Vaccines and active immunization against cancer

Introduction

Immunotherapy has now emerged as one of the most promising therapeutic approaches to treat cancer. Evidence that the immune system can recognize human cancer and that this recognition can be therapeutically leveraged to control, and even eradicate, widespread cancer has highlighted the power and promise of the immunotherapeutic approach. Antibodies that inhibit immune checkpoint pathway proteins (Programmed Cell Death Protein 1 (PD-1), Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA-4), Lymphocyte Activation Gene 3 (LAG3)) have now demonstrated antitumor efficacy and are U.S. Food and Drug Administration (FDA)-approved for use in melanoma, renal cell carcinoma (RCC), colorectal cancer (CRC), non-small cell lung carcinoma (NSCLC), and Hodgkin lymphoma (HL), among other cancers. Engineered T cells equipped with chimeric antigen receptors (CARs) are FDA-approved for hematologic malignancies including acute lymphoblastic leukemia (ALL), B-cell lymphoma, follicular lymphoma (FL), mantle cell lymphoma, and multiple myeloma. Yet because these approaches undoubtedly represent merely a fraction of the myriad ways through which the immune system controls cancer and could potentially be future therapeutic cudgels, immuno-oncology appears to be in its infancy, with a bright future.

The success of immune checkpoint inhibitors (ICIs) and CAR T cells notwithstanding, what has emerged is that these immunotherapy strategies appear to be successful in only certain tumor types. The impressive results obtained with CAR T cells have appeared restricted to hematologic cancers, and these successes have not so far extended beyond liquid cancers to solid tumors. Similarly, though ICIs have shown broader efficacy across multiple solid and some liquid tumors, their success appears to be mostly restricted to the so-called hot tumors—tumors with greater inherent antigenicity (for instance, due to a higher mutational burden or viral transformation)—which provoke baseline antitumor immune responses that are subsequently disinhibited by ICIs. In fact, ∼80% of cancers appear to be “cold” given lower inherent antigenicity; because they thus provoke weaker baseline antitumor immune responses, they remain insensitive to ICIs.

Thus it is likely that cold tumors, which comprise the majority of current cancers, fail to mount sufficient endogenous antitumor immune responses to render them sensitive to ICIs. ^, Such cold tumors hence appear halted at an early stage of an immunologic incline ( Fig. 9.1 ) and therefore may require therapies that activate immunity rather than release immune suppression. Cancer vaccines represent one promising strategy to activate immunity.

Cancer vaccines

Vaccination is arguably the most important breakthrough in the history of medicine. Vaccines have proven highly effective in preventing infectious diseases caused by viruses or bacteria and have saved hundreds of millions of lives by protecting from, and even eradicating, several deadly infectious diseases such as smallpox, polio, and diphtheria. The success of vaccination stems from its ability to therapeutically harness the inbuilt circuitry of immunologic memory against foreign antigens, namely, that when the human immune system encounters a foreign antigen, it not only rapidly activates immune cells to expand and clear the threat but empowers a subset of these cells to persist long term in the absence of the antigen to reexpand with subsequent exposures. Thus prophylactic exposure to the antigen (i.e., vaccination) activates this circuitry to protect against a future foreign encounter. It remains simple, elegant, and highly effective.

Despite the proof that the immune system protects not only against foreign infectious agents but also oncogenically transformed host cells, unlike vaccination against pathogens, vaccination against host cancer cells has proven significantly more challenging. Though several factors contribute to this challenge, the central hurdle with cancer vaccination has remained the difficulty of choosing optimal tumor antigens for vaccines. Unlike pathogens, tumor cells are intrinsically host cells; thus the majority of proteins in tumors are “self” and hence restricted by central tolerance with their cognate T cells thymically deleted during development. Thus an optimal tumor antigen for a vaccine must be both tumor specific and sufficiently “nonself” to escape central tolerance and allow antigen-specific T cells to escape thymic deletion, enter the peripheral repertoire, and expand upon antigen delivery. Furthermore, given that cancers are genetically heterogeneous collections of transformed cells (more akin to a clade of viruses), further raises the possibility that different oncogenic clones may possess different antigens. These characteristics impose two requirements to identify optimal cancer vaccines: specificity, namely, to discover cancer-specific antigens that are absent from the host proteome during T-cell development, and heterogeneity, namely, to identify cancer antigens that are both sufficiently abundant and antigenic across cancer cell clones and subclones. This necessitates individualized comparisons of tumor and normal host cell genomes and proteomes to identify optimal targets, which has for decades remained technically challenging.

However, breakthroughs in next-generation sequencing technology have made significant advances in this regard—now, comparison of entire genomes of tumor and normal cells is possible. Such analyses have unveiled that most cancers accumulate mutations as they grow, and a fraction of these mutations can generate novel protein sequences completely absent from the human proteome. These “neoantigens” are absent in normal tissues, escape central tolerance to T cells in the thymus, and become T cell targets in cancers. Next-generation sequencing advances have also revealed that T cells recognize neoantigens in cancer (for an in-depth review, see Schumacher et al. ) and induce the success of clinical immunotherapies. Tumors with more immunogenic or “high-quality” neoantigens correlate with greater patient survival ^, and response with immune checkpoint inhibitors in multiple cancers. Neoantigen-specific T cells induce these clinical responses as well as responses with transfer of autologous tumor-infiltrating T cells. Thus neoantigens have emerged as specific and fundamental immunogenic by-products of cancer pathophysiology, and thus are highly attractive targets for cancer vaccines. Nevertheless, generating effective long-lasting immune responses through vaccination against a tumor has proven much more challenging compared with viruses or other infectious agents because of different factors that will be discussed in subsequent sections.

Antigen choice

A central requirement to develop an effective cancer vaccine is to choose an appropriate antigen. An ideal cancer vaccine antigen would have following ideal characteristics:

• 1.

  High immunogenicity (less/not restricted by central tolerance)

• 2.

  Tumor specificity

• 3.

  Homogeneity across

  • (a)

    cancer clones

  • (b)

    patients with cancer.

In this regard, tumor antigens can be categorized under two groups: (1) tumor-associated antigens (TAAs) and (2) tumor-specific antigens (TSAs) ( Table 9.1 ).