There have been various attempts throughout the decades to produce a vaccine for human cancer. Most of the efforts have involved using irradiated or killed tumor cells together with an adjuvant, in the hope that an immune response to the presumed tumor antigens will give rise to either humoral or cellular immunity and, hence, eradicate the tumor. The studies have been directed toward the common cancers, such as breast, colon and melanoma, and have been based on the assumption that tumors carry a specific cell-surface component that could be antigenic, and what is needed is to boost the immune system to make an appreciable immune response. Unfortunately, the description of such tumor antigens are few and far between, and while apparently specific antigens have been detected with murine monoclonal antibodies, such as α-fetal protein and carcinoembryonic antigen, there have been few recorded antigens that are recognized as unique to tumor cells. Thus, the mystical tumor antigens are either weak or not present at all. This is not an unexpected finding, since mutations leading to the expression of highly immunogenic surface antigens that can stimulate the immune system would eradicate these tumor cells before they ever came to clinical attention – the concept of immune surveillance, which, in itself, is controversial, but at least serves to keep the concepts of immunotherapy alive and well.
More recent efforts in immunotherapy have given a firmer definition of cellular antigens, which may not be solely tumor specific but are at least present in a greater amount and in a different cell distribution in human cancers – particularly the realization that in order to be targets for T cells, the new antigens have to be presented in association with MHC class I molecules. The new molecules expressed exclusively inside cells, such as oncogene products, can appear on the cell surface by mutation and are targets for cytotoxic T lymphocytes (CTLs). The most compelling evidence for this is from studies of:
• Tumor antigens in mice, where tumors that normally fail to elicit an immune response carry weak antigens that can become targets for an effective immune response;
• Immunization with synthetic peptides, corresponding to a mutated segment of the gene, which can elicit both class I and class II restricted T-cell responses;
• Melanoma, where melanoma-associated antigens (e.g., MAGE-1, 2, 3, gp100 and MART 1) have been described after the isolation of peptides from MHC.
Many human melanoma tumors express antigens that are recognized in vitro by CTLs derived from the lymph nodes of patients with melanoma. CD8+ T cells have been found to be MHC class I restricted to HLA-A1 and HLA-A3. CD4+ T-cell clones have a weaker cytotoxic activity and are restricted to HLA-DR2. The peptide that has been identified by these CTLs is known as MAGE-1. The expression of MAGE-1 is detected in 40% of melanoma cell lines, as well as in some breast tumors, but not in a variety of normal tissues tested. Testicular tissue, however, expresses significant levels of MAGE-1. MAGE-2 and MAGE-3 have also been identified in melanoma cells. The target for CTL recognition of MAGE-1 antigen was defined as a 9-mer peptide presented by HLA-A1. Although structurally similar to MAGE-1, MAGE-2 and MAGE-3, the gene products do not contain this 9-mer peptide and are not recognized by MAGE-1 peptides. MAGE-2 and MAGE-3 were among the first to be developed as new approaches to vaccines in melanoma. More recently, numerous antigens have been identified as being expressed by melanoma cells and are used in vaccines.
Active specific immunotherapy is defined as the use of tumor-associated antigens to immunize patients in an effect to reject their tumors. In the late 1980s, a Phase I clinical trial was conducted using lysates from melanoma cell cultures mixed with DETOX (Ribi) adjuvant. The vaccine was able to immunize 50% of patients with melanoma (measured by the generation of CTLs) and tumor regression was noted in some patients. In the early 1990s, Hersey demonstrated that the immunization over a 2-year period with vaccinia melanoma viral lysates (VMCLs) in eight patients treated with VMCL, followed for 5.5 years, had improved survival and there were fewer metastases during treatment. The observed biological effects of the vaccine were lower incidence of cutaneous metastases in VMCL-treated patients relative to visceral metastases and a change in recurrence, occurring after 2 years. Tumors are poorly immunogenic because they have low antigen or MHC class I expression, lack costimulatory molecules (such as B7) and there are immune suppressive factors involved. Means for overcoming the poor immune responses elicited by tumors have included, for example, the introduction of MHC genes, introduction of costimulatory molecules and cytokine gene transfer into tumor cells. In total, 20 years have passed since these initial clinical trials and no significant advances have emerged in cancer vaccine development, with regard to complete long-term remissions. Numerous antigens have been described and have entered human clinical trials, such as MUC1, Her2/neu, CEA, PSA and melanoma antigens. All have shown evidence of immune induction in patients and, in some patients, clinical responses; however, there still remain issues with long-term tumor remission and survival. New approaches of immunization are emerging that have shown promise in human clinical trials. Some of the approaches include novel methods to deliver peptides/proteins to antigen-presenting cells, dendritic cell (DC)–tumor fusions, DCs pulsed with peptides/proteins, inclusion of Toll-like receptors in vaccine constructs and the use of novel DNA-delivery methods for vaccination. In the next 5–10 years, a number of vaccines will become available that show complete long-term regression of tumors in patients with cancer.
The book ‘Cancer Vaccines – Challenges and Opportunities in Translation’, edited by Adrian Bot and Mihail Obrocea, is a timely book in this important era in the development of cancer vaccines. The book consists of nine up-to-date chapters on ‘challenges and opportunities’ in the development of cancer vaccines. The chapters are clear and informative, and contain key tables and figures.
Chapter 1 describes the importance of antigen processing and presentation of peptides to T cells. The importance of adjuvants, in particular Toll-like receptor ligands, the appropriate selection of target antigens, T-cell epitope peptides and the use of altered peptide ligands are described.
Chapter 2 is a well-described chapter on the use of modified tumor cells. Such modified tumor cells described include, tumor-derived heat-shock protein–peptide complexes, tumor cells modified to secrete cytokines, modified to express costimulatory molecules, mixed with the adjuvant bacillus Calmete–Guérin, and idiotype vaccines.
Chapter 3 discusses allogeneic vaccines, including whole tumor cells, tumor cell lysates and cytokine-modified tumor vaccines. In addition, a detailed description of infectious diseases vaccines, in particular human papillomavirus-based vaccines, is included. The chapter concludes with a discussion of traditional vaccines versus infectious disease vaccines.
Chapter 4 introduces ‘personalized (autologous) cancer vaccines’ and presents cancer vaccines that have reached Phase III clinical trials. OncoVAX®, Oncophage®, ATL, Provenge®, Favld®, MyVax®, Stimuvax® and GSK 1572932A are described. A highly relevant issue is addressed in the importance of the use of the optimal patient population for a vaccine to work, and that more than 10 years are required to get the appropriate results is also mentioned.
Chapter 5 uses gliomas as an example of DC vaccination. Since the first DC-based clinical trial published in 1996, more than 120 similar studies have been reported since. The DC-based approach has been tested in patients with various types of cancers with encouraging results. Adverse effects generated due to DC immunization have been minimal and patients with complete and partial responses have been reported continuously. The chapter concludes with a focus on important future strategies being utilized for DC cancer vaccines.
Chapter 6 discusses peptide-based vaccines. The use of peptides is advantageous for vaccines becuase they are chemically stable entities, easily synthesized, free of bacterial or other contaminating substances and, more importantly, devoid of oncogenic potential. This chapter lists some of the most widely used tumor-associated antigens and gives a comprehensive table of peptide-based vaccines in human clinical trials.
Chapter 7 describes DNA-based vaccines for cancer and approaches to improve immunogenicity. DNA vaccines were discovered in early gene therapy experiments in 1990. The early experiments indicated that using a vector encoding a viral protein injected intramuscularly offered a simple means of inducing protective immunity without the need for self-replicating agents or adjuvants. DNA vaccines, however, are not effective in generating immune responses against diseases such as HIV and cancer in humans. Disappointing results from clinical trials have led to new efforts in designing better DNA-based vaccines. In this chapter, the mechanism of action of DNA vaccines is described, along with prime–boost strategies and methods to improve efficacy of DNA vaccines.
Chapter 8 discusses an important issue in cancer vaccine R&D. Redesigning R&D strategies for cancer vaccines, revising the role of preclinical studies and biomarkers for new molecular-targeted therapies are discussed. A case study is reported on a cancer vaccine.
Chapter 9, the final chapter, brings up an important issue on diagnostic approaches for selecting patient-customized therapies. A description of patient stratification and response monitoring is given. Examples of immunohistochemistry for a range of antigens and HLA are noted as important. Following immunization, immune response monitoring is important and the most effective method of detecting immune responses, such as ELISpot, tetramers and multiparameter flow cytometry, are given.
Overall, the book addresses a range of important issues in the development of cancer vaccines. It provides a solid introduction to cancer vaccines and is greatly useful to a range of target audiences – from immunologists, to oncologists, to clinical researchers, to investors in pharmaceutical companies.
Acknowledgements
I would like to thank Susan G Komen of the Cure Breast Cancer Foundation for providing funding for the development of breast cancer vaccines.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.