Roddie, C; (2016) Targeting interference of CTLA-4 co-inhibition to tumour specific T cells to enhance activity and reduce toxicity. Doctoral thesis , UCL (University College London).

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Abstract

Blockade of Cytotoxic T lymphocyte antigen-4 (CTLA-4) can enhance anti-tumour responses in preclinical models. A monoclonal antibody targeting human CTLA-4 (αCTLA4 mAb), is FDA approved for clinical use against metastatic melanoma. Paradigms suggest that αCTLA4 mAb blocks CTLA-4 dually on CTLA-4hi Tregs (restricting regulatory activity) and CTLA-4int-hi CD4 Teff (enhanced expansion) resulting in intratumoural Teff dominance and a net gain in anti-tumour activity. More recently, antibody-dependent cellular cytotoxicity (ADCC)-mediated depletion of CTLA-4hi Tregs in the tumour has been flagged as a critical factor driving anti-tumour immune responses. We explored the ADCC hypothesis in an adoptive cell transfer model of murine melanoma. We compared intratumoural Treg numbers in groups receiving CTLA-4+/+ or CTLA-4-/- tumour-specific T cells with/without exogenous αCTLA4 mAb. Exogenous αCTLA4 mAb resulted in diminished intratumoural tumour-specific Treg numbers in groups receiving CTLA-4+/+ but not CTLA-4-/- T-cells. Endogenous CTLA-4+/+ Tregs were depleted intratumourally with αCTLA4 mAb, irrespective of the CTLA-4 status of the adoptive cells. This data supports the proposed ADCC mechanism of αCTLA4 mAb and its dependence upon target cell CTLA-4 expression. Furthermore, we engineered tumour-specific T-cells to secrete αCTLA-4 mAb on IgG2a isotype (high ADCC activity) or IgG1 isotype (low ADCC activity) for adoptive transfer into melanoma-bearing mice. We found that transduced primary murine T-cells could engraft, infiltrate tumours and secrete biologically active αCTLA4 mAb. Secreted IgG2a αCTLA-4 mAb was strongly associated with intratumoural depletion of CTLA-4hi Tregs, but unexpectedly CTLA-4-replete transduced Teff were also vulnerable to depletion, and this significantly compromised the anti-tumour potential of this therapy. Intratumoural depletion of CTLA-4hi T-cells was not associated with (secreted) IgG1 αCTLA-4 mAb or (secreted) isotype control mAb. We believe that depletion of intratumoural Tregs is an important area for cancer immunotherapy, but our experience of αCTLA-4 mAb underlines the importance of careful immunomodulatory target selection to avoid toxicitiy.

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