Title: Targeting interference of CTLA-4 co-inhibition to tumour-specific T cells to enhance activity and reduce toxicity
Funder: Medical Research Council

Abstract: Despite significant advances, existing immunotherapies have limited clinical effectiveness in patients with cancer. Genetic engineering to produce T cell receptor (TCR)-transduced tumour-specific T cells can overcome some of the limitations associated with low precursor frequency or low TCR avidity. Alternatively, introduction of chimeric antigen receptors (CAR) allows MHC-unrestricted redirection of T cell specificity. Both strategies are being explored in clinical studies within the host institution. However, early indications suggest that immune tolerance, mediated via inhibitory immunological regulatory pathways such as Cytotoxic T-Lymphocyte Associated Antigen-4 (CTLA-4), consistently blunts the induction or maintenance of immunity. CTLA-4 provides an immunological ?brake‘ restricting uncontrolled T cell proliferation, acting both cell-intrinsically on effector T cells and via ?effector-extrinsic? pathways (mediated by regulatory T cell subpopulations). In vivo, this moderates the immune response, preventing the unwanted activation of multiple polyclonal effector T cells, the outcome of which would be overwhelming systemic autoimmune toxicity. Therapeutic Monoclonal Antibodies (MAb) capable of blocking immune inhibitory checkpoints, such as anti-CTLA-4, are being developed for clinical application. The major effect of anti-CTLA-4 MAb is mediated via CD4+ T-cells. A significant concern of their use as single agents is the development of systemic autoimmune toxicity as demonstrated in early clinical studies. Use in combination with strategies to re-direct immunity towards specific tumour-associated antigens could potentially enhance anti-tumour cytotoxicity with limited autoimmune consequences. Targeted manipulation may therefore offer the dual benefits of enhanced efficacy and reduced toxicity. The aim of this fellowship is to investigate the utility of genetically targeting interference with CTLA-4 associated co-inhibition to adoptively transferred tumour-specific T-cells with the aim of enhancing anti-tumour activity whilst limiting more widespread immune-mediated toxicities. More specifically I will first determine whether genetic silencing of CTLA-4 within tumour-specific TCR-transgenic CD4+ or CD8+ T cells enhances anti-tumour efficacy in congenically marked mice (tumour growth, infiltration), and whether this impacts on measures of systemic autoimmunity, directly comparing outcomes with unmanipulated transgenic cells in combination with anti-CTLA-4 MAb and with mock-transduced cells. I will then assess whether CTLA-4 blockade of endogenous regulatory populations is required for maximal activity, engineering effector cells to secrete anti-CTLA-4 locally. The dissection of these issues will be aided by using mice expressing human rather than murine CTLA-4 as recipients, since CTLA-4 blockade is species-specific. These studies should inform the further development of clinical strategies in our institution, with the plan that they will be incorporated in the next generation of phase I studies.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS