Induction of an antigen cascade by diversified subcutaneous/intratumoral vaccination is associated with antitumor responses

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Purpose: Cancer vaccines targeting tumor-associated antigens (TAAs) are being investigated for the therapy of tumors. Numerous strategies, including the direct intratumoral (i.t.) vaccination route, have been examined. For tumors expressing carcinoembryonic antigen (CEA) as a model TAA, we previously designed poxviral vectors that contain the transgenes for CEA and a triad of T-cell costimulatory molecules (B7-1, ICAM-1, LFA-3) designated CEA/TRICOM. Two types of poxvirus vectors were developed: replication-competent recombinant vaccinia (rV) and replication-defective recombinant fowlpox (rF). We have previously demonstrated that a vaccine regimen comprised of priming mice subcutaneously (s.c.) with rV-CEA/TRICOM and boosting i.t. with rF-CEA/TRICOM was superior to priming and boosting vaccinations using the conventional s.c. route in inducing T-cell responses specific for CEA. These studies also showed that CEA was needed to be present both in the vaccine and in the tumor for therapeutic effects. Experimental Design: To determine specific immune responses associated with vaccination mediated tumor regression, CEA-transgenic (CEA-Tg) mice bearing CEA+ tumors were vaccinated with the CEA/TRICOM s.c./i.t. regimen, and T-cell immune responses were assessed. Results: In CEA+ tumor-bearing mice vaccinated with the CEA/TRICOM s.c./i.t. regimen, T-cell responses could be detected not only to CEA encoded in vaccine vectors but also to other antigens expressed on the tumor itself: wild-type p53, and an endogenous retroviral epitope of gp70. Moreover, the magnitude of CD8+ T-cell immune responses to gp70 was far greater than that induced to CEA or p53. Finally, the predominant T-cell population infiltrating the regressing CEA+ tumor after therapy was specific for gp70. Conclusion: These studies demonstrate that the breadth and magnitude of antitumor immune cascades to multiple antigens could be critical in the therapy of established tumors.