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A novel personalized vaccine approach in combination with targeted therapy in advanced renal cell carcinoma
The historical treatment paradigm for metastatic renal cell carcinoma has focused on immunomodulatory agents, such as IFN-a and IL-2, which provide good clinical outcomes in only a subset of patients. The development of therapies that target the VEGF and mTOR pathways have significantly altered the treatment landscape for this disease, with novel inhibitors providing substantial improvements in progressionfree and overall survival over previous standards of care. Despite these advances, toxicity from targeted therapy and the development of resistance results in disease progression. By contrast, vaccine-based immunotherapy represents a promising new approach for the treatment of patients with metastatic renal cell carcinoma; however, tumor-induced immunosuppression has limited the clinical efficacy of this modality until recently. Some evidence suggests that certain targeted therapies, such as sunitinib, may reduce this immunosuppression and enhance the tumor microenvironment to promote synergy with autologous dendritic cell vaccines.
Robert A Figlin Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Saperstein Critical Care Tower 1S28, Los Angeles, CA 90048, USA Tel.: +1 310 423 1331 Fax: +1 310 659 3928 robert.figlin@ cshs.org
KEYWORDS: AGS-003 • autologous dendritic cell vaccine • immunotherapy • renal cell carcinoma • sunitinib • targeted therapy • VEGF
In 2013, it is estimated that more than 65,000 new kidney tumors will be diagnosed in the USA, with more than 13,000 deaths [1]. Renal cell carcinoma (RCC) is the most common form of kidney cancer and represents approximately 3% of all malignant tumors in adults [2,3]. Historically, immunomodulatory interventions, such as IFN-a and IL-2, dominated the treatment of metastatic RCC (mRCC) [4,5]. This is due, in part, to their clinical efficacy, as well as evidence of immune cell infiltration and antitumor activity in RCC [6,7]. Both IFN-a and IL-2 yield similar objective response rates in patients with mRCC, whereas high-dose IL-2 yields durable responses in a minority of patients [3,8]. However, because of the increased risk of cardiovascular toxicity associated with IL-2, this clinical benefit may only be observed in a limited subset of mRCC patients, although predictive biomarkers may provide a mechanism by which appropriate patients are selected to receive cytokine-based therapy upfront [9,10]. When compared with
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novel targeted therapies, several Phase III trials have shown cytokine-based immunotherapy to be clinically inferior in terms of both efficacy and toxicity [11–13]. As a result, the use of targeted agents for mRCC has become widespread in all lines of therapy. Targeted therapies in mRCC Currently approved targeted therapies for mRCC include bevacizumab, sorafenib, sunitinib, axitinib, pazopanib, everolimus and temsirolimus; broadly, these are now considered standard-of-care treatments for mRCC [3,14]. The addition of these agents to the mRCC armamentarium has radically shifted the natural course of mRCC, increasing the median overall survival (OS) of patients from 10 months to more than 40 months [15]. Given the proangiogenic phenotype of the vast majority of RCC tumors, targeted therapies, to date, have focused on the disruption of the VEGF pathway [16]. These include small-molecule inhibitors of the
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Drug Evaluation Figlin VEGF receptor (VEGFR), as well as the PDGF receptor (PDGFR). Axitinib is a multikinase inhibitor that targets VEGFR-1, VEGFR-2 and VEGFR-3, and is US FDA approved as second-line treatment following tyrosine kinase inhibitor treatment [17,18]. Sorafenib inhibits VEGFR-1, VEGFR-2 and VEGFR-3, as well as PDGFR-b and a number of other kinases, such as FLT-3, c-KIT, RET and RAF. Sorafenib has yielded limited clinical efficacy in the first-line setting of mRCC and modest clinical utility in the second-line setting [3,19]. The Phase III AGILE trial reported no significant difference between sorafenib and axitinib in terms of progression-free survival (PFS) [20]. Sunitinib is a multikinase inhibitor of VEGFR-1, VEGFR2, VEGFR-3, PDGFR-a, PDGFR-b, c-KIT, FLT-3, CSF-1R and RET. Compared with IFN-a in the first-line setting, sunitinib has yielded a statistically superior median OS and PFS [3,21]. Although clinically noninferior to sunitinib in the first-line setting, pazopanib is associated with a possibly more attractive safety and quality-of-life profile [22,23]. The Phase III COMPARZ study compared sunitinib with pazopanib in patients with treatment-naive mRCC and indicated that the two inhibitors yielded a similar clinical efficacy; however, pazopanib had a different toxicity profile [23]. Finally, bevacizumab is a humanized monoclonal antibody that targets the VEGF ligand. In the first-line setting, its combination with IFN-a is statistically superior to cytokine monotherapy in terms of PFS, although not in terms of median OS [24,25]. Clinical trials are currently evaluating the efficacy of several investigational inhibitors, including the novel molecule tivozanib, in patients with mRCC. Tivozanib has a similar molecular target profile to sunitinib, although its activity is more specifically directed at VEGFR-2 [26]. The Phase III TIVO-1 trial, which compared tivozanib to sorafenib, reported that, although patients with mRCC who received tivozanib achieved a statistically longer median PFS than those who received sorafenib, there was no difference in median OS [27]. A Phase III clinical trial (TAURUS) is currently comparing tivozanib to sunitinib in patients with mRCC in the first-line setting [71]. In addition to the preceding novel VEGFR inhibitors, inhibitors of the mTOR pathway, such as everolimus and temsirolimus, are being investigated. These agents target the PI3K/Akt/mTOR pathway, which has been shown to be activated in mRCC and contributes to tumor growth and angiogenesis [28]. Unlike everolimus, temsirolimus has demonstrated clinical efficacy in the first-line setting, yielding a statistically superior median OS and PFS compared with IFN-a, primarily in a poor prognosis group of patients [11].
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Investigational agents targeting the PD-1 inhibitor are also being explored for RCC. Preclinical evidence suggests that inhibition of the PD-1 ligand may be efficacious in treating tumors [29]. The PD-1 inhibitor MDX-1106 has yielded early efficacy in Phase I trials of patients with refractory solid tumors, including mRCC [30,31]. Vaccine immunotherapy It has been known for decades that tumors present immunologically distinct epitopes that can be recognized and targeted by both innate and adaptive components of the immune system [32]. Cancer vaccines have been designed to prompt immune responses to single epitope targets and multiple epitopes from various oncogene products or through autologous activation of host dendritic cells. Single antigen vaccines
TG-4010 is an example of a cancer vaccine designed to target a single epitope from the cell surface protein MUC1, which is expressed at high levels in a number of tumors [33]. Expression of MUC1 is hypoxia inducible factor-dependent and an independent prognostic factor in RCC [34]. This protein may contribute to tumor growth by masking surrounding tumor-associated antigens expressed on the cell surface and confounding normal immunosurveillance [35]. A Phase I trial evaluating TG-4010 in patients with different solid tumors reported T cell-mediated immunity in a subset of patients, and stable disease was transiently achieved in several patients [35]. Ongoing clinical investigations of TG-4010 are underway. A recently reported Phase II trial evaluated TG-4010 alone or in combination with cytokine therapy in patients with mRCC [36]. Although no objective clinical responses to either treatment were reported, a subset of patients in both groups experienced stable disease and T-cell activation to MUC1 epitopes was also observed [36]. A Phase IIb/III placebocontrolled clinical trial is currently evaluating TG-4010 in combination with standard chemotherapy and targeted therapy in patients with metastatic non-small-cell lung cancer in the first-line setting [72]. Another single epitope cancer vaccine, MVA-5T4, is designed to target the oncofetal antigen 5T4, which is expressed at the cell surface primarily in placental tissue, as well as a wide range of tumor tissue, including squamous carcinomas of the bladder, lung and cervix, adenocarcinomas of the stomach and pancreas, and sarcomas [37]. In addition, the expression of the 5TF antigen in the majority of mRCCs has lead to clinical investigation in this area [38]. In Phase I/II trials, MVA-5T4 provoked specific immune responses in patients with colorectal, renal and prostate cancer [38]. The Phase III
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A novel personalized vaccine approach in combination with targeted therapy in advanced renal cell carcinoma
TroVax Renal Immunotherapy Survival trial randomized patients with mRCC to receive either MVA-5T4 or placebo in addition to standard first-line therapy [38]. The efficacy analysis of this trial showed that the addition of the vaccine to standard therapy resulted in no measurable improvement in OS, although a further exploratory analysis may describe more optimal patient subsets for vaccine therapy [38]. Multipeptide vaccines
Multipeptide vaccines provide an advantage over traditional peptide-based vaccines, such as overcoming tumor heterogeneity and promoting a stronger and more comprehensive immune response [39]. IMA901 is an example of a vaccine composed of tumor-associated peptides that are naturally present in human tumors [40]. In clinical trials, patients with advanced RCC receiving IMA901 achieved clear T-cell responses, which have been correlated with improved clinical outcomes, including OS [40]. Interestingly, two serum biomarkers, APOA1 and CCL17, were identified as predictive of both immune response to IMA901 and OS [40]. However, these clinical outcomes were observed to be more pronounced in patients who had also received single-dose cyclophosphamide prior to administration of IMA901, suggesting a synergistic relationship between the two therapies [41]. A Phase III trial evaluating IMA901 in patients with advanced or mRCC is currently ongoing. Patients will be randomized to receive first-line sunitinib with or without GM-CSF-boosted IMA901 and single-dose cyclophosphamide [73]. Autologous vaccines
Rather than challenge the patient’s immune system in situ with cancer-associated epitopes, autologous vaccines rely on ex vivo manipulation of dendritic cells [42]. The first ever autologous dendritic cell vaccine approved by the FDA was sipuleucel-T, which yielded a superior OS in a pivotal Phase III trial of patients with metastatic castration-resistant prostate cancer [43]. The technology of autologous dendritic cell vaccines represents a unique opportunity to use the native function of the immune system to directly stimulate cellmediated immunity through the presentation of a targeted antigen epitope to both CD4+ and CD8+ T cells [44,45]. As dendritic cells are present in nearly all human tumors, they are an attractive target for cancer interventions and immunotherapies [46]. For the development of ex vivo dendritic cell vaccines, the dendritic cells must first be cultured from a preparation of hematopoietic progenitor cells or peripheral blood mononuclear cells (PMBCs) [46]. They may subsequently be treated with various cytokines to selectively grow specific cell subpopulations [46]. Following this, they are exposed to the
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requisite antigens isolated from the patient’s tumor and then treated with adjuvants to promote cell maturation [46]. The tumor antigen-exposed dendritic cells are reinfused into the patient, where they can activate T cells that differentiate into effector cells that antagonize the tumor. Clinical benefit from dendritic cell vaccines has already been reported in patients with RCC. A recent meta-analysis reported a statistically significant objective response rate of 12.7% and a clinical benefit rate of 48% in 166 patients [47]. Vaccine & targeted therapy combinations AGS-003 is an autologous dendritic cell vaccine developed for the treatment of mRCC. It utilizes autologous matured monocyte-derived dendritic cells that are electroporated with amplified mRNA harvested from the patient’s tumor, as well as synthetic CD40L RNA [48,49]. Briefly, the manufacturing process of AGS-003 begins with the isolation of autologous total RNA from tumor tissue acquired by nephrectomy or metastasectomy, followed by selective amplification of mRNA using the reverse transcriptase PCR, as previously described [50,51]. Patient monocytes are harvested at a convenient leukapheresis donor center, and then cultured in vitro with GM-CSF and IL-4 to give rise to immature dendritic cells. These are then fully matured in culture by exposure to TNF-a, IFN-g and PGE2. These mature dendritic cells are electroporated with a combination of the patient’s tumor RNA, as well as CD40L RNA generated in vitro using the protocol described previously [52]. In a typical immune response, dendritic cells interact with activated helper CD4+ T cells in the context of upregulated CD40L, which results in the activation of CD8+ cytotoxic T cells [53]. However, for patients with mRCC, the systemic immunosuppression of the tumor cells leads to significant dysfunction in this process [54]. The intended mechanism of action of AGS-003 is to stimulate an adaptive immune response, which will overcome this dysfunction, integrating the MHC/antigenic interaction, the engagement of costimulatory molecules, such as CD80 and CD86, as well as the intercellular activity of IL-12, which has been shown to increase following electroporation of dendritic cells with CD40L RNA and is a requirement for memory T-cell responses [55,56]. The latter functionality is of critical importance to the activity of AGS-003 because it has been shown to correlate with positive clinical outcomes in patients with solid tumors [57]. Preclinical data have indicated that sunitinib modulates the tumor microenvironment by decreasing Treg function and enhancing immune-mediated antitumor activity [58]. Furthermore, the combination of sunitinib with the vaccine in mouse tumor models has confirmed the downregulation of regulatory immune cells, as well
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Drug Evaluation Figlin as the optimization of intratumoral immune infiltration in vivo [59,60]. In the clinical setting, intriguing results were reported in two patients with mRCC who received sunitinib prior to radical nephrectomy and dendritic cell therapy. In both patients, induction of sunitinib therapy was followed by observation of disease stabilization. Following nephrectomy and dendritic vaccine therapy, both patients also experienced a significant clinical benefit and regression of metastatic lesions [61]. To further capitalize on this synergy in the clinical setting in patients with mRCC, AGS-003 has been recently evaluated in combination with sunitinib. An open-label Phase II trial of AGS-003 in combination with sunitinib enrolled 21 patients with newly diagnosed mRCC with no previous nephrectomy or at least one accessible lesion for metastasectomy. Patients received five doses of the AGS-003 vaccine therapy every 3 weeks, and then every 12 weeks along with standard 6-week cycles of sunitinib until progression [48,49]. The efficacy analysis from this trial showed clinical benefit in the majority of patients enrolled, as well as a median PFS of 11.2 months and a median OS of 30.2 months, which were double the expected survival end points for this patient population [48,49]. Both efficacy end points were shown to be higher among patients with intermediate risk features, as determined by the Heng risk assessment [49]. Building on these data, an international randomized Phase III trial (ADAPT) has been designed to evaluate standard first-line sunitinib therapy with or without AGS-003 in patients with mRCC, to determine if the addition of the autologous dendritic cell vaccine therapy confers a significant improvement in OS [74]. Previous attempts to develop and validate therapeutic cancer vaccines have had limited success, perhaps due to the confounding tumor-driven immunological dysfunction described above. Although dendritic cells are ubiquitous in tumor tissue, normal immune function may be disrupted in the tumor microenvironment, inhibiting the action of effector T cells and antigen presentation [46]. Clinical evidence now suggests that the administration of sunitinib may restore normal immune function in the tumor microenvironment. In a small clinical biomarker trial, patients with mRCC who received sunitinib monotherapy and healthy controls provided PBMCs for analysis. In samples provided from patients who had been treated with sunitinib monotherapy, both a significant increase in effector T cells and a significant decrease in IL-4 production were observed through decreased recruitment of myeloid-derived suppressor cells and Tregs to tumor tissue [62]. Importantly, in a prospective biomarker assessment of the preceding Phase II clinical trial that evaluated AGS-003 in combination
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with sunitinib, PBMCs were assessed for T-cell proliferation using flow cytometry, both prior to and during treatment. Analysis of PBMCs from patients enrolled in the trial showed decreased levels of Tregs and increased levels of CD28+ memory cytotoxic T lymphocytes following treatment with the combination therapy. These changes in the immune context of the patients’ peripheral blood were positively correlated with improved PFS [63]. These findings support the hypothetical synergy of sunitinib with AGS-003 because the combination resulted in clear modifications to the tumor microenvironment and led to enhanced clinical outcomes with the therapeutic cancer vaccine. Although sunitinib appears to be an optimal partner for mRCC-developed autologous dendritic cell vaccines such as AGS-003, available data for alternative targeted therapies show variable suitability. In contrast to sunitinib, preclinical assessment of sorafenib as an immunostimulant molecule showed that, rather than enhancing the immune response, it inhibits the activity of dendritic cells and diminishes their capacity to activate T cells in response to an antigenic challenge. Thus, sorafenib appears to be an immunosuppressant agent that would not likely be an optimal partner molecule for combinations with AGS-003 and similar vaccines [64]. A retrospective analysis of plasma cytokines in patients with mRCC receiving pazopanib reported significantly higher levels of IL-6 correlated with an objective response to therapy, although these data are not yet fully understood and further study is required before pazopanib can be evaluated as a potential combination partner for therapeutic vaccine therapy [65]. In addition to these VEGFRtargeted therapies, both temsirolimus and everolimus are already approved for the mRCC patient population and may be appropriate candidates for combination treatment with AGS-003, either in patients with poorrisk disease or in those who have progressed on VEGFtargeted therapy [11,66]. Other small molecules either in the clinical pipeline or approved for other indications, such as the MET inhibitor cabozantinib, which is currently indicated for the treatment of medullary thyroid cancer, or the FGF inhibitor dovitinib, which is being evaluated in active clinical trials for a number of solid tumors, may also serve as capable combination partners in this setting [67,68]. Conclusion & future perspective The introduction of targeted therapies within the last decade has significantly impacted the clinical management and survival outcomes of patients with mRCC. Over the next decade, key research goals will include elucidating and overcoming mechanisms of tumor resistance to VEGF- and mTOR-directed therapies, as well as other multikinase inhibitors. Particular
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A novel personalized vaccine approach in combination with targeted therapy in advanced renal cell carcinoma
attention will be paid to the immuno modulatory effects of these and other novel inhibitors within the mRCC tumor microenvironment as peptide-based and autologous vaccines are increasingly being evaluated within this disease. In addition, therapeutic sequencing of targeted therapies and immunotherapy will be an important consideration for the future development of treatment options because significant attrition of patients occurs across increasing lines of therapy for mRCC [69]. The incorporation of multiple vaccines and targeted therapies within a single line of treatment may be warranted, given their nonoverlapping functional capacity and minimal toxicity. Finally, it will also be important to evaluate financial considerations
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as vaccine therapies are implemented in combination with targeted therapies [70]. Financial & competing interests disclosure RA Figlin receives research funding from Argos Therapeutics, Novartis, Bristol Myers Squibb, Immatics and Exilexis. He is also a consultant for Galena, Pfizer, Onyx, Merck, AP Pharma and Rexahn. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Writing assistance was provided by Cadence Research and Consulting, with funding from Argos Therapeutics.
Executive summary Targeted therapies in metastatic renal cell carcinoma • Immunomodulatory therapies are the historical treatment paradigm for metastatic renal cell carcinoma (mRCC). –– Both IFN-a and IL-2 produced a similar clinical efficacy. –– These treatment options resulted in limited durable responses. • Within the past decade, targeted therapies have radically shifted the treatment landscape for mRCC. –– VEGF inhibitors include bevacizumab, sunitinib, sorafenib, axitinib and pazopanib. –– mTOR inhibitors include temsirolimus and everolimus. –– Inhibitors in development include the VEGF receptor inhibitor tivozanib and the PD-1 inhibitor MDX-1106.
Vaccine immunotherapy • Vaccines are currently being developed to treat a number of tumor types, including mRCC. • Single antigen vaccines –– Single antigen vaccines are being investigated in a variety of solid tumors, including renal cell carcinoma. • Multipeptide vaccines –– Multipeptide vaccines may provide additional benefit and overcome tumor heterogeneity. –– The multipeptide vaccine IMA901 is being investigated in mRCC in combination with cyclophosphamide. • Autologous vaccines –– Autologous vaccines combine a patient’s own dendritic cells and epitopes derived from the patient’s own tumor tissue. –– The autologous vaccine AGS-003 is being investigated in mRCC in combination with sunitinib.
Vaccine & targeted therapy combinations • Rational combinations of targeted therapies with cancer vaccines may provide synergistic clinical benefits and advance the treatment of mRCC through the next decade.
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Dall’Oglio MF, Sousa-Canavez JM, Tanno FY et al. Early experience with targeted therapy and dendritic cell vaccine in metastatic renal cell carcinoma after nephrectomy. Int. Braz. J. Urol. 37(2), 180–185; discussion: 185–186 (2011).
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Finke JH, Rini B, Ireland J et al. Sunitinib reverses type-1 immune suppression and decreases T-regulatory cells in renal cell carcinoma patients. Clin. Cancer Res. 14(20), 6674–6682 (2008).
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Figlin RA, Nicolette CA, Amin A et al. Monitoring T-cell responses in a Phase II study of AGS-003, an autologous dendritic cell-based therapy in patients with newly diagnosed advanced stage renal cell carcinoma in combination with sunitinib. J. Clin. Oncol. 29(Suppl.), Abstract 2532 (2011).
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Demonstrates preclinical justification of the role of sunitinib as an anti-immunosuppressive agent in the context of renal cell carcinoma.
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A Phase IIB/III randomized, double-blind, placebo controlled study comparing first line therapy with or without TG4010 immunotherapy product in patients with stage IV non-small cell lung cancer (NSCLC). http://clinicaltrials.gov/show/NCT01383148
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A randomized, controlled Phase III study investigating IMA901 multipeptide cancer vaccine in patients receiving sunitinib as first-line therapy for advanced/metastatic renal cell carcinoma. http://clinicaltrials.gov/show/NCT01265901
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Pivotal Phase III clinical trial evaluating the combination of targeted therapy with an autologous dendritic cell vaccine in patients with mRCC.
Vasani D, Josephson DY, Carmichael C, Sartor O, Pal SK. Recent advances in the therapy of castration-resistant prostate cancer: the price of progress. Maturitas 70(2), 194–196 (2011).
Immunotherapy (2014) 6(3)
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A novel personalized vaccine approach in combination with targeted therapy in advanced renal cell carcinoma
The historical treatment paradigm for metastatic renal cell carcinoma has focused on immunomodulatory agents, such as IFN-a and IL-2, which provide good clinical outcomes in only a subset of patients. The development of therapies that target the VEGF and mTOR pathways have significantly altered the treatment landscape for this disease, with novel inhibitors providing substantial improvements in progressionfree and overall survival over previous standards of care. Despite these advances, toxicity from targeted therapy and the development of resistance results in disease progression. By contrast, vaccine-based immunotherapy represents a promising new approach for the treatment of patients with metastatic renal cell carcinoma; however, tumor-induced immunosuppression has limited the clinical efficacy of this modality until recently. Some evidence suggests that certain targeted therapies, such as sunitinib, may reduce this immunosuppression and enhance the tumor microenvironment to promote synergy with autologous dendritic cell vaccines.
Robert A Figlin Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Saperstein Critical Care Tower 1S28, Los Angeles, CA 90048, USA Tel.: +1 310 423 1331 Fax: +1 310 659 3928 robert.figlin@ cshs.org
KEYWORDS: AGS-003 • autologous dendritic cell vaccine • immunotherapy • renal cell carcinoma • sunitinib • targeted therapy • VEGF
In 2013, it is estimated that more than 65,000 new kidney tumors will be diagnosed in the USA, with more than 13,000 deaths [1]. Renal cell carcinoma (RCC) is the most common form of kidney cancer and represents approximately 3% of all malignant tumors in adults [2,3]. Historically, immunomodulatory interventions, such as IFN-a and IL-2, dominated the treatment of metastatic RCC (mRCC) [4,5]. This is due, in part, to their clinical efficacy, as well as evidence of immune cell infiltration and antitumor activity in RCC [6,7]. Both IFN-a and IL-2 yield similar objective response rates in patients with mRCC, whereas high-dose IL-2 yields durable responses in a minority of patients [3,8]. However, because of the increased risk of cardiovascular toxicity associated with IL-2, this clinical benefit may only be observed in a limited subset of mRCC patients, although predictive biomarkers may provide a mechanism by which appropriate patients are selected to receive cytokine-based therapy upfront [9,10]. When compared with
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novel targeted therapies, several Phase III trials have shown cytokine-based immunotherapy to be clinically inferior in terms of both efficacy and toxicity [11–13]. As a result, the use of targeted agents for mRCC has become widespread in all lines of therapy. Targeted therapies in mRCC Currently approved targeted therapies for mRCC include bevacizumab, sorafenib, sunitinib, axitinib, pazopanib, everolimus and temsirolimus; broadly, these are now considered standard-of-care treatments for mRCC [3,14]. The addition of these agents to the mRCC armamentarium has radically shifted the natural course of mRCC, increasing the median overall survival (OS) of patients from 10 months to more than 40 months [15]. Given the proangiogenic phenotype of the vast majority of RCC tumors, targeted therapies, to date, have focused on the disruption of the VEGF pathway [16]. These include small-molecule inhibitors of the
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Drug Evaluation Figlin VEGF receptor (VEGFR), as well as the PDGF receptor (PDGFR). Axitinib is a multikinase inhibitor that targets VEGFR-1, VEGFR-2 and VEGFR-3, and is US FDA approved as second-line treatment following tyrosine kinase inhibitor treatment [17,18]. Sorafenib inhibits VEGFR-1, VEGFR-2 and VEGFR-3, as well as PDGFR-b and a number of other kinases, such as FLT-3, c-KIT, RET and RAF. Sorafenib has yielded limited clinical efficacy in the first-line setting of mRCC and modest clinical utility in the second-line setting [3,19]. The Phase III AGILE trial reported no significant difference between sorafenib and axitinib in terms of progression-free survival (PFS) [20]. Sunitinib is a multikinase inhibitor of VEGFR-1, VEGFR2, VEGFR-3, PDGFR-a, PDGFR-b, c-KIT, FLT-3, CSF-1R and RET. Compared with IFN-a in the first-line setting, sunitinib has yielded a statistically superior median OS and PFS [3,21]. Although clinically noninferior to sunitinib in the first-line setting, pazopanib is associated with a possibly more attractive safety and quality-of-life profile [22,23]. The Phase III COMPARZ study compared sunitinib with pazopanib in patients with treatment-naive mRCC and indicated that the two inhibitors yielded a similar clinical efficacy; however, pazopanib had a different toxicity profile [23]. Finally, bevacizumab is a humanized monoclonal antibody that targets the VEGF ligand. In the first-line setting, its combination with IFN-a is statistically superior to cytokine monotherapy in terms of PFS, although not in terms of median OS [24,25]. Clinical trials are currently evaluating the efficacy of several investigational inhibitors, including the novel molecule tivozanib, in patients with mRCC. Tivozanib has a similar molecular target profile to sunitinib, although its activity is more specifically directed at VEGFR-2 [26]. The Phase III TIVO-1 trial, which compared tivozanib to sorafenib, reported that, although patients with mRCC who received tivozanib achieved a statistically longer median PFS than those who received sorafenib, there was no difference in median OS [27]. A Phase III clinical trial (TAURUS) is currently comparing tivozanib to sunitinib in patients with mRCC in the first-line setting [71]. In addition to the preceding novel VEGFR inhibitors, inhibitors of the mTOR pathway, such as everolimus and temsirolimus, are being investigated. These agents target the PI3K/Akt/mTOR pathway, which has been shown to be activated in mRCC and contributes to tumor growth and angiogenesis [28]. Unlike everolimus, temsirolimus has demonstrated clinical efficacy in the first-line setting, yielding a statistically superior median OS and PFS compared with IFN-a, primarily in a poor prognosis group of patients [11].
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Investigational agents targeting the PD-1 inhibitor are also being explored for RCC. Preclinical evidence suggests that inhibition of the PD-1 ligand may be efficacious in treating tumors [29]. The PD-1 inhibitor MDX-1106 has yielded early efficacy in Phase I trials of patients with refractory solid tumors, including mRCC [30,31]. Vaccine immunotherapy It has been known for decades that tumors present immunologically distinct epitopes that can be recognized and targeted by both innate and adaptive components of the immune system [32]. Cancer vaccines have been designed to prompt immune responses to single epitope targets and multiple epitopes from various oncogene products or through autologous activation of host dendritic cells. Single antigen vaccines
TG-4010 is an example of a cancer vaccine designed to target a single epitope from the cell surface protein MUC1, which is expressed at high levels in a number of tumors [33]. Expression of MUC1 is hypoxia inducible factor-dependent and an independent prognostic factor in RCC [34]. This protein may contribute to tumor growth by masking surrounding tumor-associated antigens expressed on the cell surface and confounding normal immunosurveillance [35]. A Phase I trial evaluating TG-4010 in patients with different solid tumors reported T cell-mediated immunity in a subset of patients, and stable disease was transiently achieved in several patients [35]. Ongoing clinical investigations of TG-4010 are underway. A recently reported Phase II trial evaluated TG-4010 alone or in combination with cytokine therapy in patients with mRCC [36]. Although no objective clinical responses to either treatment were reported, a subset of patients in both groups experienced stable disease and T-cell activation to MUC1 epitopes was also observed [36]. A Phase IIb/III placebocontrolled clinical trial is currently evaluating TG-4010 in combination with standard chemotherapy and targeted therapy in patients with metastatic non-small-cell lung cancer in the first-line setting [72]. Another single epitope cancer vaccine, MVA-5T4, is designed to target the oncofetal antigen 5T4, which is expressed at the cell surface primarily in placental tissue, as well as a wide range of tumor tissue, including squamous carcinomas of the bladder, lung and cervix, adenocarcinomas of the stomach and pancreas, and sarcomas [37]. In addition, the expression of the 5TF antigen in the majority of mRCCs has lead to clinical investigation in this area [38]. In Phase I/II trials, MVA-5T4 provoked specific immune responses in patients with colorectal, renal and prostate cancer [38]. The Phase III
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A novel personalized vaccine approach in combination with targeted therapy in advanced renal cell carcinoma
TroVax Renal Immunotherapy Survival trial randomized patients with mRCC to receive either MVA-5T4 or placebo in addition to standard first-line therapy [38]. The efficacy analysis of this trial showed that the addition of the vaccine to standard therapy resulted in no measurable improvement in OS, although a further exploratory analysis may describe more optimal patient subsets for vaccine therapy [38]. Multipeptide vaccines
Multipeptide vaccines provide an advantage over traditional peptide-based vaccines, such as overcoming tumor heterogeneity and promoting a stronger and more comprehensive immune response [39]. IMA901 is an example of a vaccine composed of tumor-associated peptides that are naturally present in human tumors [40]. In clinical trials, patients with advanced RCC receiving IMA901 achieved clear T-cell responses, which have been correlated with improved clinical outcomes, including OS [40]. Interestingly, two serum biomarkers, APOA1 and CCL17, were identified as predictive of both immune response to IMA901 and OS [40]. However, these clinical outcomes were observed to be more pronounced in patients who had also received single-dose cyclophosphamide prior to administration of IMA901, suggesting a synergistic relationship between the two therapies [41]. A Phase III trial evaluating IMA901 in patients with advanced or mRCC is currently ongoing. Patients will be randomized to receive first-line sunitinib with or without GM-CSF-boosted IMA901 and single-dose cyclophosphamide [73]. Autologous vaccines
Rather than challenge the patient’s immune system in situ with cancer-associated epitopes, autologous vaccines rely on ex vivo manipulation of dendritic cells [42]. The first ever autologous dendritic cell vaccine approved by the FDA was sipuleucel-T, which yielded a superior OS in a pivotal Phase III trial of patients with metastatic castration-resistant prostate cancer [43]. The technology of autologous dendritic cell vaccines represents a unique opportunity to use the native function of the immune system to directly stimulate cellmediated immunity through the presentation of a targeted antigen epitope to both CD4+ and CD8+ T cells [44,45]. As dendritic cells are present in nearly all human tumors, they are an attractive target for cancer interventions and immunotherapies [46]. For the development of ex vivo dendritic cell vaccines, the dendritic cells must first be cultured from a preparation of hematopoietic progenitor cells or peripheral blood mononuclear cells (PMBCs) [46]. They may subsequently be treated with various cytokines to selectively grow specific cell subpopulations [46]. Following this, they are exposed to the
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Drug Evaluation
requisite antigens isolated from the patient’s tumor and then treated with adjuvants to promote cell maturation [46]. The tumor antigen-exposed dendritic cells are reinfused into the patient, where they can activate T cells that differentiate into effector cells that antagonize the tumor. Clinical benefit from dendritic cell vaccines has already been reported in patients with RCC. A recent meta-analysis reported a statistically significant objective response rate of 12.7% and a clinical benefit rate of 48% in 166 patients [47]. Vaccine & targeted therapy combinations AGS-003 is an autologous dendritic cell vaccine developed for the treatment of mRCC. It utilizes autologous matured monocyte-derived dendritic cells that are electroporated with amplified mRNA harvested from the patient’s tumor, as well as synthetic CD40L RNA [48,49]. Briefly, the manufacturing process of AGS-003 begins with the isolation of autologous total RNA from tumor tissue acquired by nephrectomy or metastasectomy, followed by selective amplification of mRNA using the reverse transcriptase PCR, as previously described [50,51]. Patient monocytes are harvested at a convenient leukapheresis donor center, and then cultured in vitro with GM-CSF and IL-4 to give rise to immature dendritic cells. These are then fully matured in culture by exposure to TNF-a, IFN-g and PGE2. These mature dendritic cells are electroporated with a combination of the patient’s tumor RNA, as well as CD40L RNA generated in vitro using the protocol described previously [52]. In a typical immune response, dendritic cells interact with activated helper CD4+ T cells in the context of upregulated CD40L, which results in the activation of CD8+ cytotoxic T cells [53]. However, for patients with mRCC, the systemic immunosuppression of the tumor cells leads to significant dysfunction in this process [54]. The intended mechanism of action of AGS-003 is to stimulate an adaptive immune response, which will overcome this dysfunction, integrating the MHC/antigenic interaction, the engagement of costimulatory molecules, such as CD80 and CD86, as well as the intercellular activity of IL-12, which has been shown to increase following electroporation of dendritic cells with CD40L RNA and is a requirement for memory T-cell responses [55,56]. The latter functionality is of critical importance to the activity of AGS-003 because it has been shown to correlate with positive clinical outcomes in patients with solid tumors [57]. Preclinical data have indicated that sunitinib modulates the tumor microenvironment by decreasing Treg function and enhancing immune-mediated antitumor activity [58]. Furthermore, the combination of sunitinib with the vaccine in mouse tumor models has confirmed the downregulation of regulatory immune cells, as well
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Drug Evaluation Figlin as the optimization of intratumoral immune infiltration in vivo [59,60]. In the clinical setting, intriguing results were reported in two patients with mRCC who received sunitinib prior to radical nephrectomy and dendritic cell therapy. In both patients, induction of sunitinib therapy was followed by observation of disease stabilization. Following nephrectomy and dendritic vaccine therapy, both patients also experienced a significant clinical benefit and regression of metastatic lesions [61]. To further capitalize on this synergy in the clinical setting in patients with mRCC, AGS-003 has been recently evaluated in combination with sunitinib. An open-label Phase II trial of AGS-003 in combination with sunitinib enrolled 21 patients with newly diagnosed mRCC with no previous nephrectomy or at least one accessible lesion for metastasectomy. Patients received five doses of the AGS-003 vaccine therapy every 3 weeks, and then every 12 weeks along with standard 6-week cycles of sunitinib until progression [48,49]. The efficacy analysis from this trial showed clinical benefit in the majority of patients enrolled, as well as a median PFS of 11.2 months and a median OS of 30.2 months, which were double the expected survival end points for this patient population [48,49]. Both efficacy end points were shown to be higher among patients with intermediate risk features, as determined by the Heng risk assessment [49]. Building on these data, an international randomized Phase III trial (ADAPT) has been designed to evaluate standard first-line sunitinib therapy with or without AGS-003 in patients with mRCC, to determine if the addition of the autologous dendritic cell vaccine therapy confers a significant improvement in OS [74]. Previous attempts to develop and validate therapeutic cancer vaccines have had limited success, perhaps due to the confounding tumor-driven immunological dysfunction described above. Although dendritic cells are ubiquitous in tumor tissue, normal immune function may be disrupted in the tumor microenvironment, inhibiting the action of effector T cells and antigen presentation [46]. Clinical evidence now suggests that the administration of sunitinib may restore normal immune function in the tumor microenvironment. In a small clinical biomarker trial, patients with mRCC who received sunitinib monotherapy and healthy controls provided PBMCs for analysis. In samples provided from patients who had been treated with sunitinib monotherapy, both a significant increase in effector T cells and a significant decrease in IL-4 production were observed through decreased recruitment of myeloid-derived suppressor cells and Tregs to tumor tissue [62]. Importantly, in a prospective biomarker assessment of the preceding Phase II clinical trial that evaluated AGS-003 in combination
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with sunitinib, PBMCs were assessed for T-cell proliferation using flow cytometry, both prior to and during treatment. Analysis of PBMCs from patients enrolled in the trial showed decreased levels of Tregs and increased levels of CD28+ memory cytotoxic T lymphocytes following treatment with the combination therapy. These changes in the immune context of the patients’ peripheral blood were positively correlated with improved PFS [63]. These findings support the hypothetical synergy of sunitinib with AGS-003 because the combination resulted in clear modifications to the tumor microenvironment and led to enhanced clinical outcomes with the therapeutic cancer vaccine. Although sunitinib appears to be an optimal partner for mRCC-developed autologous dendritic cell vaccines such as AGS-003, available data for alternative targeted therapies show variable suitability. In contrast to sunitinib, preclinical assessment of sorafenib as an immunostimulant molecule showed that, rather than enhancing the immune response, it inhibits the activity of dendritic cells and diminishes their capacity to activate T cells in response to an antigenic challenge. Thus, sorafenib appears to be an immunosuppressant agent that would not likely be an optimal partner molecule for combinations with AGS-003 and similar vaccines [64]. A retrospective analysis of plasma cytokines in patients with mRCC receiving pazopanib reported significantly higher levels of IL-6 correlated with an objective response to therapy, although these data are not yet fully understood and further study is required before pazopanib can be evaluated as a potential combination partner for therapeutic vaccine therapy [65]. In addition to these VEGFRtargeted therapies, both temsirolimus and everolimus are already approved for the mRCC patient population and may be appropriate candidates for combination treatment with AGS-003, either in patients with poorrisk disease or in those who have progressed on VEGFtargeted therapy [11,66]. Other small molecules either in the clinical pipeline or approved for other indications, such as the MET inhibitor cabozantinib, which is currently indicated for the treatment of medullary thyroid cancer, or the FGF inhibitor dovitinib, which is being evaluated in active clinical trials for a number of solid tumors, may also serve as capable combination partners in this setting [67,68]. Conclusion & future perspective The introduction of targeted therapies within the last decade has significantly impacted the clinical management and survival outcomes of patients with mRCC. Over the next decade, key research goals will include elucidating and overcoming mechanisms of tumor resistance to VEGF- and mTOR-directed therapies, as well as other multikinase inhibitors. Particular
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A novel personalized vaccine approach in combination with targeted therapy in advanced renal cell carcinoma
attention will be paid to the immuno modulatory effects of these and other novel inhibitors within the mRCC tumor microenvironment as peptide-based and autologous vaccines are increasingly being evaluated within this disease. In addition, therapeutic sequencing of targeted therapies and immunotherapy will be an important consideration for the future development of treatment options because significant attrition of patients occurs across increasing lines of therapy for mRCC [69]. The incorporation of multiple vaccines and targeted therapies within a single line of treatment may be warranted, given their nonoverlapping functional capacity and minimal toxicity. Finally, it will also be important to evaluate financial considerations
Drug Evaluation
as vaccine therapies are implemented in combination with targeted therapies [70]. Financial & competing interests disclosure RA Figlin receives research funding from Argos Therapeutics, Novartis, Bristol Myers Squibb, Immatics and Exilexis. He is also a consultant for Galena, Pfizer, Onyx, Merck, AP Pharma and Rexahn. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Writing assistance was provided by Cadence Research and Consulting, with funding from Argos Therapeutics.
Executive summary Targeted therapies in metastatic renal cell carcinoma • Immunomodulatory therapies are the historical treatment paradigm for metastatic renal cell carcinoma (mRCC). –– Both IFN-a and IL-2 produced a similar clinical efficacy. –– These treatment options resulted in limited durable responses. • Within the past decade, targeted therapies have radically shifted the treatment landscape for mRCC. –– VEGF inhibitors include bevacizumab, sunitinib, sorafenib, axitinib and pazopanib. –– mTOR inhibitors include temsirolimus and everolimus. –– Inhibitors in development include the VEGF receptor inhibitor tivozanib and the PD-1 inhibitor MDX-1106.
Vaccine immunotherapy • Vaccines are currently being developed to treat a number of tumor types, including mRCC. • Single antigen vaccines –– Single antigen vaccines are being investigated in a variety of solid tumors, including renal cell carcinoma. • Multipeptide vaccines –– Multipeptide vaccines may provide additional benefit and overcome tumor heterogeneity. –– The multipeptide vaccine IMA901 is being investigated in mRCC in combination with cyclophosphamide. • Autologous vaccines –– Autologous vaccines combine a patient’s own dendritic cells and epitopes derived from the patient’s own tumor tissue. –– The autologous vaccine AGS-003 is being investigated in mRCC in combination with sunitinib.
Vaccine & targeted therapy combinations • Rational combinations of targeted therapies with cancer vaccines may provide synergistic clinical benefits and advance the treatment of mRCC through the next decade.
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future science group
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