to be put into place [32].
Department of Paediatric Nursing, Faculty of Health Science, Erzurum Technical University, Turkey
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But the blood-flow measurement inside the heart is difficult. There are many reasons behind it. The deep range and fast blood-flow are difficult to measure because of limitation of acoustic velocity. Moreover, strong heart valve signals mix into the blood-flow signal. Against such difficulties, the statistics mathematical model was applied to analyze many clinical data sets. The system identification method based on the mathematical model could realize a new blood-flow measurement system that has ultrasound Doppler information as input and electrocardiogram as output.",book:{id:"4655",slug:"applications-of-digital-signal-processing-through-practical-approach",title:"Applications of Digital Signal Processing through Practical Approach",fullTitle:"Applications of Digital Signal Processing through Practical Approach"},signatures:"Baba Tatsuro",authors:[{id:"65121",title:"Dr.",name:"Baba",middleName:null,surname:"Tatsuro",slug:"baba-tatsuro",fullName:"Baba Tatsuro"}]},{id:"24302",title:"Multiple-Membership Communities Detection and Its Applications for Mobile Networks",slug:"multiple-membership-communities-detection-and-its-applications-for-mobile-networks",totalDownloads:4079,totalCrossrefCites:4,totalDimensionsCites:4,abstract:null,book:{id:"599",slug:"applications-of-digital-signal-processing",title:"Applications of Digital Signal Processing",fullTitle:"Applications of Digital Signal Processing"},signatures:"Nikolai Nefedov",authors:[{id:"66756",title:"Dr.",name:"Nikolai",middleName:null,surname:"Nefedov",slug:"nikolai-nefedov",fullName:"Nikolai Nefedov"}]},{id:"49358",title:"Optical Signal Processing for High-Order Quadrature- Amplitude Modulation Formats",slug:"optical-signal-processing-for-high-order-quadrature-amplitude-modulation-formats",totalDownloads:1974,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"In this book chapter, optical signal processing technology, including optical wavelength conversion, wavelength exchange and wavelength multicasting, for phase-noise-sensitive high-order quadrature-amplitude modulation (QAM) signals will be discussed. Due to the susceptibility of high-order QAM signals against phase noise, it is imperative to avoid the phase noise in the optical signal processing subsystems. To design high-performance optical signal processing subsystems, both linear and nonlinear phase noise and distortions are the main concerns in the system design. We will first investigate the effective monitoring approach to optimize the performance of wavelength conversion for avoiding undesired nonlinear phase noise and distortions, and then propose coherent pumping scheme to eliminate the linear phase noise from local pumps in order to realize pump-phase-noise-free wavelength conversion, wavelength exchange and multicasting for high-order QAM signals. All of the discussions are based on experimental investigation.",book:{id:"4655",slug:"applications-of-digital-signal-processing-through-practical-approach",title:"Applications of Digital Signal Processing through Practical Approach",fullTitle:"Applications of Digital Signal Processing through Practical Approach"},signatures:"Guo-Wei Lu",authors:[{id:"174507",title:"Associate Prof.",name:"Guo-Wei",middleName:null,surname:"Lu",slug:"guo-wei-lu",fullName:"Guo-Wei Lu"}]}],onlineFirstChaptersFilter:{topicId:"561",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[],lsSeriesList:[],hsSeriesList:[],sshSeriesList:[],testimonialsList:[]},series:{item:{id:"24",title:"Sustainable Development",doi:"10.5772/intechopen.100361",issn:null,scope:"
\r\n\tTransforming our World: the 2030 Agenda for Sustainable Development endorsed by United Nations and 193 Member States, came into effect on Jan 1, 2016, to guide decision making and actions to the year 2030 and beyond. Central to this Agenda are 17 Goals, 169 associated targets and over 230 indicators that are reviewed annually. The vision envisaged in the implementation of the SDGs is centered on the five Ps: People, Planet, Prosperity, Peace and Partnership. This call for renewed focused efforts ensure we have a safe and healthy planet for current and future generations.
\r\n
\r\n\t
\r\n
\r\n\tThis Series focuses on covering research and applied research involving the five Ps through the following topics:
\r\n
\r\n\t
\r\n
\r\n\t1. Sustainable Economy and Fair Society that relates to SDG 1 on No Poverty, SDG 2 on Zero Hunger, SDG 8 on Decent Work and Economic Growth, SDG 10 on Reduced Inequalities, SDG 12 on Responsible Consumption and Production, and SDG 17 Partnership for the Goals
\r\n
\r\n\t
\r\n
\r\n\t2. Health and Wellbeing focusing on SDG 3 on Good Health and Wellbeing and SDG 6 on Clean Water and Sanitation
\r\n
\r\n\t
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\r\n\t3. Inclusivity and Social Equality involving SDG 4 on Quality Education, SDG 5 on Gender Equality, and SDG 16 on Peace, Justice and Strong Institutions
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\r\n\t
\r\n
\r\n\t4. Climate Change and Environmental Sustainability comprising SDG 13 on Climate Action, SDG 14 on Life Below Water, and SDG 15 on Life on Land
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\r\n\t
\r\n
\r\n\t5. Urban Planning and Environmental Management embracing SDG 7 on Affordable Clean Energy, SDG 9 on Industry, Innovation and Infrastructure, and SDG 11 on Sustainable Cities and Communities.
\r\n
\r\n\t
\r\n
\r\n\tThe series also seeks to support the use of cross cutting SDGs, as many of the goals listed above, targets and indicators are all interconnected to impact our lives and the decisions we make on a daily basis, making them impossible to tie to a single topic.
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