While adoptive cell transfer (ACT) using chimeric antigen receptor-expressing (CAR) T cells has led to remarkable complete responses in leukemia, complete responses of solid tumors in patients are few. Similarly, previous investigations in mice have demonstrated clearance of large burdens of disseminated cancer using CAR T cells, but large solid tumors (>1 cm2) have not responded fully. Here we report the generation of transgenic mice containing dual specific CAR T cells with specificity for Her2 and the melanoma-associated antigen pMEL (gp100), designated CARaMEL mice. In response to Her2-positive cancer cells, T cells from CARaMEL mice could secrete cytokines and engage in cytolysis mediated by an anti-Her2 CAR. Through their endogenous TCR, CARaMEL T cells could proliferate extensively in response to gp100. We demonstrate the ability of CARaMEL T cells in ACT incorporating vaccination (ACTIV) therapy to induce eradication of large tumors of various histologies, including orthotopic breast tumors, subcutaneous sarcoma and colon carcinoma liver tumors. Tumor models were performed in immunocompetent mice expressing human Her2 in normal brain and breast tissue. Effective ACTIV therapy included a lymphodepleting preparative regimen, ACT, high-dose IL-2 and recombinant vaccinia virus expressing gp100. ACTIV therapy was associated with expansion of dual-specific T cells and extensive tumor infiltration by CARaMEL T cells. Infiltration of CARaMEL T cells was also observed in normal tissues including brain. Long term surviving mice were totally resistant to rechallenge with Her2-expressing tumor cells, and partially resistant to Her2-negative tumor cells. We anticipate studies currently underway to provide mechanistic insight into the antitumor activity of ACTIV therapy.
Citation Format: Clare Y. Slaney, Jennifer A. Westwood, Paul A. Beavis, Phillip K. Darcy, Michael H. Kershaw. Eradication of large solid tumors in immunocompetent mice using dual specific CAR T cells and vaccination. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A104.
- ©2016 American Association for Cancer Research.