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CHAPTER 27 COMPONENTS OF THERAPEUTIC

CANCER VACCINES
VACCINE THERAPY Most therapeutic cancer vaccines that are being tested in clinical tri-

als have at least three components: antigenic material derived from
Katayoun Rezvani and Jeffrey J. Molldrem* the tumor, a carrier, and an adjuvant. The antigenic material is usually
a protein or peptide derived from the tumor that is either uniquely
expressed or is overexpressed in the tumor, compared with normal
tissues. A unique tumor antigen or the overexpression of the antigen to
SUMMARY prevent the tumor is necessary to prevent the induction of an unwanted
autoimmune response against normal tissues following vaccination.
Vaccines are biologic substances that are designed to stimulate the host The carrier is necessary for delivery of the tumor antigen to antigen-
immune system to elicit a neutralizing response against clinically relevant presenting cells, such as dendritic cells, so as to induce the immune
targets, including pathogens and tumors. Active immunotherapy with vac- response against the tumor antigen. The third component of a cancer
cines has been extremely effective as prevention against infectious pathogens. vaccine, the adjuvant, is usually a cytokine or other nonspecific immune
However, effective vaccine therapy of chronic infectious diseases or cancer, stimulant to facilitate an enhanced immune response against the tumor
in the therapeutic setting, remains a promising but largely unrealized goal. antigen.
Hematologic malignancies are an excellent model system for vaccine thera-
pies, in part because of accessibility to the hematopoietic and lymphatic space
and susceptibility to immune effector mechanisms and availability of tumor ANTIGEN DISCOVERY
cells for mechanistic studies. Both conventional and novel technologies used to define cancer-
associated antigens, such as serologic analysis by recombinant expres-
sion cloning (SEREX), serial analysis of gene expression (SAGE), screen-
ing tumor complementary DNA (cDNA) libraries with tumor-reactive
T cells, and characterization of peptides eluted from tumor-derived
ADVANTAGES OF CANCER human leukocyte antigen (HLA) molecules, have resulted in a rapidly
growing list of candidate tumor antigens for various hematologic malig-
VACCINE THERAPY nancies (Table 27–1). The majority of these candidate antigens have
been identified since 1998. Furthermore, the application of genomic
Immunity elicited by therapeutic cancer vaccines offers several advan- and proteomic techniques, combined with the feasibility of isolating
tages over passive immunotherapy using monoclonal antibodies. In sufficient quantities of clonogenic tumor cells from individual patients,
active immune therapy, all components of the effector immune response should identify additional targets that are differentially expressed in
are host derived without murine or xenogeneic components that could tumors as compared with normal tissues.
cause indirect toxicity. The lack of foreign components also allows the Desirable characteristics for candidate target antigens for immune
host response to be sustained. Also, if the vaccine contains more than therapy include antigens that are selectively or aberrantly expressed by
a single determinant of the target antigen, the immune response could the tumor or that are required to maintain the malignant cell phenotype
be broad in scope, recognizing more than a single epitope in the antigen or cell survival. Even though the adaptive immune response is com-
(polyclonal). This feature might be of particular importance for cancer prised of both humoral and cellular components, most efforts at tumor
immunotherapy, as mutation of individual peptide epitopes is a possi- vaccination have focused on eliciting T-cell responses because of their
ble mechanism of immune evasion by tumors. In addition to inducing central role in regulating and mediating the overall adaptive response
antibodies, which can recognize intact proteins on the surface of tumor (Chap. 76). Host T-cell recognition of such antigens requires that they
cells, vaccines activate T cells that can recognize peptide fragments are naturally processed and presented by tumor cells into peptides that
derived from proteins that may be endogenously processed and pre- bind host HLA molecules. Optimally, the candidate antigen should
sented on the surface of tumor cells. Such T cells have various effector contain both CD4+ and CD8+ T-cell epitopes. Antigens recognized
mechanisms capable of neutralizing tumor cells, including lysis of the by humoral immune responses must be expressed on the tumor cell
tumor cell by cell-to-cell contact and the local production of cytokines surface, and the relevant epitopes must be accessible to antibody mol-
that might directly neutralize tumor cells (e.g., interferon-γ). ecules. Immunogenic tumor antigens should provoke a strong effector
response and not induce tolerance.
Vaccine therapy does not necessarily require a completely defined
tumor antigen. Vaccines can consist of whole tumor cells or subcellu-
lar components containing putative antigens. For example, autologous
Acronyms and Abbreviations: cDNA, complementary DNA; CTLA-4, cytotoxic tumor cells engineered to overexpress cytokines such as granulocyte-
T-lymphocyte antigen-4; GM-CSF, granulocyte-monocyte colony-stimulating factor; macrophage colony-stimulating factor (GM-CSF), 15,16 or activated
17
HLA, human leukocyte antigen; IL, interleukin; KLH, keyhole limpet hemocyanin; ex vivo by CD40 receptor engagement, can be effective at inducing
PD-1, programmed cell death protein-1; PD-L, programmed death ligand. tumor-specific T cells with as yet undefined antigen specificity. Simi-
larly, transfer of the gene encoding CD40-ligand into chronic lym-
phocytic leukemia cells induced CD4+ and CD8+ T-cell responses in
human patients. Vaccination with membrane proteins extracted from
18
* This chapter was written by Sattva S. Neelpu and Larry W. Kwak in the eighth tumor cells and incorporated into liposomes along with interleukin
edition and portions of that text have been retained. (IL)-2 is another strategy that is in clinical testing. 19

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