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Originally published as JCO Early Release 10.1200/JCO.2005.09.908 on December 21 2004 © 2005 American Society of Clinical Oncology.
Integrating Bench With Bedside: The Role of Vaccine Therapy in the Treatment of Solid TumorsColumbia University, New York, NY The treatment of solid tumors continues to be one of the major challenges facing both patients and the oncology community. An improved understanding of how the immune system recognizes and eradicates tumor cells has led to an intense interest in therapeutic vaccine development, representing one of the most successful applications of bench-to-bedside translational research. Extensive "proof of principle" evidence from the bench has used murine models to demonstrate that active immunization can mediate effective tumor treatment.1 In 1991, a vaccine strategy employing recombinant vaccinia virus engineered to express carcinoembryonic antigen (CEA) was reported.2 Initial animal experiments documented the ability of vaccinia-CEA to induce humoral and cellular immunity by targeting a commonly expressed solid tumor antigen in a highly immunogenic vaccine—a result since confirmed in transgenic mice and in vitro experiments with human T cells. The first clinical trial with this vaccine was published in 1996, and numerous other studies, largely phase I in format, were conducted throughout the last 8 years, demonstrating the safety and feasibility of various poxvirus vaccines in patients with advanced solid tumors.3-9 While these studies were not designed or powered to determine clinical effectiveness, intriguing anecdotal evidence suggested that vaccination induced CEA-specific T cells, and even objective clinical responses, in some patients. The completion of these early-phase clinical trials provided important safety data and guided additional bench experiments aimed at improving the therapeutic effectiveness of CEA-based poxvirus vaccines. For example, careful analysis of in vitro T-cell responses from vaccinated patients led to the identification of HLA-restricted T-cell epitopes and later demonstrated that poxvirus vaccines could break tolerance against these epitopes in patients. This also allowed Schlom et al to identify a modified CEA agonist peptide that was more efficient in inducing T-cell responses against the native CEA peptide and CEA-expressing tumor cells.10 Another problem identified from early clinical trials was that repeated administration of vaccinia virus induced strong neutralizing antibodies that prohibited subsequent boosting of immune responses against the tumor antigen. Animal studies utilizing a prime-boost approach, wherein vaccinia virus is used once for priming followed by booster vaccinations with nonreplicating poxvirus vectors such as fowlpox virus, were shown to be superior to using either vector alone. This was later confirmed in a clinical trial.7 Additional vaccine improvements were provided by the coexpression of powerful costimulatory molecules in the viral genome, designed to augment the activation of T cells after engagement of the T-cell receptor.5,6 Preclinical experiments in mice and with human T cells in vitro resulted in selecting a triad of costimulatory molecules (B7-1, ICAM-1, and LFA-3) that significantly enhanced immune responses of the poxvirus vaccines, and augmented tumor regression in animals. Other studies evaluated the benefits of adjuvant cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2) for promoting CEA-specific immunity in clinical trials after a benefit was seen in murine models.6,7 In this issue of the Journal of Clinical Oncology, Marshall et al,9 combine many of these methods for improving poxvirus vaccination into a single vaccine strategy for patients with advanced CEA-expressing solid tumors. They utilized a vaccinia virus expressing CEA encoding the agonist epitope, along with three costimulatory molecules (B7-1, ICAM-1, and LFA-3) for priming an immune response, followed by booster vaccinations with a fowlpox virus expressing the same transgenes. In addition, they treated some cohorts with GM-CSF administered near the vaccine site to promote local recruitment of dendritic cells. They also evaluated a split dose of the booster vaccine in an attempt to increase systemic immunity. Finally, they allowed booster vaccines every 3 months; if patients progressed, they were able to receive monthly boosters. This phase I study enrolled 58 patients; toxicity, as expected, was minimal. An increase in CEA-specific T cells was observed in nearly every patient tested, suggesting that this approach may represent a real improvement in CEA-targeted vaccines. Overall, 23 patients (40%) had stable disease, 11 patients demonstrated a decrease or stabilization in serum CEA levels, and one patient with small-cell lung cancer exhibited a complete pathologic response. One of the more intriguing results was that six of 12 patients whose disease progressed on the 3-month booster vaccinations stabilized after reverting to monthly immunizations. While these results are interesting, do they really help advance the field? The study by Marshall et al highlights some of the problems in using standard phase I clinical trial designs to draw meaningful conclusions on the effectiveness of tumor vaccines. In this study, the authors use a fairly nonstandard response criteria, classifying patients as having primary stable disease if they had no evidence of disease progression during the first 4 months, and secondary stable disease if they progressed after 2 months but achieved stable disease at 4 months (after completing the scheduled four vaccinations). They defend this criterion by stating that the kinetics of vaccine-induced tumor regression may require longer periods of time to see an effect. Thus, strict adherence to objective tumor response criteria at defined time points may lead to rejection of potentially efficacious vaccines. Thus, there is a compelling need to develop more efficient clinical trial designs that can detect disease stabilization over time. This clinical trial also accrued 58 patients into a fairly standard dose-escalation study design. Since there has been little toxicity seen with previous generations of vaccine, and no dose-response relationship has emerged from prior investigation, the dose escalation of the two vectors seems unnecessary. Similarly, while the approach used incorporated many different adjuvant therapies to improve responses, not all of these could be directly tested with the design employed. The prime/boost approach and the addition of GM-CSF could be evaluated since some patient cohorts could act as controls; but no conclusions can be drawn about the addition of the costimulatory molecules or the agonist epitope from this trial. Before embarking on large, randomized phase III clinical trials, are there any other ways to determine which vaccines and adjuvant therapies are worthy of moving forward? The answer may lie in the opportunity to evaluate immune responses from patients enrolled on these vaccine studies. Immune monitoring has been an important correlate in the development of infectious disease vaccines, and there is increasing evidence that this will also be true for tumor vaccines. In the study by Marshall et al, they were able to determine antibody and T-cell responses against CEA and found that nearly all patients tested developed evidence of CEA-specific immune responses. Although T-cell responses were only measured in HLA-A2–positive patients, making a detailed analysis difficult in this trial, a trend was seen between highly positive T-cell responses and survival. The role of vaccination in mediating these responses was further supported by the lack of changes in the response against influenza or fowlpox virus in the study subjects. The measurement of immune responses is not trivial, and further research is needed to optimize and validate these assays. Until this is done, what should we expect as proof that a vaccine is immunogenic? We should expect to see evidence of vaccine potency based on both the magnitude and prevalence of immune responses induced by vaccination. Although somewhat arbitrary, significant increases in antibody titers or T cell responses using quantitative assays should be observed in a majority of vaccinated patients. The magnitude of response should be equivalent to levels observed against infectious disease antigens such as cytomegalovirus or tetanus toxoid, which are commonly evaluated in tumor vaccine trials as positive controls. This can be rationalized since these levels of response, as, for example, in smallpox vaccination, are where protection against disease has been documented.11 This may be more difficult in the cancer patients on early-phase studies due to inclusion of heavily pretreated patients. For example, in the Marshall et al study, 48 of 58 patients had received two or more prior chemotherapy regimens, making this a challenging group for initiating immunity and detecting low-level immune responses. Once safety and high-level immunity have been documented, vaccines should be moved into phase II testing with the goal of selecting the optimal patient population, with an appropriate clinical end point. Similar to infectious disease models, vaccines will likely show the most promise in prevention, or at least in minimal disease burden settings. Therefore, patients at high risk for tumor development, based on established genetic predisposition, or those at high risk of recurrent disease, may represent a better study population as compared with patients with bulky metastatic disease. In this scenario, tumor response or overall survival end points may not be scientifically or economically practical. However, the time to disease recurrence may be a good substitute, and every effort should be made to document whether recurrent tumors represent antigen loss variants or have escaped immune detection through other mechanisms. Although vaccine development has been moving forward slowly, it is unlikely that single-agent vaccination will be able to eradicate established tumors. Furthermore, most patients with solid tumors benefit from combined-modality therapy. This raises the possibility that combination treatment may be more successful, a concept supported by recent preclinical studies suggesting synergy between vaccines and radiation or chemotherapy.12,13 This sort of unexpected additive or synergistic activity has been seen with trastuzumab plus chemotherapy in breast cancer and bevacizumab plus chemotherapy in colorectal cancer. Initially, trastuzumab was thought to mediate tumor responses through immune mechanisms such as antibody-dependent cellular cytotoxicity, and administration with cytotoxic chemotherapy was expected to diminish the response through inhibition of effector T and natural killer cells. However, this hypothesis was not substantiated, as taxane chemotherapy did not suppress natural killer activity, and the down-modulation of HER-2/neu receptors was identified as another possible mechanism of trastuzumab therapy. Although the exact mechanism remains controversial, these findings highlight the importance of clinical investigation. These studies also demonstrate how the integration of basic science in the clinic can lead to changes in treatment paradigms and identify new hypotheses that can be actively tested. The potential for developing vaccines for the treatment of solid tumors has been recognized for more than a decade, and significant progress has been made. Recombinant poxviruses expressing CEA have been extensively tested in murine models, and numerous improvements have been made in the construction and administration of these vaccines based on observations made in early-phase clinical trials. A considerable amount of safety and feasibility data have been amassed from these trials, which laid the foundation for understanding the biology and toxicology of the vaccines in cancer patients. The studies have also been instrumental in establishing validated immune assays for monitoring CEA-specific responses. The clinical trial reported in this issue of the Journal of Clinical Oncology combines much of this knowledge and demonstrates the potential of targeting solid tumors with vaccines. The scientific community must continue to refine vaccine strategies based on clinical information, while clinicians must define appropriate patient populations, rapidly incorporate promising vaccines with other modalities, and complete the validation of correlative immune assays. Statisticians must help design more powerful studies for candidate vaccines, and patients must be referred for participation in such studies in order to maximize the benefit for all patients. The evaluation of CEA-based poxvirus vaccines represents an important example of how such translational research can generate new insights in basic immunology and lead to new testable hypotheses. The continued integration of bench and bedside is needed to firmly define the role of vaccines in patients with solid tumors. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES 1. Waldmann TA: Immunotherapy: Past, present, and future. Nat Med 9:269-277, 2003[CrossRef][Medline] 2. Kaufman HL, Kantor J, Schlom J: A recombinant vaccinia virus expressing human carcinoembryonic antigen (CEA). Int J Cancer 48:900-907, 1991[Medline] 3. McAneny D, Ryan C, Beazley R, et al: Results of a phase I clinical trial using a recombinant vaccinia-carcinoembryonic antigen (CEA) vaccine in patients with advanced colorectal cancer. Ann Surg Oncol 3:495-500, 1996[Abstract]
4. Marshall JL, Hawkins MJ, Tsang KY, et al: Phase I study in cancer patients of a replication defective avipox recombinant vaccine that expresses human carcinoembryonic antigen. J Clin Oncol 17:332-337, 1999 5. Horig H, Lee DS, Conkright W, et al: B7.1 costimulation enhances the response of a recombinant canarypoxvirus (ALVAC) vaccine expressing human carcinoembryonic antigen (CEA). Cancer Immunol Immunother 49:504-514, 2000[CrossRef][Medline]
6. von Mehren, Arlen P, Tsang KY, et al: Pilot study of a dual gene recombinant avipox vaccine containing both carcinoembryonic antigen and B7.1 transgenes in patients with recurrent CEA-expressing adenocarcinomas. Clin Cancer Res 6:2219-2228, 2000
7. 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-carcinembryonic antigen immune responses. J Clin Oncol 18:3964-3973, 2000
8. Ullenhag GJ, Frodin JE, Jeddi-Tehrani M, et al: Durable carcinoembryonic antigen (CEA)-specific humoral and cellular immune responses in colorectal carcinoma patients vaccinated with recombinant CEA and granulocyte/macrophage colony-stimulating factor. Clin Cancer Res 10:3273-3281, 2004
9. Marshall JL, Gulley JL, Arlen PM, et al: Phase I study of sequential vaccinations with fowlpox-CEA(6D)-TRICOM alone and sequentially with vaccinia-CEA(6D)-TRICOM, with and without granulocyte-macrophage colony-stimulating factor, in patients with carcinoembryonic antigen-expressing carcinomas. J Clin Oncol 23:720-731, 2005
10. Zaremba S, Barzaga E, Zhu M, et al: Identification of an enhancer agonist cytotoxic T lymphocyte peptide from human carcinoembryonic antigen. Cancer Res 57:4570-4577, 1997
11. Frey SE, Newman FK, Cruz J, et al: Dose-related effects of smallpox vaccine. N Engl J Med 346:1275-1280, 2002 12. Terando A, Mule JJ: On combining antineoplastic drugs with tumor vaccines. Cancer Immunol Immunother 52:680-685, 2003[CrossRef][Medline]
13. 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 Related Article
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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