Recent clinical studies of systemic treatment in malignant pleural mesothelioma.
Induced pluripotent stem cells (iPSCs) are expected to be a novel cell source for regenerative therapy [1, 2]. Their capacity for self-proliferation and multilineage potential is promising for induction of regenerative cells without a natural capacity for self-renewal. In 2014, a groundbreaking advance in iPSC research occurred when iPSC-derived sheets of retinal pigment epithelium were transplanted to a patient with age-related macular degeneration, the first report of iPSC treatment in humans [3]. Since then, explosive expansion clinical iPSC treatment of patients with otherwise intractable diseases has been expected. However, expanding the clinical use of iPSCs requires a well-defined quality standard. Generating clinical-grade iPSCs for regenerative treatments presents many challenges, and concerns over safe iPSC use must be solved promptly. For instance, ensuring that culture conditions are not exposed to risk of contamination by predictable or unpredictable agents requires a great deal of investment in terms of cost and equipment. In addition, the most clinically applicable method of generating and selecting a suitable iPSC line is under debate. Furthermore, although the construction of iPSC banks for allo-transplantation has progressed [4], generating sufficient qualified cell lines for clinical use requires several years to cover a large segment of the population. In this chapter, we discuss the current issues for expanding the clinical applications of human iPSCs.
\nIn regard to the standardization of human pluripotent stem cells, a consensus for using embryonic stem cells (ESCs) was previously announced by the International Stem Cell Banking Initiative (ISCBI) contributors and the Ethics Working Party of the International Stem Cell Forum [5]. This consensus defined general principles for human ESC banking and described quality control processes for human ESC lines. Although many of these criteria can be applied to iPSCs, standardization of iPSC lines for clinical application is not fully established because there exist various iPSC generation methods and differences between iPSC lines. The tumorigenic and differentiation properties of iPSC lines are not identical, even for those generated by the same procedure [6]. Therefore, to establish iPSC quality standards for clinical use, determining which factors can affect iPSC quality and setting up requirements for clinical application of iPSCs are critical issues. This challenge intrinsically questions whether iPSCs can be equated with ESCs. To date, the existence of epigenetic differences between iPSCs and ESCs has been shown [7], although these differences do not negate the applicability of iPSCs.
\nRecently, the previous consensus on human pluripotent stem cells was revisited with consideration of iPSCs [8]. However, international standardization of iPSC generation techniques and quality verification is challenging. Many problems must be solved, including the scientific validity of new insight into iPSCs, to determine their applicability to consensus guidelines. In addition, these guidelines mainly target requirements for cell banking. In the case of iPSCs, there will be clinical research using autogenic iPSCs similar to the first case in RIKEN [3]. Therefore, the number of institutions in which autogenic iPSCs are generated could increase above the number of institutions for cell banking. Whether the institutional criteria for generating autogenic iPSCs should be equal to those for cell banking remains vague. These points should respectively be verified and adjusted based on scientific acceptability.
\nWhen human iPSCs are applied for clinical use as a transplantation cell source, the requirements for iPSCs to satisfy clinical conditions must be validated in advance. Although most provisions for “clinical-grade” iPSCs are associated with “safety,” this term encompasses many elements at each stage of iPSC application to regenerative medicine. However, the most suitable and the safest method for generating iPSCs for clinical use has not been defined because experience in treating patients with iPSC-derived regenerative cells remains limited. Therefore, to establish novel iPSC-based regenerative therapy, all factors that might affect safety must be presented and discussed in each case.
\nFor clinical application of iPSCs, safety is mainly divided into two considerations. The first is that iPSCs must meet standards for general cell products. To establish iPSCs of clinical grade, cell culture protocols must avoid any risk of contamination with unpredictable pathogens and meet the standards for general cell products, such as good manufacturing practice (GMP) [5, 8]. Removing animal-derived products from the culture system is important for this purpose. Furthermore, iPSCs and iPSC-derived cells must not include pathogens such as harmful viruses or bacteria before clinical use. With respect to establishing cell culture protocols, accurate sample identification must be provided throughout iPSC generation and differentiation. Therefore, to meet the standards for general cell products, the establishment of extensive systems and equipment for culturing iPSCs is required.
\nThe second aspect of safety is meeting the high quality standards for clinical applicability. However, whereas standards for general cell products have been defined, standards for high-quality iPSCs that meet applicability to clinical use remain vague. For example, methods for denying the possible tumorigenicity of iPSCs and their derivatives remain undefined. In addition, in the course of generating iPSCs, many steps affect iPSC quality. Worldwide standardization of each stage of iPSC generation is desirable, but there are numerous problems to be solved before achieving this goal.
\nThe first step for applying iPSCs application to clinical use is sampling somatic cells from donors. Although this step appears simple, it already includes safety considerations. When treatment with iPSCs is proposed, whether iPSCs are generated from the patient’s own somatic cells or brought from a pool of allogeneic iPSCs such as the iPSC bank project [4] must be decided. Using allogeneic iPSCs requires co-treatment with an immune suppressor and can lead to a risk of malignant tumor and adverse effects. Generating autogenic iPSCs for each patient is ideal, but it requires a tremendous cost and time investment. Particularly, if the patient’s condition demands expediency, autogenic iPSCs might not be suitable. Even if autogenic iPSCs are available, the appropriateness of applying quality standards for the allogenic iPSC bank to autogenic iPSCs has to be considered. In addition, the choice of somatic cell sources for iPSC generation is important. Naturally, invasive cell sampling is not preferable, but the type of original cells can affect iPSC features through the residual epigenetic status of the original cells [9–12]. Therefore, this first step already requires evaluation of the appropriate choice for each case.
\nThe step following somatic cell sampling is somatic cell reprogramming. In this stage, the suitability of the combination of reprogramming factors and gene introduction vehicles must be verified. Although achievement of residual transgene-free iPSC lines was already established [13–19], the safest and most preferred type of gene vehicle and combination of reprogramming factors for clinical use are now in discussion. In addition, there are many reagent options for culturing human iPSCs, and reagent selection must be verified in advance.
\nThe next stage of clinical therapy using iPSCs is the induction of targeted cells from iPSCs. iPSC lines do not exhibit identical points of differentiation [6, 12]. Although efficient induction of intended differentiated cells and selection of suitable cell lines are important, ensuring the safety of iPSC derivatives is a more important consideration. In particular, avoiding contamination of undifferentiated cells is essential for achieving clinical application. However, methods for detecting residual undifferentiated cells also remain undefined. Selection of appropriate iPSC lines is also important for avoiding tumorigenesis, which is known to differ among cell lines [20].
\nAfter obtaining targeted cells for treatment, the method by which these cells are transplanted is also associated with safety concerns. An appropriate transplantation protocol must be examined and established in advance. In addition, establishment of safety nets for post-treatment patients is also important.
\nTherefore, although the requirements for establishing a definitive standard for clinical-grade iPSCs are unresolved, many points that affect the safety of treatments must be recognized and appropriately verified before initiating treatment.
\nAs described above, meeting standards for general cell products is required for clinical use of iPSCs. A culture condition for human pluripotent stem cells was first established for maintaining human ESCs [21] and contained several animal-derived products such as mouse embryonic fibroblasts for feeder layers and fatal bovine serum in culture medium. This culture system was applied to human iPSCs, and it successfully maintained their pluripotency and self-proliferation [2]. Since then, toward realizing the clinical use of human iPSCs, the need for an established, chemically defined condition for human iPSCs has attracted attention.
\nTo this end, many researchers have challenged the removal of animal-derived feeder cells from culture conditions. The initial condition for culturing human iPSCs contained mouse embryonic fibroblasts or immortalized mouse fibroblasts such as SNL cells [2]. Although auto-fibroblasts were applied and successfully served as alternative to animal-derived feeder cells for human iPSC generation [22], the availability of human auto-fibroblasts is quantitatively limited. Therefore, to apply human iPSCs to clinical use, replacing feeder layers with a chemically defined substitute is required.
\nPreviously, gelatinous protein mixtures were applied to culturing human pluripotent stem cells. For example, human ESCs were successfully maintained with Matrigel and chemically defined medium [23]. Although Matrigel was applicable for maintenance of human pluripotent stem cells [24–26] and achieved feeder-free human iPSC generation [27, 28], this condition was not animal product-free because the matrix is derived from Engelbreth-Holm-Swarm mouse tumor [29] and contains many types of collagens, laminin, and proteoglycans. Therefore, the essential components for human iPSC culture have been investigated.
\nOther types of matrices, such as CellStart [30, 31] and synthetic polymers [32, 33], were tested and successfully used as feeder cell substitutes for the maintenance and generation of human pluripotent stem cells. In addition, recombinant cell adhesion proteins have received attention as a defined alternative for feeder cells. For example, vitronectin is a glycoprotein present in the extracellular matrix that mediates cell adhesion and was shown to be an alternative for feeder cells in human pluripotent stem cell culture [34]. Laminin, a component of the basal lamin, is another possible alternative to feeder cells in maintenance and generation of human iPSCs [35, 36]. These products allow removal of animal-derived feeder layers from human iPSC cultures and, therefore, are useful for establishing xeno-free culture conditions for human iPSCs.
\nThe initial culture medium for iPSCs also contained animal products such as fatal bovine serum. There have been many subsequent reports of xeno-free media such as TeSR2 [37], NutriStem [38], Essential E8 [34], and StemFit [39] for human iPSC generation and maintaining. The combination of these matrices and media can achieve generation of human iPSCs under completely defined conditions, thus making iPSC generation in xeno-free conditions achievable.
\nThere are two considerations when choosing the types of donor cells. The first is whether allogenic iPSCs or autogenic iPSCs will be used. Applying autogenic iPSCs to each patient is ideal because this method is not expected to require co-treatment with an immune suppressor [40, 41]. The first case of therapy using iPSCs was performed using autogenic iPSCs [3] and was important for reaffirming the usefulness of iPSCs as a source of autogenic regenerative cells. Nevertheless, because of the immense amount of time and effort required to make autogenic iPSCs from each patient, allogenic iPSCs that are matched in human leukocyte antigen (HLA) type are an important option for establishing treatment with iPSC-derived cells [4], especially in cases that demand expedient treatment. However, covering an entire population with HLA-matched allogenic iPSCs is nearly impossible due to the high diversity of HLA genes [42]. Therefore, to achieve complete coverage of the population with iPSC banks is an important issue. In previous reports, hypoimmunogenic human pluripotent stem cells were successfully generated through genome editing [43–45]. Although these methods could complete the missing part of the iPSC bank, whether these genome-edited pluripotent cells are safe needs further validation. At this time, the imperfect coverage of iPSC banks has to be recognized. When the time limit for generating iPSCs is not severe, autogenic iPSCs might become an important option. Therefore, whether standard guidelines for clinical-grade iPSCs can be defined equally for allogenic and autogenic iPSCs is in question. In a recent report, contaminated undifferentiated iPSC-derived cells readily grew teratomas in syngeneic conditions but not in allogenic conditions supported with an immune suppressor [46]. This difference of tumorigenesis between iPSC derivatives in autogenic and allogenic conditions could complicate definition of standards for clinical-grade iPSCs.
\nThe other consideration about choosing types of donor cells is selection of the type of somatic cells for reprogramming. To date, there have been many efforts to minimize the invasiveness of sample acquisition. Previously, generating iPSCs from keratinocytes derived from plucked hair [47], fibroblasts derived from oral mucosa [48], and peripheral blood cells obtained by venipuncture [49–51] was established as less-invasive methods. However, the characteristics of iPSCs can be affected by the type of somatic cells used for their generation [10–12]. Whether residual epigenetic memory derived from original somatic cells is permissible in clinical-grade iPSCs must be considered. In addition, although blood cells are becoming the preferred material for iPSC generation, the best choice for generating iPSCs of high quality avoiding capture of somatic mutations and aberrant epigenetic memory remains undefined. These questions remain important issues toward standardization of iPSC quality.
\nIn generating iPSCs for clinical use, achieving residual transgene-free products is essential because of the possibly harmful effect of residual transgenes. Since the first report of human iPSC generation with retroviral gene introduction [2], there has been much technical progress in methods of gene introduction for iPSC generation. Currently, methods of generating transgene-free human iPSCs are established using adenovirus vectors [13], sendai virus vectors [14], transposons [16], RNA [18], recombinant protein [15, 17], or episomal vectors [19]. Even when non-viral methods such as episomal vectors are used, there is low incidence of genomic insertion of exogenous sequence. In the case of viral vectors, transposons, and episomal vectors, verification of vehicle elimination in iPSCs is necessary. Because methods for verifying the removal of these vehicles are not identical in each case, unionization and standardization of verification methods are difficult. An appropriate method must be established for each type of vehicle, or whole-genome sequencing to detect aberrant vehicle-derived sequence insertions might be essential for identifying residual transgene sequences in iPSCs.
\nIn the first report of successful mouse somatic cell reprogramming with exogenous gene introduction, forced expression of
At the other extreme, there have been many efforts to generate iPSCs using chemical compounds. Although progress in developing gene vehicles enabled generation of residual transgene-free iPSCs, the ultimate goal is to generate iPSCs without gene introduction. Many previous reports demonstrated improved reprogramming efficiency with small molecules, with some specific small molecules serving as a substitute for reprogramming factors [58]. Finally, in mice, a combination of small molecules completely reprogrammed somatic cells into pluripotent states without forced expression of exogenous genes [59, 60]. Although these chemically generated iPSCs require further verification in terms of quality such as residual epigenetic modification of somatic cells, they have the potential to become mainstream for iPSC-associated researches.
\nThe quality of mouse iPSCs has been mainly evaluated through chimerism experiments [61]. Germline contribution of iPSCs and induction of iPSC-derived mice have been the ultimate verifications of pluripotency. Previous reports of iPSC generation with TBX3 [55], L-MYC [56], or GLIS1 [57] also evaluated the quality of iPSCs through mouse chimera formation and germline contribution. However, these experiments are not applicable to human iPSCs because of ethical concerns. In addition, although an in vivo teratoma formation assay has also been used to establish the differentiation capacity of iPSCs, quantifying teratoma formation is rather difficult in contrast to in vitro differentiation because the amount of time to teratoma formation and pathological interpretation are needed. Therefore, the quality of human iPSCs has been evaluated with an in vitro differentiation assay.
\nFor example, the in vitro differentiation assay of human iPSCs revealed that differentiation was affected by donor cell types [10–12]. This phenomenon is termed “epigenetic memory” and, interestingly, does not arise from somatic cell reprogramming with nuclear transfer. Although epigenetic memory decreases with increasing culture time [12], residual epigenetic modification of iPSC origin cells must be considered when iPSCs are applied to clinical use. In addition, the gene expression of iPSCs showing a tumorigenic tendency after neural differentiation was analyzed [20], revealing that activated expression of genes containing specific LTR7 sequences in iPSCs was statistically associated with tumorigenesis. Such predictive markers for the quality of human iPSCs are important for rapid selection of cell lines suitable for clinical use.
\nRecent progress in next-generation sequencing (NGS) techniques has provided platforms for exhaustive analysis of iPSC RNA, genome, and epigenome. This type of analysis can detect chromosomal aberrations in human iPSCs as sequence abnormalities [62]. Although whether somatic cell reprogramming itself can lead to genomic abnormalities in iPSCs is in discussion, long-term culture of pluripotent stem cells is known to lead to genomic abnormalities [63]. Because mutations in protein-coding regions of the genome could trigger tumorigenesis of iPSCs, analysis of iPSCs with NGS can assume a large role in evaluating iPSC quality and selecting iPSCs suitable for clinical use.
\nAs presented above, evaluation of human iPSC quality has been performed without chimera assays. Whether all of perceptions in mouse iPSC experiments are directly applicable to human iPSCs remains a matter of debate. Therefore, investigating the chimeric contribution capacity of human iPSCs has an ultimate importance in quantifying the pluripotency of human iPSCs. In this regard, recent analysis indicated the possibility of transcending boundaries between human iPSCs and chimera formation assays. Human iPSCs and ESCs have features similar to mouse epiblast stem cells, which are in an advanced differentiation state compared to mouse ESCs [64]. Common human iPSCs and mouse epiblast stem cells are thought to be in a “primed state” distinct from the “naïve state” of mouse ESCs. Pluripotent stem cells in a primed state have difficulty in contributing chimeras in preimplantation embryos [65]. In addition, generating chimeras of human and mouse cells is ethically problematic. Therefore, methods for evaluating the quality of human iPSCs have not been standardized. However, a recent report showed that human iPSCs could contribute to chimeras in stage-matched post-implantation mouse embryos [66]. Although the observation period of chimeric embryos was limited, chimera formation experiments with human iPSCs and stage-matching post-implantation mouse embryos might represent a novel assay for evaluating the quality of human iPSCs.
\niPSCs are used as a cell source for inducing intended types of differentiated cells and are not transplanted to patients directly. Therefore, as with quality control of iPSCs, quality control of iPSC-derived products is important for ensuring the safety of clinical application of iPSCs and contains two important considerations for achieving safety.
\nThe first is purification of intended cells from a mixture of differentiated cells. Even a small contamination of undifferentiated cells in the final product could lead to teratoma development after transplantation [67]. Therefore, appropriate methods for purification are required to ensure safety. Purification of products derived from pluripotent stem cells has been previously attempted using a surface marker of pluripotent stem cells to remove undifferentiated cells [68, 69] or cell sorting targeting surface markers specific to intended cells [70, 71]. However, fluorescence-activated cell sorting with cell surface markers is difficult to apply to mass culture systems because of the large time investment required. To achieve applicability to mass culture systems, purification with medium conditions [72, 73] or with reagents with specific cytotoxic effects against undifferentiated cells [74, 75] was developed. These techniques are expected to be useful for achieving safe iPSC-derived products.
\nTo validate the quality of products derived from iPSCs, detection of residual undifferentiated cells in the product is another essential technique for avoiding tumorigenesis after transplantation. If the methods described above for purification achieve high accuracy, methods for evaluating the elimination of undifferentiated cells and assuring safety are required. However, current validation methods for detecting residual undifferentiated cells in final products from iPSCs are limited. Examining expression of pluripotent markers in products from iPSCs with qRT-PCR [76, 77] and detecting specific glycoproteins in the cell culture supernatants [78] were reported as useful methods for evaluating elimination of undifferentiated cells. To ultimately demonstrate safety, the absence of tumorigenesis in in vivo transplantation assays is required, but the appropriate observation period and numerous transplanted cells remain evasive. In addition, whether xeno-transplantation experiments truly replicate transplantation of human cases needs further validation.
\nOne of the most important issues for clinical iPSC application is the establishment of safety nets for post-treatment patients. If tumorigenic cell contaminates the final iPSC-derived product and might be transplanted into patients, measures to avoid health hazard to patients must be established. Although surgical resection of iPSC-derived tumors is one conceivable method, there will be cases that cannot be managed through surgery due to the invasiveness of the operation.
\nIntroducing a suicide system into human iPSCs before transplantation is another useful approach for ensuring safe clinical application of iPSCs. When iPSC-derived tumors occur in patients, ablation of iPSC-derived cells by switching the suicide system “on” can prevent invasive surgery in high-risk patients. For example, herpes simplex virus thymidine kinase (HSV-TK) phosphorylates ganciclovir (GCV) and leads to cytotoxicity in the presence of GCV. HSV-TK has been widely used as “suicide gene” in human ESC experiments [79]. The combination of HSV-TK and GCV was also tested in an in vivo mouse model with mouse iPSCs [80, 81]. Another possibility is the combination of inducible caspase-9 and a chemical inducer of dimerization, which was shown to work as suicide system in human iPSC derivatives [82]. Whereas the HSV-TK suicide system is cell cycle dependent, inducible caspase-9 achieves cell cycle-independent ablation of target cells. Although these systems can become an important option for treatment of iPSC-derived tumors, modified genomic introduction methods of suicide genes are required for clinical use. Because random exogenous introduction using lentiviral and retroviral vectors could break functional gene sequences in iPSCs, validation of target sites for suicide gene insertion and targeted genome editing in iPSCs is required for clinical application.
\nThis type of strategy has a disadvantage in that all iPSC-derived cells are diminished with the suicide system. When iPSC-derived tumors occur, diminishing only tumor cells while retaining the useful cells in the engrafted treatment is ideal. With this in mind, some reports showed selective suicide systems in which the suicide gene is inserted under control of a promoter of pluripotent markers [80]. However, in this area of research, how selective removal of tumor cells should be ensured remains to be solved.
\nCurrently, in contrast to research ensuring the safety of iPSCs and iPSC-derivatives, research establishing methods to manage cases in which iPSC-derived tumors occur in post-treatment patients is less common. To ensure safe clinical application of iPSCs, countermeasures for every possible contingency after treatment using iPSCs must be prepared in advance. Thus, this type of research is of considerable importance in the area of regenerative medicine.
\niPSCs are expected to serve as a novel cell source for regenerative medicine, although there are many points that require verification before expanding their application to broad clinical uses. Standardization of iPSC quality is required, but current verification and validation procedures are not perfect. This incompleteness must be widely recognized. To establish safe iPSC use in regenerative therapy, appropriate improvements of these issues and defined guidelines for iPSCs are expected.
\nMalignant pleural mesothelioma (MPM) is a rare neoplasm with a poor prognosis. MPM is strongly associated with past exposure to asbestos [1]. Radical surgeries, such as an extrapleural pneumonectomy or pleural decortication, have been performed for treating patients with MPM previously, but favorable results have been observed in only a limited number of patients [2, 3]. Most patients that present with advanced, non-resectable MPM at diagnosis are candidates for systemic treatments. However, systemic chemotherapy can only be administered to patients with good performance status (PS) [4].
In 2003, Vogelzang et al. reported that the combination of pemetrexed and cisplatin (pemetrexed/cisplatin) improved the response rate (RR), progression-free survival (PFS), and overall survival (OS), compared to cisplatin alone [5]. Since then, systemic chemotherapy with platinum and pemetrexed combination has been considered standard therapy for advanced MPM. However, even with this treatment, the PFS and OS have been estimated at 5.7 months and 12.1 months, respectively [5, 6]. A second-line treatment has not been established. According to the US Surveillance, Epidemiology, and End Results Medicare investigation, the most common second-line treatments are pemetrexed-based retreatment or gemcitabine [6].
There is strong evidence that angiogenesis is an important determinant in the development and progression of MPM. There are two main targets for inhibiting angiogenesis. One is the potent mitogen for endothelial cells, vascular endothelial growth factor (VEGF), which transduces signals by binding to two receptors, VEGF receptors −1 and 2. The other is platelet-derived growth factor (PDGF), which functions as an autocrine growth stimulator in the pathogenesis of MPM [7, 8]. With the introduction of angiogenesis inhibitors, several clinical studies have investigated treatments for MPM.
An alternative approach is to target the complex interaction between cancer and host immunity: cancer cells can acquire the ability to evade the host immune system, which curtails their growth [9, 10]. Cancer cells can also actively subvert the immunosuppressive function of T cells and immune checkpoint molecules, such as cytotoxic T lymphocyte antigen (CTLA)-4, programmed cell death (PD)-1, and PD-ligand (PD-L)-1. In recent years, immune checkpoint inhibitors (ICIs) have shown remarkable results in treating multiple types of neoplasms. The etiology and pathogenesis of MPM are mostly attributed to the generation of an immune microenvironment favorable to tumor growth, caused by asbestos-induced damage [11]. There is evidence that ICIs might play an important role in the treatment of MPM; in fact, some encouraging results have emerged in recent years.
Here, we discuss the results of recent trials on systemic therapies against MPM, with a focus on anti-angiogenic inhibitors and ICIs.
Most early studies on anti-angiogenic agents explored their clinical efficacy as single drugs for treating cancer in the relapsed or recurrent setting. However, the outcome of those studies was generally disappointing. Later, anti-angiogenic agents were combined with cytotoxic agents, mainly pemetrexed/cisplatin.
Bevacizumab is a monoclonal antibody that binds VEGF-A. Bevacizumab was tested in combination with the standard-of-care, cisplatin and pemetrexed, as a first-line treatment. An open-label, randomized phase 2/3 study that added bevacizumab to cisplatin and pemetrexed in chemotherapy-naïve patients showed a beneficial effect [12]. In that study, 448 patients were randomized to either pemetrexed/cisplatin with bevacizumab or chemotherapy alone. Patients were treated for up to 6 cycles. OS was statistically prolonged in the bevacizumab arm; the median OS was 18.8 months, versus 16.1 months for chemotherapy alone (HR: 0.77, 95% CI: 0.62–0.95).
Nintedanib is a multi-target angiokinase inhibitor, with activity against the receptors for VEGF (receptors 1, 2, and 3), PDGF, and fibroblast growth factor. A phase II study on patients with MPM showed that the addition of nintedanib to pemetrexed/cisplatin improved PFS (median 9.4 vs. 5.7 months; hazard ratio [HR]: 0.54; 95% CI: 0.33–0.87; p = 0.010). Moreover, the nintedanib arm showed a trend toward improved OS (median 18.3 vs. 14.2 months; HR: 0.77; 95% CI: 0.46–1.29; p = 0.319), compared to placebo. These positive effects were observed in patients with epithelioid histology. However, the findings were not confirmed in the subsequent phase 3 study [13].
Recently, ramucirumab, an anti-VEGF receptor-2 antibody, was tested in a double-blind, placebo-controlled, phase 2 trial for patients with pretreated MPM. In that trial, 161 patients were randomly assigned to gemcitabine (1000 mg/m2 intravenously, on days 1 and 8 every 3 weeks) or gemcitabine plus ramucirumab (10 mg/kg, intravenously, on day 1 every 3 weeks) [14]. The OS was prolonged in the ramucirumab arm (HR: 0·71, 70% CI: 0·59–0·85; p = 0·028); the median OS was 13·8 months (70% CI: 12·7–14·4) with gemcitabine plus ramucirumab and 7·5 months (70% CI: 6·9–8·9) with gemcitabine plus placebo. Hypertension was more common in the gemcitabine plus ramucirumab group, but no events were related to bleeding.
Anti-CTLA-4 antibodies include tremelimumab and ipilimumab. Drugs that block PD-(L)-1 include pembrolizumab, nivolumab, durvalumab, and avelumab.
The MERIT trial was a phase 2, single-phase study that evaluated the safety and efficacy of nivolumab in Japanese patients with advanced or recurrent MPM, who were refractory or intolerant to 1–2 regimens of therapy [15]. In that study, 34 patients received nivolumab (240 mg intravenously) every 2 weeks, until they displayed progressive disease or unacceptable toxicity. The primary endpoint was the objective RR, which was 29.4% (10/34). The median OS and PFS times were 17.3 and 6.1 months, respectively. Among the 34 patients, 11 (32%) experienced grades ≥3 treatment-related adverse events, including 4 patients (12%) with adverse events that led to study treatment discontinuation (2 events of interstitial pneumonia, and 2 events of pneumonitis). Based on those results, nivolumab was approved for patients with MPM that were refractory or intolerant to prior chemotherapy.
The therapeutic efficacy of nivolumab was confirmed in a phase III trial, which demonstrated that single-agent nivolumab provided a significant improvement in both OS and PFS [16]. In that study, 332 adult patients with previously treated, unresectable, histologically confirmed malignant mesothelioma were randomized to nivolumab or placebo. The median OS was immature, but it was significantly prolonged with nivolumab (9.2 vs. 6.6 months; HR: 0.72; 95% CI: 0.55–0.94; p = 0.02). The median PFS was also prolonged with nivolumab compared to placebo (3.0 vs. 1.8 months; HR: 0.62; 95% CI: 0.49–0.78; p < 0.001). Grades 3–4 treatment-related adverse events occurred in 19% of the nivolumab arm and 6.3% of the placebo arm. Treatment discontinuation due to toxicity occurred in 13.1% of the nivolumab arm, versus 2.7% of the placebo arm.
The MAPS2 trial was a multicenter randomized, open-label, phase 2 trial that investigated nivolumab plus ipilimumab versus single-agent nivolumab, as a salvage treatment [17]. In the intention-to-treat population, 12-week disease control was achieved by 32 of 62 patients (52%; 95% CI: 39–64) in the nivolumab plus ipilimumab group and 25 of 63 patients (40%; 95% CI: 28–52) in the nivolumab group. Asthenia was among the most frequent grade 3 adverse events (n = 3 [5%] in the combination arm and n = 1 [2%] in the nivolumab arm).
The CheckMate 743 trial was a global, open-label, randomized, phase 3 study that investigated first-line nivolumab plus ipilimumab versus the standard platinum plus pemetrexed chemotherapy [18]. In that study, 605 patients with previously untreated, unresectable MPM were randomly assigned to nivolumab (3 mg/kg intravenously once every 2 weeks) plus ipilimumab (1 mg/kg intravenously once every 6 weeks), administered for up to 2 years, or platinum (cisplatin or carboplatin) plus pemetrexed chemotherapy, administered once every 3 weeks for up to 6 cycles. The primary endpoint was OS. The OS was significantly extended in the nivolumab plus ipilimumab arm, with a median of 18.1 months (95% CI: 16.8–21.4), compared to 14.1 months (95% CI: 12.4–16.2) in the chemotherapy arm. The HR was 0.74 (96.6% CI: 0.60–0.91). The 1-year and 2-year OS rates were, respectively, 68% (95% CI: 62.3–72.8) and 41% (95% CI: 35.1–46.5) in the nivolumab plus ipilimumab arm, and 58% (95% CI: 51.7–63.2) and 27% (95% CI: 21.9–32.4) in the chemotherapy arm. Across most subgroups, OS was more favorable with nivolumab plus ipilimumab compared to chemotherapy. The most frequently reported grade 3 or higher serious treatment-related adverse events were colitis (3%), in the nivolumab plus ipilimumab arm, and anemia (2%) in the chemotherapy arm.
The DREAM trial was a multicenter, single-arm, open-label, phase 2 trial conducted in 9 institutions in Australia [19]. In that study, 54 patients received cisplatin, pemetrexed, and durvalumab, in 3-week cycles, for up to 6 cycles. Durvalumab was continued for maintenance for up to 12 months. The primary endpoint was PFS at 6 months. Among 54 patients, 31 (57%; 95% CI: 44–70) were alive and progression-free at 6 months. The most frequent grade 3–4 adverse events were neutropenia (13%), nausea (11%), and anemia (7%). Five patients died during the study treatment, but none of the deaths were attributed to the study treatment.
The efficacy and safety of cisplatin, pemetrexed, and nivolumab were tested as first-line therapy for MPM in a phase II study, called JME-001 [20]. Cisplatin, pemetrexed, and nivolumab were administered intravenously every 3 weeks, for a total of 4 to 6 cycles. Patients that did not progress during the combination phase received maintenance therapy with nivolumab until disease progression or unacceptable toxicity. Among 18 enrolled patients, 14 (77·8%; 95% CI: 52·4–93·6) showed an objective response. Ten (55·6%) patients experienced grade 3 or worse adverse events, including disorders of metabolism or nutrition (33·3%), loss of appetite (27·8%), anemia (16·7%), and hyponatremia (11·1%). No treatment-related deaths occurred.
The efficacy and safety of pembrolizumab in combination with standard pemetrexed and platinum-based chemotherapy is currently being tested as a first-line treatment for MPM in phase II/III randomized study (NCT02784171) and in multicenter, open-label, non-randomized study (NCT04153565). Those results will be disclosed within a couple of years.
Cisplatin plus pemetrexed has been the mainstay of systemic treatment for MPM. A phase III trial of platinum, pemetrexed plus the anti-VEGF inhibitor, bevacizumab, showed favorable results, with prolonged PFS and OS. The National Comprehensive Cancer Network (NCCN) guidelines advocate adding bevacizumab as an option; however, that regimen has not been approved in most countries. In recent years, ICIs have shown remarkable progress in treating MPM. Summaries of the major trials, with a focus on recent trials, are shown in Table 1. They include both salvage treatments and first-line treatments. Based on the CheckMate 743 trial results, the ICI-ICI combination of ipilimumab plus nivolumab could be considered a new standard front-line treatment.
Trial (Reference) | Phase | Primary endpoint | Drug | Number of patients | Histology | ORR (%) (CI) | median PFS (months) (CI) | median OS (months) (CI) |
---|---|---|---|---|---|---|---|---|
First-line | ||||||||
MAPS [12] | III | OS | cisplatin + pemetrexed + bevacizumab | 223 | Epi: 179/223 (80%) non-Epi:44/223 (20%) | N.A. | 9.2 (8.5–10.5) | 18.8 (15.9–22.6) |
cisplatin + pemetrexed | 225 | Epi: 182/335 (81%) non-Epi:43/335(19%) | N.A. | 7.3 (6.7–8.0) | 16.1 (14.0–17.9) | |||
Checkmate 743 [18] | III | OS | pembrolizumab | 303 | Epi: 229/303 (76%) non-Epi: 74/303 (24%) | 40 (34.1–45.4) | 6.8 (5.6–7.4) | 18.1 (16.8–21.4) |
cisplatin + pemetrexed | 302 | Epi: 227/302 (75%) non-Epi: 75/302 (25%) | 43 (37.1–48.5) | 7.2 (6.9–8.0) | 14.1 (12.4–16.2) | |||
DREAM [19] | IIb | PFS | platinum + pemetrexed + durvalmab | 54 | Epi: 45/54 (83%) non-Epi: 9/54 (17%) | 48 (35–6) | 6.9 (5.5–9.0) | 18.4 (13.1–24.8) |
JME-001 [20] | II | ORR | cisplatin + pemetrexed + nivolumab | 18 | Epi: 14/18 (78%) non-Epi: 4/18 (22%) | 78 (52.4–93.6) | 8.0 (5.6–14.1) | 20.8 |
Second-line or later | ||||||||
MERIT [15] | IIb | ORR | nivolumab | 34 | Epi: 27 (79%) non-Epi: 7 (21%) | 29 (17–46) | 6.1 (2.9–9.9) | 17.3 (11.5–N.R.) |
MAPS2 [17] | III | If disease control was achieved in at least 40% | nivolumab + ipilimumab | 62 | Epi: 52 (83%) non-Epi: 11 (17%) | 28 (16–40) | 5.6 (3.1–8.3) | 15.9 (10.7–N.R.) |
placebo | 63 | Epi: 53 (85%) non-Epi:9(15%) | 19 (8–29) | 4.0 (2.8–5.7) | 11.9 (6.7–11.7) | |||
RAMES [14] | II | OS | gemcitabine + ramcirumab | 80 | Epi: 68/80 (85%) non-Epi: 12 (15%) | 6.3 (2–14) | 6.4 (5.5–7.6) | 13.8 (12.7–14.4) |
gemcitabine | 81 | Epi: 70/81 (86%) non-Epi:11/81(14%) | 10 (4–19) | 7.5 (6.9–8.9) | 7.5 (6.9–8.9) | |||
CONFIRM [16] | III | PFS OS | nivolumab | 221 | Epi: 195/221 (88%) non-Epi: 26/221 (12%) | 11 (N.A.) | 3.0 (2.8–4.1) | 10.2 (8.5–12.1) |
placebo | 111 | Epi: 98/111 (88%) non-Epi: 13/111 (12%) | 1 (N.A.) | 1.8 (1.4–2.6) | 6.9 (5.0–8.0) |
Recent clinical studies of systemic treatment in malignant pleural mesothelioma.
ORR: objective response rate; CI: confidence interval; PFS: progression-free survival; OS: overall survival; Epi: epithelioid; N.A.: not available; and DCR: disease control rate.
Some unresolved problems should be investigated to make further improvements in the outcome of patients with MPM. One is the rapid drop-off in PFS observed among patients that receive ICIs. A recent study on patients with non-small cell lung cancer showed that ipilimumab plus nivolumab combined with 2 cycles of cytotoxic chemotherapy could reduce the rapid drop-offs in both PFS and OS [21]. Those results supported the notion that the ICI-chemotherapy combination should undergo further clinical development. Results are also anticipated from an ongoing trial that is testing a more aggressive strategy, with a combination of platinum, pemetrexed, atezolizumab, and bevacizumab (BEAT-meso, NCT03762018).
The results of various clinical trials that examined ICIs and angiogenesis inhibitors have been published in recent years. These trials have demonstrated better treatment options for MPM, but personalized medicine remains in the distant future. Although, MPM is a rare disease, the prognosis remains extremely poor. Therefore, it is necessary to conduct more clinical trials and translational investigations to establish personalized treatment options that can provide the most benefit to individual patients.
This study was supported by grants-in-aid from the Ministry of Health, Labor, and Welfare, Japan.
Dr. Fujimoto received consultancy fees from Boehringer Ingelheim, Ono, and Bristol-Myers Squibb, and honoraria or research funding from Chugai, Ono, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, and MSD.
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He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. 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She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:null},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. He has authored and reviewed a number of journal articles and book chapters.",institutionString:"National Veterinary Research Institute",institution:{name:"National Veterinary Research Institute",country:{name:"Nigeria"}}},{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",country:{name:"India"}}},{id:"94928",title:"Dr.",name:"Takuo",middleName:null,surname:"Mizukami",slug:"takuo-mizukami",fullName:"Takuo Mizukami",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94928/images/6402_n.jpg",biography:null,institutionString:null,institution:{name:"National Institute of Infectious Diseases",country:{name:"Japan"}}},{id:"233433",title:"Dr.",name:"Yulia",middleName:null,surname:"Desheva",slug:"yulia-desheva",fullName:"Yulia Desheva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/233433/images/system/233433.png",biography:"Dr. Yulia Desheva is a leading researcher at the Institute of Experimental Medicine, St. Petersburg, Russia. She is a professor in the Stomatology Faculty, St. Petersburg State University. She has expertise in the development and evaluation of a wide range of live mucosal vaccines against influenza and bacterial complications. Her research interests include immunity against influenza and COVID-19 and the development of immunization schemes for high-risk individuals.",institutionString:'Federal State Budgetary Scientific Institution "Institute of Experimental Medicine"',institution:null},{id:"238958",title:"Mr.",name:"Atamjit",middleName:null,surname:"Singh",slug:"atamjit-singh",fullName:"Atamjit Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/238958/images/6575_n.jpg",biography:null,institutionString:null,institution:null},{id:"333753",title:"Dr.",name:"Rais",middleName:null,surname:"Ahmed",slug:"rais-ahmed",fullName:"Rais Ahmed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333753/images/20168_n.jpg",biography:null,institutionString:null,institution:null},{id:"252058",title:"M.Sc.",name:"Juan",middleName:null,surname:"Sulca",slug:"juan-sulca",fullName:"Juan Sulca",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252058/images/12834_n.jpg",biography:null,institutionString:null,institution:null},{id:"191392",title:"Dr.",name:"Marimuthu",middleName:null,surname:"Govindarajan",slug:"marimuthu-govindarajan",fullName:"Marimuthu Govindarajan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/191392/images/5828_n.jpg",biography:"Dr. M. Govindarajan completed his BSc degree in Zoology at Government Arts College (Autonomous), Kumbakonam, and MSc, MPhil, and PhD degrees at Annamalai University, Annamalai Nagar, Tamil Nadu, India. He is serving as an assistant professor at the Department of Zoology, Annamalai University. His research interests include isolation, identification, and characterization of biologically active molecules from plants and microbes. He has identified more than 20 pure compounds with high mosquitocidal activity and also conducted high-quality research on photochemistry and nanosynthesis. He has published more than 150 studies in journals with impact factor and 2 books in Lambert Academic Publishing, Germany. He serves as an editorial board member in various national and international scientific journals.",institutionString:null,institution:null},{id:"274660",title:"Dr.",name:"Damodar",middleName:null,surname:"Paudel",slug:"damodar-paudel",fullName:"Damodar Paudel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274660/images/8176_n.jpg",biography:"I am DrDamodar Paudel,currently working as consultant Physician in Nepal police Hospital.",institutionString:null,institution:null},{id:"241562",title:"Dr.",name:"Melvin",middleName:null,surname:"Sanicas",slug:"melvin-sanicas",fullName:"Melvin Sanicas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241562/images/6699_n.jpg",biography:null,institutionString:null,institution:null},{id:"337446",title:"Dr.",name:"Maria",middleName:null,surname:"Zavala-Colon",slug:"maria-zavala-colon",fullName:"Maria Zavala-Colon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Puerto Rico, Medical Sciences Campus",country:{name:"United States of America"}}},{id:"338856",title:"Mrs.",name:"Nur Alvira",middleName:null,surname:"Pascawati",slug:"nur-alvira-pascawati",fullName:"Nur Alvira Pascawati",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universitas Respati Yogyakarta",country:{name:"Indonesia"}}},{id:"441116",title:"Dr.",name:"Jovanka M.",middleName:null,surname:"Voyich",slug:"jovanka-m.-voyich",fullName:"Jovanka M. Voyich",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Montana State University",country:{name:"United States of America"}}},{id:"330412",title:"Dr.",name:"Muhammad",middleName:null,surname:"Farhab",slug:"muhammad-farhab",fullName:"Muhammad Farhab",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"349495",title:"Dr.",name:"Muhammad",middleName:null,surname:"Ijaz",slug:"muhammad-ijaz",fullName:"Muhammad Ijaz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Veterinary and Animal Sciences",country:{name:"Pakistan"}}}]}},subseries:{item:{id:"93",type:"subseries",title:"Inclusivity and Social Equity",keywords:"Social contract, SDG, Human rights, Inclusiveness, Equity, Democracy, Personal learning, Collaboration, Glocalization",scope:"\r\n\tThe environment is subject to severe anthropic effects. Among them are those associated with pollution, resource extraction and overexploitation, loss of biodiversity, soil degradation, disorderly land occupation and planning, and many others. These anthropic effects could potentially be caused by any inadequate management of the environment. However, ecosystems have a resilience that makes them react to disturbances which mitigate the negative effects. It is critical to understand how ecosystems, natural and anthropized, including urban environments, respond to actions that have a negative influence and how they are managed. It is also important to establish when the limits marked by the resilience and the breaking point are achieved and when no return is possible. The main focus for the chapters is to cover the subjects such as understanding how the environment resilience works, the mechanisms involved, and how to manage them in order to improve our interactions with the environment and promote the use of adequate management practices such as those outlined in the United Nations’ Sustainable Development Goals.
",coverUrl:"https://cdn.intechopen.com/series_topics/covers/39.jpg",keywords:"Anthropic effects, Overexploitation, Biodiversity loss, Degradation, Inadequate Management, SDGs adequate practices"},{id:"38",title:"Pollution",scope:"\r\n\tPollution is caused by a wide variety of human activities and occurs in diverse forms, for example biological, chemical, et cetera. In recent years, significant efforts have been made to ensure that the environment is clean, that rigorous rules are implemented, and old laws are updated to reduce the risks towards humans and ecosystems. However, rapid industrialization and the need for more cultivable sources or habitable lands, for an increasing population, as well as fewer alternatives for waste disposal, make the pollution control tasks more challenging. Therefore, this topic will focus on assessing and managing environmental pollution. It will cover various subjects, including risk assessment due to the pollution of ecosystems, transport and fate of pollutants, restoration or remediation of polluted matrices, and efforts towards sustainable solutions to minimize environmental pollution.
",coverUrl:"https://cdn.intechopen.com/series_topics/covers/38.jpg",keywords:"Human activity, Pollutants, Reduced risks, Population growth, Waste disposal, Remediation, Clean environment"},{id:"41",title:"Water Science",scope:"