Recent Developments in Cancer Vaccines

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Recent Developments in Cancer Vaccines Karolina Palucka, Hideki Ueno and Jacques Banchereau J Immunol 2011; 186:1325-1331; ; This information is current as doi: 10.4049/jimmunol.0902539 of October 2, 2021. http://www.jimmunol.org/content/186/3/1325

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2011 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Recent Developments in Cancer Vaccines x Karolina Palucka,*,†,‡, Hideki Ueno,* and Jacques Banchereau*,‡,1 TheadoptivetransferofcancerAg-specificeffector T cells are expanded ex vivo and reinfused to patients. Adop- T cells in patients can result in tumor rejection, thereby tive T cell therapy appears to be an effective treatment for illustrating the immune system potential for cancer patients suffering from EBV-associated lymphomas (9) as well therapy. Ideally, one would like to directly induce as solid tumors (10, 11). The alternative strategy is to ex- efficient tumor-specific effector and memory T cells pand tumor-associated Ag-specific T cells in vivo through vac- through vaccination. Therapeutic vaccines have two cination, a procedure of potentially wider use. objectives: priming Ag-specific T cells and reprogramming memory T cells (i.e., a transformation from one Cancer vaccines: lessons from the past and key recent progress type of immunity to another, for example, regulatory Vaccination for the prevention of infectious diseases (12) rep- to cytotoxic). Recent successful phase III clinical trials resents a great success of medicine. One example showing great Downloaded from showing benefit to the patients revived cancer vaccines. promise with regard to cancer is the prevention of human Dendritic cells (DCs) are essential in generation of im- papillomavirus-positive cervical cancer by vaccinating with a mune responses, and as such represent targets and vec- recombinant viral capsid protein (13). The generation of ef- tors for vaccination. We have learned that different DC ficacious therapeutic vaccines faces, however, many hurdles, subsets elicit different T cells. Similarly, different acti- among which the selection of the appropriate target Ags and the vation methods result in DCs able to elicit distinct quality of pre-existing T cell memory appear critical. Target http://www.jimmunol.org/ T cells. We contend that a careful manipulation of ac- tumor Ags include unique (mutated) Ags and shared non- tivated DCs will allow cancer immunotherapists to mutated self-Ags (3, 14). The choice between these types of Ags produce the next generation of highly efficient cancer for vaccination could be viewed as a choice between inducing vaccines. The Journal of Immunology, 2011, 186: immunity (mutated Ags) or breaking tolerance and inducing 1325–1331. autoimmunity (self-Ags). The debate about which type of Ag will be more efficient is ongoing. Mutated Ags have potential advantages, such as the following: 1) their T cell repertoire

he question of whether the natural immune response should not be deleted and they should be recognized as nonself by guest on October 2, 2021 has a role in modulating the progress of spontaneous by the immune system, as is the case with viral Ags; and 2) their T tumors in patients has been debated for many years. potential resistance to negative selection in case the mutated However, it is now accepted that the immune system is able protein is essential for cell survival (14). These Ags often require to control cancer both in mice (1, 2) and humans (reviewed priming. For the sake of broadly applicable vaccines, often the in Ref. 3). Perhaps the most compelling evidence of tumor targeted cancer Ags are nonmutated self-Ags for which 1) the immunosurveillance in humans is provided by the studies in repertoire of high avidity clones might be depleted through breast cancer and paraneoplastic diseases. Onconeural Ags, negative selection (15), and 2) the existing memory T cells which are normally expressed on neurons, can also be ex- might be polarized. These often include regulatory T cells pressed in breast cancer cells (4). Some patients develop a (Tregs), either thymus-derived naturally occurring Tregs strong Ag-specific CD8+ T cell response that controls tumor CD4+CD25high (reviewed in Ref. 16) or periphery-induced expansion, but concomitantly results in autoimmune cerebel- Tr1 cells, which mainly produce IL-10 (17, 18), and Th3 cells, lar degeneration (5), leading to severe neurologic disease. which mainly produce TGF-b (19). Another important com- The molecular identification of human cancer Ags has al- ponent of existing repertoire are Th2 cells (20, 21). Thus, lowed the development of Ag-specific immunotherapy (6, 7) the existing memory repertoire requires reprogramming from based on different approaches. In one approach, adoptive nonprotective immunity toward protective IFN-g–secreting T cell therapy (reviewed in Ref. 8), autologous Ag-specific Th1 cells.

*Baylor Institute for Immunology Research, Baylor University Medical Center, Dallas, Sante´ et de la Recherche Me´dicale. K.P. holds the Michael A. Ramsay Chair for Cancer TX 75204; †Sammons Cancer Center, Baylor University Medical Center, Dallas, TX Immunology Research. J.B. holds the Caruth Chair for Transplant Immunology Re- 75204; ‡Department of Gene and Cell Medicine Immunology Institute, Mount Sinai search. x School of Medicine, New York, NY 10029; and Department of Medicine, Immunology Address correspondence and reprint requests to Dr. Karolina Palucka, Baylor Insti- Institute, Mount Sinai School of Medicine, New York, NY 10029 tute for Immunology Research, 3434 Live Oak, Dallas, TX 75204. E-mail address: 1Current address: Hoffman-La Roche, Inc., Nutley, NJ. [email protected] Received for publication July 6, 2010. Accepted for publication November 10, 2010. Abbreviations used in this article: cDC, classical dendritic cell; DC, dendritic cell; LC, Langerhans cell; PROSTVAC, poxviral-based vaccine targeting prostate-speciﬁc Ag; This work was supported by the National Institutes of Health (P01 CA084514, U19 Treg, regulatory T cell. AIO57234, R01 CA089440, and CA078846), the Dana Foundation, the Susan Komen Foundation, the Baylor Health Care System, the Baylor Health Care System Founda- Ó tion, the Agence Nationale de Recherches sur le SIDA, and the Institut National de la Copyright 2011 by The American Association of Immunologists, Inc. 0022-1767/11/$16.00 www.jimmunol.org/cgi/doi/10.4049/jimmunol.0902539 1326 BRIEF REVIEWS: CANCER VACCINES AND DENDRITIC CELLS

Numerous approaches have been tested for the therapeutic criteria patients need to be taken off the study. Furthermore, vaccination of cancer patients, including the following: auto- tumors might appear clinically enlarged because of inflam- logous and allogeneic tumor cells modified to express various mation associated with active immune responses and lym- cytokines, peptides, proteins, and DNA vaccines (reviewed in phocyte infiltration. Along the same lines, sipuleucel-T and Ref. 22). The clinical results have overall been of limited impact, PROSTVAC failed endpoint of improved progression-free although tumor-specific immune response could be measured survival (30). Yet, the treatment resulted in prolonged me- in some cases. These first generation cancer vaccines have been dian overall survival (30). In all of these studies, the analysis of designed with a limited understanding of the role of dendritic survival curves shows the separation only after 4 mo, and even cells (DCs) in the initiation and regulation of immunity. up to 12 mo, suggesting a delay in the treatment effect, just Cancer vaccines are entering a renaissance era thanks to a as one would expect if efficacy could occur only after the in- series of clinical trials that yielded encouraging clinical out- duction or reprogramming of antitumor immunity. comes. First, treatment of metastatic prostate cancer with Thus, it may be tempting to conclude that overall survival sipuleucel-T (APC8015), a cellular vaccine based on enriched may be the only true parameter of clinical efficacy. However, blood APCs briefly cultured with a fusion protein of prostatic surrogate markers are needed because trials based on overall acid phosphatase with GM-CSF, resulted in ∼4-mo–prolonged survival can be exceedingly long and costly and would prevent median survival in phase III trials (23). Sipuleucel-T has been the performance of innovative trials by academic investigators. approved by the FDA for treatment of metastatic prostate The need for objective, quantifiable response criteria cannot be cancer, thereby paving the clinical development and regula- overemphasized. In this context, a number of studies in small tory path for the next generation of cellular immunotherapy groups of cancer patients demonstrated that a success or failure Downloaded from products. Second, a phase III trial in metastatic melanoma of therapeutic vaccination is correlated with the immune re- testing peptide vaccine in combination with high dose IL-2 sponse to vaccination defined by the expansion of Ag-specific versus IL-2 alone showed significant improvement in overall effector T cells (31). Thus, Ag-specific immune responses response rate and progression-free survival in patients who should remain among the key parameters of efficacy. A better received vaccine (24). Third, a phase III trial in patients with understanding of how effective vaccines, for example, influenza follicular lymphoma showed that idiotype vaccine therapy vaccine or yellow fever vaccine, stimulate protective immune http://www.jimmunol.org/ (BiovaxID) significantly prolongs the duration of chemo- responses (32, 33) might contribute to a better understanding therapy-induced remission (25). Furthermore, a randomized of immune parameters of vaccine efficacy in cancer. phase II trial of a poxviral-based vaccine targeting prostate- specific Ag (PROSTVAC) in men with metastatic castration- Reprogramming the immune system in cancer via DC subsets resistant prostate cancer showed an improved overall survival Understanding of how DCs induce, regulate, and maintain in patients when compared with patients receiving control T cell immunity (12, 34) is essential for the design of novel vectors (an observed difference in median survival of 8.5 mo) cancer vaccines with improved clinical efficacy. Indeed, DCs (26). play a critical role in T cell priming, direct and cross-priming, by guest on October 2, 2021 Naturally, these first successful trials bring many new ques- as evidenced by studies in mice (for review, see Refs. 35 and tions. For example, which APCs are present in the sipuleucel-T 36). DCs also regulate the immune response. Thus, in the product and which APCs are targeted by the poxviral-based steady state, nonactivated (immature) DCs present self-Ags vaccine in vivo? Also, to what extent can the observed im- to T cells, which leads to tolerance through different me- provement in patients’ survival be linked to enhanced pros- chanisms (37). Once activated (mature), Ag-loaded DCs are tatic acid phosphatase-specific T cell immunity? Yet, these geared toward the launching of Ag-specific immunity (38), studies will help define the basic principles of cancer vaccines leading to T cell proliferation and differentiation into helper that set this treatment modality apart from chemotherapy, and effector cells. DCs are also important in launching hu- radiotherapy, targeted therapies, and even adoptive T cell moral immunity partly due to their capacity to directly in- transfer. teract with B cells (39) and to present unprocessed Ags (40). These, and earlier phase I/II studies, bring forward two Two critical features, subsets and functional plasticity, allow critical questions: 1) how to measure vaccine efficacy, and 2) DCs to mount functionally distinct types of responses. The how to define the correlates of therapeutic immunity (27). In two major DC subsets are the classical DCs (cDCs, also this context, a major conceptual shift has recently taken place referred to as myeloid DCs) and the plasmacytoid DCs. in the assessment of clinical efficacy in vaccine and immu- Plasmacytoid DCs are considered the front line in antiviral nomodulation trials (27, 28). Indeed, the use of conventional immunity owing to their capacity to rapidly produce high response evaluation criteria in solid tumor measures to judge amounts of type I IFN in response to viruses (41). cDCs are efficacy has been challenged by recent clinical trials testing composed of subsets displaying different phenotype and anti-CTLA4 (ipilumimab) in patients with stage IV mela- functions. In human skin, epidermis hosts only Langerhans noma. There, in a randomized phase III clinical trial, a 2-fold cells (LCs), whereas the dermis contains two cDC subsets, improved overall survival in patients who received anti- CD1a+ DCs and CD14+ DCs, as well as macrophages (42, CTLA4 with or without Ag was observed, as compared with 43). CD14+ dermal DCs are efficient in the generation of single short-peptide vaccine (29). Interestingly, there were no humoral immunity through different mechanisms (43, 44). In early indications of tumor shrinkage in anti–CTLA4-treated contrast, LCs are potent for priming of high avidity Ag- patients, an observation that might be interpreted as the slow specific CD8+ T cells (45) (Fig. 1). Induction of potent buildup of antitumor immunity. During this phase, tumors CTL response by LCs is observed in mouse studies by s.c. might progress before they actually regress, including the ap- injections of peptide-loaded epidermal LCs (45). Mouse LCs pearance of new lesions, a point at which according to standard can actually cross-present Ags to CD8+ T cells in vivo (46). The Journal of Immunology 1327

sponses; 2) one group showing some immunological response, but no clinical responses; and 3) one group composed of a few patients showing both immunological and clinical responses. These later patients are essential for performing in-depth mechanistic studies that will eventually permit us to under- stand the immune responses that lead to control tumor growth and eliminate established tumors. In the context of ex vivo derived DC-based vaccines, the combination of cytokines used to differentiate monocytes into DCs might play a critical role in determining the quality of the elicited T cell responses. For example, DCs generated with GM-CSF and IFN-a are highly potent in priming T cells (50). DCs generated with GM-CSF and IL-15 display the phenotype and characteristics of LCs. In particular, they are more FIGURE 1. Functional plasticity of DCs: subsets. Human LCs induce + potent CTL responses, possibly via IL-15. At least four lines of evidence efficient in priming melanoma-Ag–specific CD8 Tcellsin indicate that human LCs are remarkable at inducing CTL responses ex vivo: 1) vitro than DCs derived with GM-CSF and IL-4 (51). Thus, + LCs loaded with a MHC class I peptide potently induce the proliferation of vaccination with IL-15 DCs might elicit stronger CD8 Tcell peptide-specific naive CD8+ T cells; 2) LCs expand naive CD8+ T cells with responses that may lead to improved clinical responses. The

+ Downloaded from high avidity against peptide/MHC class I complex; 3) naive CD8 T cells selection of methods for activating DCs also represents a criti- primed by LCs express high levels of cytotoxic molecules, such as granzymes cal parameter in the design of DC vaccines (Fig. 2). Indeed, A, B, and perforin, and display a high cytotoxicity; and 4) LCs are efficient at cross-presentation of Ags. Human CD14+ dermal DCs induce potent hu- injection of immature GM-CSF/IL-4 monocyte-derived DCs moral responses via IL-12. When DCs form the complex with T cells and B results in expansion of Ag-specific IL-10–secreting T cells (52). cells at extrafollicular sites, IL-12 derived from activated DCs promotes B cells These observations yield an explanation for earlier clinical to differentiate into Ab-secreting cells by two different paths: a direct path studies in which peptide immunization in adjuvant was more via DC–B interaction, and an indirect path through induction of IL-21– immunogenic than peptide-pulsed immature GM-CSF/IL-4 http://www.jimmunol.org/ + producing T follicular helper-like cells. Thus, the most efficient CD8 T cell monocyte-derived DCs (53). Injection of mature Ag-loaded vaccines might be those that build on DCs expressing the molecular signatures DCs allows expansion of Ag-specific T cells (54). However, of LCs, for example, IL-15 DCs. not all DC maturation signals are equal. For example, IL-4 DCs activated with a mixture of IFN-a, polyinosinic-poly- In contrast, several mouse studies, for example, models using cytidylic acid, IL-1b, TNF, and IFN-g induce up to 40 times HSV, have questioned the contribution of LCs to the in- more melanoma-specific CTLs in vitro than DCs matured duction of Ag-specific responses in vivo. These studies attri- with the standard mixture of IL-1b/TNF/IL-6/PGE2 (55). bute the HSV-specific immunity to CD8a+ DCs, rather than Studies with the new generation of ex vivo DC vaccines will by guest on October 2, 2021 to LCs (47). Thus, it remains to be determined whether these permit us to assess the type of immune responses elicited by differences with regard to the function of LCs between mice human DCs generated in different cytokine environments and humans derive from the differences in their immune in vivo. systems. Another cDC subset, BDCA-3+ DCs, was recently Another, novel, approach to cancer vaccines via DCs is based proposed to be the equivalent of mouse CD8+ DC subset on the delivery of Ags directly to DCs in vivo using chimeric (reviewed in Ref. 48) that efficiently cross-presents Ags to proteins made of anti-DC receptor Ab fused to a selected Ag CD8+ T cells. (DC targeting). Studies in mice demonstrate that the specific Ex vivo generated DCs have been used as therapeutic vac- targeting of Ag to DCs in vivo results in considerable po- cines in patients with metastatic cancer for over a decade (for tentiation of Ag-specific CD4+ and CD8+ T cell immunity. detailed reviews, see Refs. 34 and 49). It was concluded that The induction of immunity is observed only when the DC DCs can expand T cells specific for nonmutated self proteins maturation signal is provided (56, 57), as, otherwise, tolerance that are overexpressed in cancer. The analysis of immuno- ensues (57). Studies in animal models demonstrate that tar- logical and clinical responses yields three patient groups : 1) geting of tumor Ags to DCs and LCs (58, 59) can induce the one group showing neither clinical nor immunological re- generation of therapeutic antitumor immunity (60, 61).

FIGURE 2. Functional plasticity of DCs: maturation signals. DCs exist in distinct functional states, resting and activated, or immature and mature. Depending on the signal, DCs will undergo activation/maturation, the quality of which will determine the type of elicited adaptive immunity. 1328 BRIEF REVIEWS: CANCER VACCINES AND DENDRITIC CELLS

studies targeting mannose receptor and DEC205 are ongoing. Selection of an appropriate adjuvant is also a critical parameter for the induction of the immunity of the desired type. For in- stance, TLR2 ligation, which promotes the induction of Tregs rather than Th1 or Th17 cells (67), does not appear to be a preferred option for cancer vaccines. Thus, the challenge is to match the molecular target on DCs with the desired immune outcome, mimicking in many ways the natural role of these DC receptors to fine-tune responses appropriate to the infection. It is also likely that targeting distinct DC surface molecules will lead to specific types of immunity. Clinical correlates of such immune responses will require extensive studies over the next decade. The interpretation of these studies will require a deeper understanding of the biology of human tissue resident DCs, FIGURE 3. DC vaccines in combination therapies. Current active im- lymphoid DCs, as well as tumor-infiltrating DCs. munotherapy trials have shown durable tumor regressions in a fraction of patients. However, clinical efficacy of current approaches is limited, possibly because tumors invade the immune system by means of myeloid-derived The quality of immune responses suppressor cells, inflammatory type 2 T cells, and Tregs. To improve the clinical efficacy of immunotherapies, we need to design novel and improved At least four components of the immune response appear Downloaded from strategies that can boost adaptive immunity to cancer, help overcome Tregs, critical for that response to be of therapeutic potential, as and allow the breakdown of an immunosuppressive tumor microenvironment. follows: 1) the quality of the elicited CTLs; 2) the quality This can be achieved by developing combination therapies targeting these three of induced CD4+ Th cells; 3) the elimination and/or non- major components. activation of Tregs; and 4) the breakdown of the immunosuppressive tumor microenvironment. Indeed, the immune

Targeting tumor Ags to human DCs ex vivo can lead to responses elicited by the first generation DC vaccines might http://www.jimmunol.org/ generation of CD4+ T cell (62) and CD8+ T cell (63, 64) not be of the quality required to allow the rejection of bulky responses. The BDCA-3+ cDCs might be of special interest tumors. For example, the induced CD8+ T cells might not with respect to their potential for priming CD8+ T cell re- migrate into the tumor lesions (15, 68), necessitating a better sponses. Importantly, certain lectins, including Dectin-1 and understanding of the trafficking into tumors of the elicited DC-specific intercellular adhesion molecule-3–grabbing non- effector T cells. Furthermore, low avidity CD8+ T cells might integrin, as well as other DC surface molecules (e.g., CD40), not be able to recognize peptide-MHC class I complexes on also provide activation signals (65, 66). They can thus be tumor cells and/or to kill them (15). Ideally, elicited CD8+

exploited for both Ag delivery and activation pathway in T cells should express high levels of granzyme and perforin, by guest on October 2, 2021 a single targeted vaccine. The therapeutic success of these molecules essential for cytotoxic activity against cancer cells vaccines will build on the recent knowledge and progress in (15, 43). Finally, the tumor microenvironment might inhibit our understanding of the biology of human DC subsets, cu- effector CD8+ T cell functions, for example, by action of taneous cDCs in particular. myeloid-derived suppressor cells and Tregs as summarized in A major challenge of this approach will be to elicit T cell recent reviews, respectively (69, 70). responses that are sufficiently robust and long lasting so as to Besides the quality of CD8+ T cells, the quality of CD4+ be clinically active. Indeed, the efficacy of DC targeting in vivo T cells represents another key parameter of immune efficacy needs to be established in clinical trials in patients, and early for antitumor immunity (71). CD4+ T cells act through dif-

FIGURE 4. Approaches to DC-based immune intervention in cancer. 1) Vaccines based on Ag with or without adjuvant that targets DCs randomly. That might result in vaccine Ags being taken up by a “wrong” type of DCs in the periphery, which might lead to “unwanted” type of immune response. Vaccine Ags could also flow to draining lymph nodes, where they can be captured by resident DCs. 2) Vaccines based on ex vivo generated tumor Ag-loaded “artificial” DCs that are injected back into patients. 3) Specific in vivo DC targeting with anti- DC Abs fused with Ags and with DC activators. 4) Next generation clinical trials will test optimized DC vaccines combined with patient-adjusted approaches to block Tregs and to break down the tumor environment. These therapies will be tested in preselected patients, thereby leading to personalized therapy. The Journal of Immunology 1329 ferent mechanisms, including the following: 1) provision of functional effector CD8+ T cells able to reject tumors and help in the expansion of tumor Ag-specific CTLs (72); 2) long-lived memory CD8+ T cells able to prevent relapse. The activation of macrophages at tumor sites (73); and 3) active capacity of LCs and CD14+ DCs to preferentially prime, killing of tumor cells (74). Furthermore, it is now well es- respectively, cellular immunity and humoral immunity has tablished that Ag-specific CD4+ T cells are fundamental for significant implications, most particularly in the context of the induction of long-term memory CD8+ T cells (75). How- novel cancer vaccines. Therapeutic vaccination in patients ever, CD4+ T cells can also be detrimental. There, regulatory/ with nonresectable metastatic cancer will require combination suppressor T cells dampen elicited CD8+ T cell responses therapies. These will be tailored to the patient and to the (17). Furthermore, type 2 cytokine-secreting CD4+ T cells specific suppressive pathways that the patient displays. These counteract antitumor immunity by promoting tumor devel- pathways will be determined using system biology approaches opment (21) and/or by polarizing tumor-associated macro- incorporating genomic studies on blood and tumor samples, phages (76). Clearly, understanding DC biology in tumor as well as polychromatic flow cytometry and assessment of Ag- environment will provide rationale for their modulation, be it specific T cell repertoire (88, 89). Lessons learned from the with targeting Abs or with adjuvants. This in turn will allow current studies will lay the ground for preventive vaccination, reprogramming of the immune environment at the tumor for example, in neoadjuvant setting. site, thereby facilitating tumor rejection. Acknowledgments Combining cancer vaccines with other therapies This work is dedicated to patients and volunteers who participated in our stud- Downloaded from In view of the remarkable diversity of regulatory/suppressive ies. We thank former and current members of the Institute for their contribu- tions and the following people in particular: Joseph Fay, Lee Roberts, Gerard pathways present in patients with metastatic cancer, any du- Zurawski, and Virginia Pascual. Due to space limitation, we could cite only rable clinical response elicited by vaccination is already an selected papers. achievement. However, to improve the outcomes, DC vaccines will need to be combined with other therapies that might target various components of tumor development, such as tumor cell Disclosures The authors have no financial conflicts of interest. http://www.jimmunol.org/ apoptosis, angiogenesis, tumor stroma, and inflammation, to offset the suppressive environment created by tumors (22). Such combination regimens will involve several intervention References 1. Shankaran, V., H. Ikeda, A. T. Bruce, J. M. White, P. E. Swanson, L. J. Old, and strategies that target different pathways (Fig. 3). R. D. Schreiber. 2001. IFNgamma and lymphocytes prevent primary tumour de- In particular, blocking Abs or soluble receptors can be velopment and shape tumour immunogenicity. Nature 410: 1107–1111. exploited for the blockade of cytokines in the tumor micro- 2. Dunn, G. P., A. T. Bruce, H. Ikeda, L. J. Old, and R. D. Schreiber. 2002. Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol. 3: 991– environment that either suppress the effector T cells directly 998. or act via macrophages and myeloid-derived suppressor cells. 3. Finn, O. J. 2008. Cancer immunology. N. Engl. J. Med. 358: 2704–2715.

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