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INTRODUCTION

SUMMARY

Vaccines are biologic substances that are designed to stimulate the host immune system to elicit a neutralizing response against clinically relevant targets, including pathogens and tumors. Active immunotherapy with vaccines has been extremely effective as prevention against infectious pathogens. However, effective vaccine therapy of chronic infectious diseases or cancer, in the therapeutic setting, remains a promising but largely unrealized goal. Hematologic malignancies are an excellent model system for vaccine therapies, in part because of accessibility to the hematopoietic and lymphatic tissue, tumor susceptibility to immune effector mechanisms, and availability of tumor cells for mechanistic studies.

Acronyms and Abbreviations

APC, antigen presenting cell; cDNA, complementary DNA; CTLA-4, cytotoxic T-lymphocyte antigen-4; DC, dendritic cell; ELISA, enzyme-linked immunoabsorbent assay; ELISPOT, enzyme-linked immunospot assay; GM-CSF, granulocyte-monocyte colony-stimulating factor; HLA, human leukocyte antigen; IFN, interferon; IL, interleukin; KLH, keyhole limpet hemocyanin; mRNA, messenger RNA; PD-1, programmed cell death; protein-1; PD-L, programmed death ligand, RT-PCR, reverse transcriptase polymerase chain reaction; PR1, pathogenesis-related protein 1;SAGE, serial analysis of gene expression; SEREX, serologic analysis by recombinant expression cloning; TCR, T-cell receptor; Th, T-helper; WT1, Wilms tumor 1 protein.

ADVANTAGES OF CANCER VACCINE THERAPY

Immunity elicited by therapeutic cancer vaccines offers several advantages over passive immunotherapy using monoclonal antibodies. In active immune therapy, all components of the effector immune response are host derived without murine or xenogeneic components that could cause indirect toxicity. The lack of foreign components also allows the host response to be sustained. Also, if the vaccine contains more than a single determinant of the target antigen, the immune response could be broad in scope, recognizing more than a single epitope in the antigen (polyclonal). In the setting of T-cell immunity, vaccines that use whole-cell lysates and proteins elicit immune responses that are not restricted by the human leukocyte antigen (HLA) of the recipient, thereby allowing for immune responses targeting the most dominant epitopes for the cognate HLA. This feature might be of particular importance for cancer immunotherapy because mutation of individual peptide epitopes is a possible mechanism of immune evasion by tumors. In addition to inducing antibodies, which can recognize intact proteins on the surface of tumor cells, vaccines activate T cells that can recognize peptide fragments derived from proteins that may be endogenously processed and presented on the surface of tumor cells. Such T cells have various effector mechanisms capable of neutralizing tumor cells, including lysis of the tumor cell by cell-to-cell contact and the local production of cytokines that might directly neutralize tumor cells (eg, interferon-γ). Last, unlike approaches that use passive immune responses, which are often transient, cancer vaccines can elicit memory immune responses that are critical for controlling disease relapse.

COMPONENTS OF THERAPEUTIC CANCER VACCINES

Most therapeutic cancer vaccines that are being tested in clinical trials have at least three components: antigenic material derived from the tumor cell, a carrier, and an ...

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