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13 Cancer Vaccines
Adrian Bot, Elliot M. Berinstein, and Neil L. Berinstein
THE CONCEPT OF CANCER VACCINES IS system to reshape, direct, and empower it to destroy cancerous
cells. Nevertheless, we anticipate that various therapeutic plat-
ANCHORED IN CLASSICAL VACCINOLOGY forms in immune-oncology, including both vaccines and
The idea of inducing or enhancing an immune response immunotherapy, will be used in conjunction with each other,
against cancerous cells is strongly anchored in the concept of leveraging their strengths and complementing their mecha-
prophylactic vaccination against a number of infectious agents, nisms of action leading to more effective and durable protec-
one of the most important and successful achievements of tion against the disease process. Thus, based on all evidence
medicine. Adequate preexposure of the immune system to a to date, vaccines can no longer be seen as a standalone thera-
truncated or surrogate version of a particularly infectious agent peutic platform, but must be seen as a component of a broader,
reshapes the immune repertoire and enables it to effectively integrated therapeutic armamentarium against cancer that is
counter a subsequent infectious inoculum. Thus, the immune still under development.
system is intrinsically endowed with enough plasticity and
potency to support an efficient antimicrobial vaccination.
A second line of evidence dating back to Coley1 proposed UNDERSTANDING TUMOR IMMUNOBIOLOGY
the concept of enhancing immunity as a means to cope with IS KEY TO DESIGNING EFFICACIOUS
cancer. Anecdotal evidence of tumor regression after an infec-
tion2 or exposure to microbial byproducts3 has been tantaliz-
CANCER VACCINES
ing enough to encourage study of this approach with increasing Several aspects of tumor immunobiology are very important
effort in the field of “cancer vaccines” during the last two to appropriately design cancer vaccines. Until recently, the lack
decades. of adequate understanding of tumor immunology, especially
Nevertheless, even though therapeutic cancer vaccines have mechanisms of immune tolerance and evasion, has hampered
proved challenging, with only one vaccine licensed to date4 cancer vaccine development.
out of hundreds of clinical development programs, the field
of immune-oncology has expanded greatly based on a deeper
understanding of the role of immune system in cancer,5 suc-
Tumor Antigens
cessful clinical application of the concept of immune check- Cancer antigens can be recognized by T cells. Like viral anti-
point blockade,6 and tantalizing evidence of clinical efficacy gens, they are peptides derived from degraded proteins that
of cancer vaccines mediated by tumor antigen-directed T cells.7 are associated with human leukocyte antigen (HLA) mol-
More specifically, cancer vaccine development has been ecules on the surface of APCs.12 Peptides from intracellular
guided by the paradigm of immunity to viruses.8 During a proteins, degraded by the proteasome and bound to HLA class
successful cell-mediated immune response to a viral infection I heavy-chain domains in the endoplasmic reticulum, are rec-
in a target organ, viral antigens are presented to antigen- ognized by CD8+ T cells. Peptides from “endocytosed” mem-
reactive T cells by professional antigen-presenting cells (APCs; brane or extracellular proteins are degraded in endosomes
particularly dendritic cells [DCs]) within secondary lymphoid where they bind to HLA class II proteins and are subsequently
organs. Activated T cells then proliferate and differentiate to recognized by CD4+ T cells.12
cytotoxic T lymphocytes (CTLs) that secrete cytokines, includ- In a few instances, cancers are caused by oncogenic virus
ing interferon (IFN)-γ and tumor necrosis factor (TNF)-α. Acti- infections. In these situations, foreign viral proteins can serve
vated CTLs enter the circulation and are guided to the site of as targets for cancer vaccines. More commonly, DNA damage,
the viral infection by chemokines and adhesion molecules, faulty DNA repair, or aberrant chromosomal rearrangements
where the CTLs kill the virally infected cells by releasing gran- can lead to mutant self-proteins or new breakpoint regions
zymes and perforin or by activating death receptors on the that are found only in tumor cells. These are called tumor-
surfaces of the target cells. For example, in the case of Epstein- specific antigens (e.g., m-Ras, bcr-abl) as they are not encoun-
Barr viral infection9 the magnitude of the CTL response must tered in noncancerous cells. Most recently these have been
be sufficiently strong (on the order of 1 to 10 virus-specific termed neoantigens and may or may not play a role in onio-
CTLs per 100 CTLs) to clear the infection and must be main- genesis. This is in contrast to the broad category of tumor-
tained for a sufficient time (at least weeks to months10) to be associated antigens (TAAs), which also comprise unmodified
effective. The former requirement is usually mediated by high- self proteins that are selectively upregulated or expressed in
avidity T cells and the latter requirement is fulfilled by the cancerous cells (e.g., “cancer-testes antigens”). TAAs may also
induction of memory T cells.11 Cancer vaccines should ideally arise through oncogenic signaling processes that increase the
mimic the same steps as those seen with viral infections (Fig. expression of proteins or polysaccharides that are otherwise
13.1), except that the ultimate targets are cancer cells instead weakly or transiently expressed.13 Because tumor-specific anti-
of virally infected cells. These steps are discussed in more gens are novel proteins they are unlikely to be seen by devel-
detail as they apply to cancer vaccines. oping T cells in central lymphoid organs (which is more
Although the field of immunotherapy is rapidly expanding common with tumor-specific antigens), they do not induce
and diversifying in oncology, our focus in this chapter remains tolerance, and they can be recognized by peripheral T cells.
on “vaccines” that provide exogenous antigens to the immune More details on tumor antigens are provided below.
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13 Cancer Vaccines

Adrian Bot, Elliot M. Berinstein, and Neil L. Berinstein

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