Peptide-Based Cancer Vaccines

Leukemia (2002) 16, 970–971  2002 Nature Publishing Group All rights reserved 0887-6924/02 $25.00 www.nature.com/leu

BOOK REVIEW Peptide-Based Cancer Vaccines Edited by W Martin Kast 239 pages, ISBN 1-58706-026-4 Hardcover price $119; Website price $95 Landes Bioscience Medical Intelligence Unit series Leukemia (2002) 16, 970–971. DOI: 10.1038/sj/leu/2402436 Cancer is a major health concern worldwide. To date, the morbidity and mortality associated with cancer is second in frequency only to heart disease. With increases in effective management of heart disease and projected increases in average life expectancy, cancer looms as the number one health concern for the near and distant future. Although many malignancies are clinically managed quite effectively with what has become conventional therapy, the most common and life-threatening cancers such as lung, breast and prostate have presented clinicians and scientists with the ongoing challenge of developing more effective and curative treatments. Surgery, where appropriate, remains a leading treatment for many cancers. Less invasive therapies have historically been divided into chemical and radiological. When employed individually or in combination, surgery, chemotherapy and radiation therapy have proven successful in treating many forms of cancer. The sometimes life-threatening side-effects associated with chemotherapy and radiation therapy have left oncologists and cancer researchers searching for new approaches to treat cancer. Immunotherapy, the active harnessing of the power of the immune system and its focused ability to destroy cancer cells, is at the forefront of experimental cancer therapies. Although many approaches based on the employment of immune cells or immune molecules to treat cancer have been and are being studied, active immunization is likely the most promising. The notion of vaccinating to treat cancer, that is the administration of a therapeutic vaccine, is not new. Researchers have studied and debated the possibility of vaccinating against cancer for decades. Only in recent years has the debate changed from being focused on pre-clinical proofof-principle to discussions on what defines a tumor antigen and how best to optimally deliver vaccines based on defined antigens to induce anti-cancer immunity. Vaccines consisting of peptides derived from the protein sequence of candidate tumor-associated or specific antigens represent the tip of the anti-cancer vaccine spear. In the book Peptide-Based Cancer Vaccines, Dr Kast has assembled the work of many of the pioneers in the field into a text that will prove valuable to all who claim the moniker of cancer vaccinologist. As Dr Kast suggested in the preface of the book, peptide-based cancer vaccines were among the first defined vaccines demonstrating both protective and therapeutic efficacy in animal models and currently comprise the majority of clinical trials addressing the biological therapy of

Correspondence: RK Bright, Robert W Franz Cancer Research Center, Earle A Chiles Research Institute, Portland, OR, USA; Fax: 1 503 215 6841 Received 21 August 2001; accepted 17 December 2001

cancer. Peptide-Based Cancer Vaccines provides a detailed account of research describing how to identify candidate peptides, what makes up a peptide-based vaccine, what has been learned about delivery of peptides, and strategies for improvement of delivery. It also includes data from clinical trials based on peptide-formulated vaccines and future directions for improving the efficacy of peptide-based cancer vaccines. So, why peptides? The vast majority of published pre-clinical studies have demonstrated the requirement of T-lymphocytes for the eradication of solid tumors. Cytotoxic T-lymphocytes (CTLs) or CD8+ T cells, represent the primary effector cells involved in tumor-specific immune-mediated destruction of cancer cells. CTLs recognize, engage and destroy targets cells through the tri-molecular interaction of the antigen-specific receptor (TCR) on the CTL and peptides that are presented by the target cell to the CTL in the context of class I major histocompatibility antigens (referred to in people as human leukocyte antigens or HLA). All somatic cells in the human body express HLA molecules on their surfaces under normal circumstances. A cell uses HLA molecules to give the immune system an external view of the internal contents of the cell by enzymatically digesting whole proteins within the cell into small peptide fragments (eight to 10 amino acids in length) then displaying this peptide library on its surface in the context of HLA molecules, thus enabling CTLs to recognize aberrant changes (tumor-associated antigens) in the cell that are indicative of malignant transformation. This survey allows for the recognition of cancer cells as dangerous and results in the targeted destruction of the cancer cell by the CTL. All cancer cells arise from a normal somatic cell, therefore most primary cancers express adequate amounts of HLA molecules and are capable of being recognized and destroyed by tumorassociated antigen (TAA)-specific CTLs. If one could identify the specific peptides that mark the tumor as ‘dangerous’ and reintroduce them in increased concentration to the immune system via vaccination, then it may be possible to activate and deploy the appropriate CTLs to destroy the original cancer cells. How does one identify peptides that may be developed as anti-cancer vaccines? The most often used approaches for tumor-derived peptide discovery include cloning of cDNAs that encode TAAs that are recognized by CTLs followed by the use of computer algorithms to predict candidate peptide epitopes from the known amino acid sequence of the TAA, elution of peptides from the HLA on the surface of tumor cells followed by sequencing of the peptide, and what has been referred to as ‘reverse immunology’. The latter approach uses molecular methods such as serial analysis of gene expression (SAGE) or differential display RT-PCR to identify genes expressed differentially between tumor and normal cells. Sequencing of these expressed genes enables the determination of a likely amino acid sequence of the candidate TAA protein that can then be applied to algorithms to predict peptides from the amino acid sequence that may bind to an HLA of interest. The opening chapter in Peptide-Based Cancer Vaccines addresses the issue of peptide epitope identification and subsequent evaluation of the immunogenicity of the candidate peptides using methods of in vitro immunization of cultured T cells and various immunologic readout assays. To elucidate the potential of peptide-based cancer vaccines

Book review

derived from TAAs, Kast has included chapters from some of the leading investigators in the field to include seminal work from his group on peptide-based cancer vaccines for cervical carcinoma. These contributions include discussions on the studies of some of the prototypical TAAs to include mutated Ras, HER-2/neu, the tumor suppressor p53 and CEA. Several chapters cover the evaluation of peptide-based vaccines for each of these TAAs in both pre-clinical models and clinical trials for human cancers of the colon, breast and lung. Some of the best-known tumor-specific antigens are the E6 and E7 gene products from HPV 16 and their association with the majority of human cervical carcinomas. Pioneering work, from basic science through ongoing clinical trials, on the evaluation of E6 and E7 as vaccines for this lethal human malignancy, was also detailed concisely in the text. Though these tumor antigens represent some very important targets for immunologic intervention in human cancer and are among the first studied in this context, thus paving the way for future studies and advances in the field, the majority of human tumor antigens being studied to date have been cloned from malignant melanoma. Several melanoma TAAs have been identified and are being evaluated as peptide-based cancer vaccines in clinical trials around the world. In general, the melanoma antigens can be divided into two main categories. One group includes the MAGE, BAGE and GAGE gene family of TAAs, also referred to as cancer testis antigens, which are expressed on melanomas and a variety of other tumors including lung cancers, but not on normal cells (the exception are the testes). The second group is comprised of normal melanocyte, nonmutated differentiation or lineage antigens (involved in skin pigmentation), which include tyrosinase, MART-1, gp100 and tyrosinase-related proteins-1 (TRP-1) and 2 (TRP-2). Several tumor antigens from each of the groups are currently being evaluated in clinical trials as therapeutic vaccines for melanoma. Since trials for the immunologic intervention of melanoma based on melanoma TAAs have become the standard bearer for the field of cancer vaccinology, several chapters from experts in melanoma vaccines have been appropriately included. Recent advances in the field of molecular biology have enabled the rapid identification of dozens of candidate TAAs for several important human cancers. The challenges for future studies are to determine the most efficient means of administering the vaccine and to develop methods to determine if the vaccine is effective. Acknowledging these important challenges, Kast has included chapters with discussions on methods of peptide delivery that include soluble peptide in adjuvant, DNA based vaccines containing genetic sequences that encode the protein and/or peptide(s) of interest, recombinant viral vectors that carry the TAAs, and injection of dendritic cells that have been engineered to express

the TAA or have been simply coated with synthetic peptides. With the clinical administration of therapeutic cancer vaccines comes the challenge to evaluate the induction of immunity in the patients following immunization and correlation of that immunity to tumor rejection. This task has evolved into the sister field of immunologic monitoring. A few of the chapters that focused on the clinical application of peptide-based vaccines included limited discussion on monitoring patients’ immune responses to the vaccine. It is becoming clear that multiple immunologic assays are needed to ensure the appropriate evaluation of immunity in a patient following vaccination. The ELISPOT assay is an immunologic monitoring method for the elucidation of the frequency of T cells in the total lymphocyte population of the patient that specifically recognize the immunizing antigen. Two additional monitoring assays based on flow cytometry are peptide loaded HLAtetramer staining of T cells and intracellular staining of immune cytokines such as IFN-␥ expressed in T cells, following stimulation with the immunizing antigen. A limitation of tetramer staining is the availability of purified tetramers that represent all the HLA molecules of interest in a given patient population. To generate information critical for continued advances in anti-cancer vaccine development, it will be necessary for future vaccine trials to include a strong immunologic monitoring component. Cancer vaccine development is becoming more complex and challenging with each advance in the field. It ranges from the molecular characterization of candidate vaccine antigens or peptides, to formulation of an optimal vaccine, to administration and monitoring of the vaccine in ‘appropriately’ designed clinical trials. It would be a Herculean task to attempt to compile all that has been and is being studied in the field of cancer vaccinology into a single manageable text. In this light, discussions of immunologic escape by tumor cells, tolerance of the immune system to the vaccine, and the menace of the possible induction of autoimmunity following immunization with TAAs are absent or lightly covered. However, as Dr Kast pointed out in the preface, the aim of the publication was to pay tribute to key researchers in the field of peptide-based cancer vaccine development. Peptide-Based Cancer Vaccines does just that and provides a valuable compilation of much of the groundbreaking work done in the field from basic science to clinical trials. Though rather technical for the newcomer and somewhat lacking in its coverage of a few application-focused topics such as immunologic monitoring, Peptide-Based Cancer Vaccines should prove to be a well used and often cited reference for those actively pursuing the development of anti-cancer vaccines.

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RK Bright Robert W Franz Cancer Research Center Earle A Chiles Research Institute, Portland, OR, USA

Leukemia