Dr. Marshall has done an excellent job in his review of the current status of the design, development, and delivery of cancer vaccines with emphasis on vaccines for the treatment of gastrointestinal cancers. He has clearly delineated both the promise and potential limitations of this actively emerging field of investigation. Historical Background
Important distinctions are made upfront between "first-generation" vaccines analyzed in previous and, in some cases, recently completed clinical trials, and the more sophisticated vaccines and vaccine strategies that are currently available for clinical evaluation. The use of cancer vaccines for the potential treatment of a range of malignancies has now reached new milestones in scientific discovery. Areas of intense investigation include the development and characterization of (a) tumor-associated antigens and tumor-specific antigens that are overexpressed or selectively expressed by malignant cells as compared with normal adult tissues, (b) novel vaccine delivery systems for the induction of more efficient host antitumor immune responses, and (c) cytokines and other immunostimulants to further augment immunogenic properties of vaccine preparations. The combination of gene discovery with each of these areas has accelerated the rate of both basic mechanistic findings and potential clinical applications. Recent Innovations in Vaccine Design and Delivery
There have been numerous recent advances in our basic understanding of immune mechanisms, tumor immunology, and vaccinology. For example, T-cell activation has now been shown to be a complex phenomenon involving the interaction of the major histocompatibility complex (MHC) and peptide, on the antigen-presenting cell, with the T-cell receptor on the T cell. Both CD8+ cytolytic Tcell and CD4+ helper T-cell responses are most likely essential to achieve antitumor effects.[1,2] For weak antigens such as tumorassociated antigens, however, accessory molecules are necessary for efficient T-cell activation. These have been termed "T-cell costimulatory molecules." Preclinical studies have demonstrated that when costimulatory molecules are placed into a syngeneic tumor cell that is weakly immunogenic or nonimmunogenic in a host, the transduced tumor cell may become immunogenic to the point that it elicits antitumor immunity. Genes for costimulatory molecules can be placed into vectors along with tumor-antigen genes for use in more conventional vaccines. This strategy has also been shown to increase the avidity, ie, potency of T-cell responses. CEA-TRICOM Vaccines
Dr. Marshall has chronicled the hypothesis-driven preclinical research that has led to science-based clinical trials in defining more effective vaccines directed against the tumorassociated carcinoembryonic antigen (CEA). While CEA is expressed on the vast majority of gastrointestinal cancers, it is also expressed on many other carcinoma types such as lung, breast, and head and neck cancers. Early clinical trials demonstrated that recombinant vaccinia viruses expressing CEA as well as the replication- defective avipox viruses expressing CEA were safe and effective in enhancing T-cell responses to CEA in vaccinated patients with advanced GI malignancies. A diversified prime-and-boost strategy was then used to enhance T-cell responses and gave the first indication of enhanced survival in a small cohort of patients. The addition of one costimulatory molecule (B7.1) to these vaccines, and then the addition of a triad of costimulatory molecules (B7.1, ICAM-1, and LFA-3, designated TRICOM), led to the generation of enhanced T-cell responses and evidence of increased survival in patients with advanced CEA-expressing carcinomas, especially with the use of granulocyte macrophage colony-stimulating factor (GM-CSF [Leukine]) with vaccine. These studies have led to the initiation of a multicenter randomized phase III trial in patients with advanced pancreatic cancer employing recombinant vaccinia and avipox vaccines containing five transgenes (CEA, MUC-1, TRICOM). Paradigm Shifts
The evaluation of cancer vaccines in clinical trials may well necessitate a new paradigm, as follows.
- Mode of Action- Cancer vaccines and cytotoxic drugs act quite differently in terms of mode of action. Cytotoxic drugs either kill or do not kill tumor cells. Lack of efficacy is due to either drug resistance by tumor cells, inadequate amounts of drug delivered to the tumor, and/or drug-induced toxicity in the host. Thus, if a patient's disease is progressing on a cytotoxic drug, that drug is immediately withdrawn. The use of a cancer vaccine involves a dynamic process in which the patient's own immune system is activated. To maximize the host immune response, however, one must not only give a primary vaccination but also multiple booster vaccinations. Multiple vaccinations are especially important due to the fact that factors may be given off by the tumor that will blunt the immune response. It is quite conceivable that a patient's disease will continue to progress following early vaccinations, only to see disease stabilization or a reduction in tumor burden following multiple vaccinations.[ 6] Thus, the paradigm of "drug withdrawal upon progression" should be revisited with the use of cancer vaccines.
- Phase I, II, III Paradigm- Clinical trials with a new drug are traditionally evaluated in patients with advanced cancers-often with a large tumor burden-who have failed prior cytotoxic therapies. Objective clinical responses are evaluated by Response Evaluation Criteria in Solid Tumors (RECIST), looking for a greater than 50% reduction in tumor volume. Since the generation of an immune response to a vaccine is a dynamic process in which T cells can be continually generated upon booster vaccines, a more appropriate end point for evaluation should be time to progression and, more importantly, survival. In addition, a more appropriate setting would be the evaluation of cancer vaccines earlier in the disease setting in patients with either a small tumor burden or a high probability of disease progression. This should particularly be considered in light of the relatively low level of toxicity seen in the use of cancer vaccines.
- Combination Therapies- One of the major advantages in the use of cancer vaccines is their reduced toxicity. One of the "conventional wisdom" paradigms that is now being reevaluated is that one cannot use cancer vaccines in combination with chemotherapy or radiation therapy. Preclinical studies, and now several clinical studies, have shown that patients can mount an immune response to cancer vaccine when given in combination with certain cytotoxic drugs, hormones, or local irradiation[ 9] of tumor. Indeed, recent preclinical studies have shown that when tumor cells are exposed to radiation[ 10] or certain chemotherapeutic agents at levels insufficient to kill tumor, the phenotype of tumor cells is actually modulated to make them more susceptible to T-cell-mediated killing.
Finally, as reviewed by Dr. Marshall, not all cancer vaccines are created equal. The development of cancer vaccines should be considered an immunologic platform building on preclinical and clinical knowledge of gene discovery, vectorology, cytokines, and the mechanism of activation of the immune response.
The Laboratory of Tumor Immunology and Biology has a Cooperative Research and Development Agreement (CRADA) with Therion Biologics Corp, Cambridge, Mass.
1. Ruiz M, Kobayashi H, Lasarte JJ, et al: Identification and characterization of a T-helper peptide from carcinoembryonic antigen. Clin Cancer Res10:2860-2867, 2004.
2. Kobayashi H, Omiya R, Ruiz M, et al: Identification of an antigenic epitope for helper T lymphocytes from carcinoembryonic antigen. Clin Cancer Res 8:3219-3225, 2002.
3. Hodge JW, Chakraborty M, Kudo-Saito C, et al: Multiple costimulatory modalities enhance CTL avidity. J Immunol 174:5994-6004, 2005.
4. Marshall JL, Hoyer RJ, Toomey MA, et al: Phase I study in advanced cancer patients of a diversified prime-and-boost vaccination protocol using recombinant vaccinia virus and recombinant nonreplicating avipox virus to elicit anti-carcinoembryonic antigen immune responses. J Clin Oncol 18:3964-3973, 2000.
5. Hodge JW, Sabzevari H, Yafal AG, et al: A triad of costimulatory molecules synergize to amplify T-cell activation. Cancer Res 59:5800-5807, 1999.
6. Marshall J, Gulley JL, Arlen PM, et al: A phase I study of sequential vaccinations with fowlpox-CEA(6D)-TRICOM alone and sequentially with vaccinia-CEA(6D)- TRICOM, with and without granulocytemacrophage colony-stimulating factor, in patients with carcinogenic antigen–expressing carcinomas. J Clin Oncol 23:720-731, 2005.
7. Machiels JP, Reilly RT, Emens LA, et al: Cyclophosphamide, doxorubicin, and paclitaxel enhance the antitumor immune response of granulocyte/macrophage-colony stimulating factor-secreting whole-cell vaccines in HER-2/neu tolerized mice. Cancer Res 61:3689-3697, 2001.
8. Arlen PM, Gulley JL, Todd N, et al: Antiandrogen, vaccine, and combination therapy in patients with nonmetastatic hormone refractory prostate cancer. J Urol 174:539-546, 2005.
9. Gulley JL, Arlen PM, Bastian A, et al: Combining a recombinant cancer vaccine with standard definitive radiotherapy in patients with localized prostate cancer. Clin Cancer Res 11:3353-3362, 2005.
10. Chakraborty M, Abrams SI, Coleman CN, et al: External beam radiation of tumors alters phenotype of tumor cells to render them susceptible to vaccine-mediated T-cell killing. Cancer Res 64:4328-4337, 2004.