Principles of Anticancer Drug Development

Abstract

Chapter 26 / p53 Vaccines 491 26 p53-Based Immunotherapy of Cancer Albert B. DeLeo, PhD CONTENTS INTRODUCTION CANCER VACCINES PRECLINICAL MURINE STUDIES OF P53-BASED IMMUNOTHERAPY PRECLINICAL DEVELOPMENT OF P53-BASED IMMUNOTHERAPY CRITICAL ISSUES AND CONCERNS THAT CONFRONT THE CLINICAL INTRODUCTION OF P53-BASED CANCER VACCINES CLINICAL TRIALS OF P53-BASED IMMUNOTHERAPY OF PATIENTS WITH CANCER SUMMARY ACKNOWLEDGMENTS REFERENCES SUMMARY In recent years, there has been an increasing awareness that the immune system, in particular the T-cell component, plays a significant role in tumor eradication. Advances in molecular immunology and identification of T-cell-defined human tumor antigens have accelerated the development of vaccines to promote T-cell-mediated antitumor immune responses. In general, many shared human tumor antigens are derived from proteins overexpressed or derepressed in tumors relative to normal cells. Alteration in the tumor suppressor gene product, p53, is one of the most common events in human cancers, but mutant p53-based immunotherapy would require “custom-made” vaccines for use in relatively few patients. Because most mutations in p53 are associated with accumulation or “overexpression” of mutant p53 in the cytosol, the protein is more readily available for antigenic processing and presentation than are the low levels of p53 molecules expressed in normal cells. A vaccine targeting wild-type sequence (wt) or nonmutant sequence peptides derived from altered p53 molecules, therefore, is a more attractive approach for developing broadly applicable cancer vaccines. Extensive preclinical murine tumor model studies using peptide-based and DNA vaccines have demonstrated that wt p53-based vaccines can induce tumor eradication in the absence of deleterious antitumor autoimmune side effects. Like any T-cell-based immunotherapy, effective p53-based immunotherapy will be dependent on patients’ responsiveness to wt p53 peptides and the ability of their tumors to present these pep- tides for T-cell recognition. These and other issues and concerns related to p53-based