Abstract IA45: Prospect of a vaccine to prevent cancer in BRCA1-2 mutation carriers

Abstract

New, effective immune approaches to treat cancer not only underscore the power of the immune system in the therapeutic setting, but also spark renewed efforts to develop specific immune approaches to prevent cancer. We are focused on developing a novel vaccine that prevents BRCA1/2-related cancer when administered prophylactically to healthy individuals who carry BRCA1/2 mutations a polio vaccine for BRCA1/2-related cancer. An increasing understanding of cancer risk in BRCA1/2 mutation carriers provides an opportunity to test immune prevention in individuals at extremely high risk for developing cancer. It is in this prevention setting for which it is now hypothesized that vaccines will work (as they do in infectious diseases) in contrast to post-exposure vaccines which generally do not, especially in cancer-bearing individuals. In initial efforts, a first-in-human clinical trial is being conducting in which a next-generation DNA vaccine is used to target the telomerase reverse transcriptase hTERT as a potential universal tumor antigen exploitable for cancer prevention. Telomerase is expressed by the vast majority of human cancers including those related to BRCA1/2 mutation, whereas telomerase expression in normal tissue is restricted. Extensive data demonstrate that TERT can be recognized by human cytotoxic T lymphocytes (CTLs) despite being a product of the human genome potentially subject to the forces of immune tolerance. Peptides derived from TERT are naturally processed by tumors, presented on MHC, and can trigger effector functions of specific CTLs. TERT-specific CTLs lyse TERT positive tumor cells in vitro in an antigen-specific, MHC-restricted fashion; except for activated B cells, normal hTERT+ MHC+ cells are not lysed by TERT T cells. Because hTERT is involved in the transformation of cancer cells and is required for oncogenesis, tumor downregulation of hTERT expression in the face of T cell immune responses may be incompatible with ongoing tumor growth, addressing immune escape by antigen-loss. Clinical studies of peptide- and cell-based vaccines demonstrate the immunogenicity of TERT in patients. In multiple studies, we have observed the induction of hTERT-specific T cells both systemically and intratumorally after peptide vaccination. hTERT-specific CD8+ T cells exhibit effector functions in vitro including proliferation, IFNγ production, and tumor lysis. Median overall survival is significantly longer in those patients who achieved an immune response to hTERT peptide compared with patients who did not. Some formulations of TERT vaccination have been immunologically weak. In mice, immunization with optimized TERT DNA that is robustly immunogenic can inhibit growth of preexisting tumors and also prevent formation of cancer in challenge experiments without toxicity. A clinical trial testing a novel DNA formulation is underway and will be discussed.

Citation Format: Robert H. Vonderheide. Prospect of a vaccine to prevent cancer in BRCA1-2 mutation carriers. [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 IA45.