The overall objective of this application is to develop a vaccine approach for the treatment of T cell malignancies. The unique T cell receptor (TCR) expressed by a tumor will be used to stimulate a tumor specific immune response in the host. The applicant proposes to: 1. Establish and characterize a mouse T cell tumor model. In order to evaluate TCR vaccines, a murine tumor model has been adopted. It consists of C6VL, a T cell tumor which expresses a well defined TCR, and the inbred mouse strains C57B1/6 and BA. C6VL grows well in vitro, and is lethal when injected into host mice. The growth pattern of C6VL has been characterized and reagents necessary to monitor tumor growth have been assembled. Factors which alter tumor growth in vitro will be analyzed. 2. Produce TCR based vaccines. Three different types of TCR vaccines will be evaluated: TCR protein, transfected cells which express TCR and naked DNA which encodes the TCR. The TCR protein vaccines will be generated in both an eukaryotic and a prokaryotic expression system. Cytokine hybrid protein molecules will also be produced. Several different immunologic adjuvants will be studied including SAF-1, QS-21 (a purified component of saponin) and the cytokine IL-12. 3. Characterize the immune response to TCR vaccines. The intensity, specificity, complexity and time course of both cellular and humoral immunity stimulated by various vaccines will be measured. The effect TCR vaccinations have on TCR variable region repertoire usage will also be analyzed. Examining different facets of the immune response will establish a foundation from which to explore new types of vaccines. 4. Evaluate the efficacy of clonotype TCR vaccinations. The ability of TCR vaccinations to stimulate a tumor protective immune response will be evaluated including the degree of tumor protection induced by TCR vaccines, uniformity of the protection and its specificity. Tumor protection will be compared with other measurements of the immune response to establish a correlation between tumor protection and levels of humoral and/or cellular response. TCR vaccines will also be used to treat mice with established tumors. 5. Investigate mechanisms of TCR vaccine induced tumor protection. The role of anti-TCR humoral and cellular immunity will be studied using adoptive transfer experiments. The role of CTL/NK activity will be defined using perforin knockout mice. The ability of tumor cells to adapt to the defense mechanism of the TCR vaccinated mice will also be studied.
| Lambert, Stacie L; Okada, Craig Y; Levy, Ronald (2004) TCR vaccines against a murine T cell lymphoma: a primary role for antibodies of the IgG2c class in tumor protection. J Immunol 172:929-36 |
| Wong, C P; Levy, R (2000) Recombinant adenovirus vaccine encoding a chimeric T-cell antigen receptor induces protective immunity against a T-cell lymphoma. Cancer Res 60:2689-95 |
| Wong, C P; Okada, C Y; Levy, R (1999) TCR vaccines against T cell lymphoma: QS-21 and IL-12 adjuvants induce a protective CD8+ T cell response. J Immunol 162:2251-8 |
| Okada, C Y; Wong, C P; Denney, D W et al. (1997) TCR vaccines for active immunotherapy of T cell malignancies. J Immunol 159:5516-27 |
