Therapeutic Cancer Vaccines: How Much Closer Are We?

Abstract

The promise of immune-based therapies to treat cancer has been realized over the last several years with several breakthrough therapies, including T-cell checkpoint inhibitors and CAR-T cell therapies. While cancer vaccines have been investigated for many decades, to date only one has been approved in the U.S. as a treatment for existing cancer. The failure of several anti-tumor vaccines in large phase III trials has led many to question their future role in cancer treatment. Trials to date have demonstrated that many cancer vaccines can elicit tumor-specific T cells, however these T cells may be insufficient to mediate substantial anti-tumor effects without concurrent blockade of tumor resistance mechanisms. Emerging data from preclinical models and clinical trials demonstrate that cancer vaccines have greater activity in low-volume disease and in combination with other immune-modulating therapies, including T-cell checkpoint blockade, targeting these resistance mechanisms. Because T-cell checkpoint therapies likely require the presence or activity of tumor-specific T cells, cancer vaccines may actually be optimal agents to use in combination to enable these therapies to work for greater numbers of patients. Future trials will explore optimal vaccine approaches and antigens that work best in combination treatment approaches and in earlier stages of disease.

1. Introduction

For over a century there has been interest in using the immune system to target malignant cells as a treatment for cancer. That long history has been punctuated with some evidence of activity, leading to the approval of specific cytokines (e.g. IFNα and interleukin-2) for the treatment of melanoma and renal cell cancer, and non-specific immune-modulating therapies (e.g. BCG) for the treatment of superficial bladder cancer. Efforts to generate clinically effective tumor-specific immunity by means of vaccination, however, have largely been unsuccessful, despite evidence of anti-tumor activity in preclinical models. Over the last several years, there have been great strides in the field of cancer immunotherapy due in large part to greater understanding of T-cell signaling and regulation. In particular, the use of T-cell checkpoint inhibitors (anti-CTLA-4, anti-PD-1, and/or anti-PD-L1) has revolutionized the care of patients for melanoma, lung cancer, renal cell cancer, bladder cancer, among others (1–4). In 2010, the first anti-tumor vaccine, sipuleucel-T, was approved for the treatment of advanced prostate cancer (5). These successes led cancer immunotherapy to be deemed the scientific breakthrough of the year in 2013 (6). In 2015, an oncolytic herpes virus, talimogene laherparepvec, delivered as an in situ immunotherapy, was approved for the treatment of melanoma (7). Within the last two months of this writing in 2017, the first immunotherapeutic gene therapy, using autologous T cells engineered to express a chimeric antigen receptor T cells recognizing CD19, was approved as a treatment for B cell malignancies, on the basis of clinical trials demonstrating dramatic and durable eradication of disease (8). Together, all of these advances have furthered enthusiasm in the field to develop other immune-based therapies and apply these therapies in combination with other cancer therapies. The current article will focus on the potential role of anti-tumor vaccines in this quickly developing armamentarium of novel cancer immunotherapies.

2. Anti-Tumor Vaccines - Overview

The concept of anti-tumor vaccination gained enthusiasm nearly 100 years ago following on successes of anti-viral vaccines. Specifically, given the findings that delivery of inactivated viruses could protect individuals from subsequent challenge with live virus, many early efforts attempted to treat patients with inactivated autologous or allogeneic tumor cells to generate tumor-specific immunity. These early attempts did not have much success, and hence later attempts focused on different adjuvants and means to increase the immunogenicity of tumor cells. For example, Dranoff and colleagues demonstrated that engineering tumor cells to secrete GM-CSF enabled them to confer better protective immunity to subsequent tumor challenge (9). This approach has been evaluated as a treatment approach for many different types of cancer, and while early trials demonstrated evidence of clinical activity, randomized phase III trials did not meet endpoints demonstrating superiority over other treatments when used as a single agent (10,11).

2.1 Anti-Tumor Vaccines – Choice of Target

Whole cell vaccine approaches such as those described above have an advantage of being agnostic about the specific target of the immune response, permitting the host to “choose” a relevant antigenic target. However, a theoretical disadvantage is that an immune response elicited with vaccination may be ineffective (targeting an irrelevant antigen) or that a potentially therapeutic immune response may be diluted in the context of concurrent immunization with many other irrelevant antigens. Investigators studying anti-microbial vaccines identified that immunity to specific microbial antigens could confer protective immunity. For example, immunity to the hepatitis B surface antigen (HBsAg) was most associated with protection and resistance to re-infection by hepatitis B (12). This led to the development of recombinant vaccines specifically targeting HBsAg, an approach which simplified vaccine development, and enabled evaluation of antigen-specific immunity as a measure of vaccine efficacy. Coincidentally, protection from hepatitis B by vaccination has led to a worldwide decrease in the incidence of hepatocellular carcinoma (13). Similarly, targeting human papillomavirus by vaccination has led to worldwide decreases in cervical cancer and likely other HPV-driven tumors (14,15). This concept drove the tumor vaccine field for several decades to identify optimal tumor-associated antigens, and to begin prioritizing tumor antigens as targets for vaccines to treat human cancers (16). In addition, the realization from preclinical models that effective anti-tumor immunity was more dependent on T-cell immunity than humoral immunity suggested that vaccination methods needed to demonstrate antigen-specific T-cell immunity. Consequently, efforts to identify preferred immunization approaches, with specific tumor-associated antigens, have dominated efforts in preclinical studies and human trials over the last 20 years. Some early studies have suggested anti-tumor effects, and have led to large randomized trials. One vaccine, sipuleucel-T, an autologous antigen presenting cell vaccine loaded ex vivo with a prostate-associated antigen, prostatic acid phosphatase (PAP), did demonstrate improved overall survival in a randomized, placebo controlled phase III trial, leading to its approval by FDA in 2010 (5). To date, this is the only vaccine approved in the U.S. as a treatment for existing cancer, and it continues to be used to treat patients with advanced prostate cancer. Of note, patients with the greatest survival benefit did have evidence of immune response to the target antigen, consistent with the proposed mechanism of action (17). In addition, retrospective studies have suggested that patients with the greatest degree of benefit were those with lower volume disease (18). Many other cancer vaccines, predominantly peptide-based vaccines, have failed to demonstrate clinical anti-tumor efficacy in phase III trials despite evidence of immunological activity (Table 1). These observations have led many to question whether vaccines will be “successful” as anti-tumor therapies.

Table 1.

Selected Phase III Clinical Trials of Cancer Vaccines Not Completed or Not Meeting Primary Endpoint

Tumor Type	Vaccine	Approach	Clinical Trial Identifier
Breast	Tecemotide	Synthetic lipopeptide derived from MUC1	NCT00925548
	E75	HLA-A2-restricted peptide from HER-2/neu	NCT01479244
	Theratope	Cancer-associated carbohydrate linked to KLH neoantigen	NCT00003638
Glioblastoma	CDX-110	EGFRvIII peptide with GM-CSF adjuvant	NCT01480479
NSC Lung	Tecemotide	Synthetic lipopeptide derived from MUC1	NCT00409188
	GSK1572932A	Peptide vaccine targeting MAGE-A3	NCT00480025
Lymphoma	Idiotype	Ig idiotype conjugated to KLH and given with GM-CSF adjuvant	NCT00089115
Multiple myeloma	MAGE-A3 and NY-ESO-1	Peptide vaccines targeting MAGE-A3 and NY-ESO-1 with GM-CSF adjuvant	NCT00090493
Ovarian cancer	Abagovomab	Anti-idiotype monoclonal antibody mirroring CA-125 antigen	NCT00418574
Pancreatic	GV1001	Telomerase peptide with GM-CSF adjuvant	NCT00358566
	Algenpantucel-L	Allogeneic cell line transfected to express murine α-1,3-galactosyltransferase	NCT01836432
Prostate	Prostvac	Vaccinia expressing PSA prime followed by fowlpox expressing PSA booster immunizations	NCT01322490
	GVAX	Allogeneic prostate cancer cell lines expressing GM-CSF	NCT00089856
Renal	IMA901	Multiple HLA-A2-restricted peptides with GM-CSF adjuvant and cyclophosphamide	NCT01265901
	Oncophage	Autologous tumor-derived heat-shock protein + peptide	NCT00033904

2.2 Anti-Tumor Vaccines – Increasing Immunogenicity

Early failures of anti-tumor vaccines in clinical trials, in many cases with little evidence of systemic immunity elicited to the target antigen, led many investigators to seek to improve the immunogenicity of vaccines, assuming that a higher magnitude of immune cells elicited should confer a better outcome. However, several clinical trials, despite demonstrating evidence of immunity, failed to demonstrate substantial anti-tumor efficacy. Moreover, studies of adoptive immunotherapy, in which high numbers of antigen-specific T cells with demonstrable cytolytic activity could be infused, have similarly demonstrated little anti-tumor efficacy in the absence of pre-conditioning regimens that might deplete the host of immune-suppressive mechanisms (19). Collectively, these findings suggest that anti-tumor vaccines can elicit anti-tumor responses and memory immune responses, and the limitation is not one of eliciting sufficient numbers of the “right kind” of cells, rather that these cells can be inactivated in tumor-bearing hosts. Such findings suggest that anti-tumor vaccines, when used in the context of patients with existing tumors, are unlikely to succeed without accounting for mechanisms of resistance within tumors to avoid immune detection and destruction.

2.3 Anti-Tumor Vaccines – Lessons from Prior Successes

Notwithstanding, anti-tumor vaccines have demonstrated activity in multiple immune-competent animal models. Anti-microbial vaccines have clear efficacy, in some cases leading to the eradication of human disease by preventing infection and spread. So what can be learned from these successes that could be applied to human cancer vaccines? Clearly the greatest difference is that anti-microbial vaccines are not used to treat existing infections, but rather to generate protective immunity to prevent subsequent challenge. In contrast, with few exceptions anti-tumor vaccines have been evaluated in patients with existing disease, and in most cases in patients with large tumor burdens. Most preclinical models have suggested that while vaccines can protect from tumor challenge, they are less effective in treating established tumors (20). This is perhaps obvious, because a hallmark of cancer is the development of mechanisms of evading immune detection, including decreased expression of MHC class I, expression of immunosuppressive cytokines, and infiltration by immune regulatory/suppressive cell populations (21). Thus, using vaccines in combination with efforts to target these mechanisms of resistance would seem logical (22). When tumor vaccines have been evaluated in murine models with established tumors, anti-tumor effects are generally greater when vaccines are initiated with small tumor volumes rather than large volumes (23,24). Fewer clinical trials have been performed in adjuvant settings or settings of minimal residual disease, which would be predicted to be the settings in which vaccines could potentially have anti-tumor activity for established tumors. In addition, with the exception of vaccines targeting MUC1, few studies have been conducted in the preventive setting, a setting in which vaccines might be most expected to have single-agent activity (25).

What can be learned from the successes of other immunotherapy approaches that could be applied to human cancer vaccines? Over the last 5 years, the most dramatic anti-tumor responses have been observed with T-cell checkpoint inhibitors, notably agents targeting CTLA-4, PD-1/PD-L1, and CAR-T cell approaches targeting CD19. These agents interfere with or supplant normal T cell signaling and regulation, suggesting this may be important to the efficacy of vaccine-induced T cells. CTLA-4 blockade timed with vaccination would be predicted to augment the number and proliferation of elicited T cells, and also specifically target regulatory T cells expressing CTLA-4. In fact, murine studies in a transgenic prostate tumor model demonstrated that neither a GM-CSF-expressing vaccine nor CTLA-4 blockade had substantial anti-tumor activity unless used together (26). These findings have been confirmed in human clinical trials for prostate cancer in which GM-CSF secreting vaccines or CTLA-4 blockade did not demonstrate significant anti-tumor activity used alone (27,28), but had more substantial activity when used in combination (29). In the case of PD-1/PD-L1 blockade, these agents presumably require T cells responsive to tumor that express PD-1 to mediate anti-tumor effects. Thus, therapies that can augment tumor-reactive PD-1-expressing CD8+ T cells, including tumor vaccines, would be predicted to improve the efficacy of PD-1/PD-L1 blockade. In fact, in the case of prostate cancer, a disease for which an anti-tumor vaccine has been approved and for which there has been less evidence of single-agent activity of T-cell checkpoint inhibitors, it is perhaps noteworthy that these cancers typically do not have increased numbers of infiltrating T cells relative to tumors like melanomas (30). Consequently, vaccine therapies aimed at increasing the number of tumor-specific T cells, in combination with therapies that can increase their ability to infiltrate tumors and lyse tumor cells, should theoretically be of even greater benefit. Moreover, it is known that PD-1 expression increases with T-cell activation induced by vaccination (31). We have demonstrated that PD-1 blockade at the time of T-cell activation with vaccines can mediate more substantial anti-tumor efficacy in murine models and in patients with advanced, metastatic prostate cancer in an ongoing clinical trial (32–34).

3. Anti-Tumor Vaccines – Components of Combination Immunotherapy

So how do we integrate this information and what is the future for anti-tumor vaccines? First, it is clear that anti-tumor vaccines “work” in that they can clearly elicit or augment immunity to the intended tumor-associated target antigen(s). And the overwhelming data from clinical trials to date is that they are safe and cause few adverse effects. However, vaccines alone have generally not been able to overcome the mechanisms of resistance present within tumors to avoid detection and destruction mediated by vaccine-induced immune cells. Thus it seems clear that these therapies, if not used in a setting of low or absent tumor volume, will need to be used in combination, as has been suggested by others (22,35). Murine studies and early clinical studies have already demonstrated this, and a large part of future research will be to determine optimal agents and sequencing of these agents. It should be highlighted that despite the revolutionary impact of T-cell checkpoint inhibitor therapies, these therapies still only work as monotherapies for a minority of patients. Having existing tumor-specific T cells, and CD8+ T cells in particular, is likely critical to the success of these therapies, at least for PD-1/PD-L1 blockade (36). Hence, it seems logical that agents that can increase the number of tumor-reactive CD8+ T cells should be preferred agents to use in combination with T-cell checkpoint therapies, and potentially increase the number of patients who could benefit from these therapies. While certainly chemotherapy, radiation therapy, hormonal therapy and some small molecule targeted therapies might activate CD8+ T cells and are being evaluated in combination with T-cell checkpoint inhibitors, the ability of vaccines to elicit or augment only tumor-specific CD8+ T cells should be preferable. That is, in addition to the safety of vaccines compared with some of these other therapies, by targeting tumor-specific T cells this should minimize toxicity and increase the likelihood of activating T cells reactive only to tumor. The use of other agents to disrupt physical or vascular barriers, or other immunosuppressive cell populations, within the tumor microenvironment may also be necessary to optimally treat established tumors in combination with vaccines. Second, if cancer vaccines are to be evaluated as single agents, this should be in settings of low or absent tumor volume. This has been in contrast to the general approach of evaluating new cancer therapies for single-agent activity in patients with advanced disease prior to considering combination therapies. Given the safety of vaccines observed to date, it is our opinion that they can be reasonably evaluated in the adjuvant or minimal disease setting. Moreover, single agent studies in these settings permit an evaluation of biological/immune effect over a longer period of time, as we have previously demonstrated, to identify appropriate treatment schedules (37,38). Finally, the optimal vaccine approach(es) and target antigen(s) remains unknown, and will continue to be evaluated in clinical trials. There is currently great enthusiasm to identify tumor-specific mutation-associated neo-epitopes as possible vaccine antigens, based on preclinical studies demonstrating that these are frequently the epitopes recognized by CD8+ T cells “unleashed” by PD-1 blockade (39). It remains unknown, however, whether targeting these epitopes is in fact superior to other non-mutated, shared antigens if similarly delivered in combination with T-cell checkpoint inhibitors or other immune-modulating therapies. This is a critically important question because the most common solid tumors do not have high mutation burdens and may not have identifiable mutation-associated neo-epitopes. Recently, two clinical trials using vaccine approaches targeting mutation-associated neo-epitopes were reported (40,41). In both trials, some patients experienced objective responses, however these individual patients also received T-cell checkpoint inhibitors. Since objective responses have also been observed in patients treated with vaccines targeting shared antigens in combination with T-cell checkpoint blockade (29,42), it remains important to determine if there is an advantage to specifically targeting mutation-associated neo-epitopes. That is, if targeting these neo-epitopes by vaccination with T-cell checkpoint blockade is no better than targeting an “off-the-shelf” antigen with the same T-cell checkpoint blockade, then it may not be reasonable to employ this higher-cost, individualized vaccine therapy.

4. Summary

In summary, cancer vaccines have demonstrated activity in preclinical models, and have been safe, and immunologically active, but demonstrated only modest anti-tumor activity when employed as single agents in clinical trials. While one anti-tumor vaccine has been approved as a therapy for advanced stage prostate cancer, most have not demonstrated superior activity in randomized phase III trials. Data from preclinical models has demonstrated that they have their greatest effect in settings of low or absent tumor volume, suggesting that their best likelihood of success as monotherapies will be as prophylactic treatments, or in adjuvant or minimal residual disease settings. Emerging data from preclinical studies and early clinical trials demonstrate that anti-tumor vaccines can treat established tumors when used in combination with agents targeting tumor mechanisms of resistance. Hence, cancer vaccines for treatment of established tumors will be best used in combination with T-cell checkpoint inhibitors and/or other immune- and tumor microenvironment-modulating therapies. In fact, cancer vaccines may be required to increase the number of patients who could benefit from T-cell checkpoint inhibitor therapies. Over the next several years, clinical trials will continue to explore optimal vaccine approaches and target antigens for use in patients with earlier stages of disease and in combination treatments.

KEY POINTS.

• Cancer vaccines have demonstrated efficacy in eliciting anti-tumor responses in preclinical models, and safety and immune responses to intended target antigens in clinical trials

• Preclinical studies and emerging clinical data suggest that the efficacy of cancer vaccines will likely be greater, and applicable to many cancer types, when used in combination with treatments targeting mechanisms of tumor immune evasion