Integrating bench with bedside: the role of vaccine therapy in the treatment of solid tumors.

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. In 1991, a vaccine strategy employing recombinant vaccinia virus engineered to express carcinoembryonic antigen (CEA) was reported. 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. 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 CEAexpressing tumor cells. 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. 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. 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. In this issue of the Journal of Clinical Oncology, Marshall et al, 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 JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 4 FEBRUARY 1 2005