Targeting interference of CTLA-4 co-inhibition to tumour-specific T cells to enhance activity and reduce toxicity
Lead Research Organisation:
University College London
Department Name: Cancer Biology
Abstract
Lay Title: Easing the brakes restricting anti-cancer immunity: targeting therapy to limit side effects
Lay Statement: We now have the basic building blocks to allow more effective anti-cancer immune therapies. We can genetically redirect immune cells to more specifically recognise cancer cells, enhancing the function they play in policing immunity. However, various immunological ?brakes? limit the effectiveness of these approaches. Significant progress has been made in developing therapies that will interfere with these restrictive checkpoints to unleash the potential of the immune system, but these checkpoints have probably evolved at least in part to prevent the uncontrolled activation of immunity which would result in damage to many tissues (autoimmunity). It is perhaps no surprise, therefore, that the major side effect of these therapies is undirected immune activation causing severe inflammation in multiple tissues.
This fellowship aims to explore the possibility of targeting the blockade of these restricting brakes to within the actual tumour-reactive immune cells, examining the idea that this will localise their effects, enhancing anti-cancer activity whilst limiting more widespread toxicities. We hope that this will inform the next generation of clinical trials improving both survival and quality of life for patients with cancer.
Lay Statement: We now have the basic building blocks to allow more effective anti-cancer immune therapies. We can genetically redirect immune cells to more specifically recognise cancer cells, enhancing the function they play in policing immunity. However, various immunological ?brakes? limit the effectiveness of these approaches. Significant progress has been made in developing therapies that will interfere with these restrictive checkpoints to unleash the potential of the immune system, but these checkpoints have probably evolved at least in part to prevent the uncontrolled activation of immunity which would result in damage to many tissues (autoimmunity). It is perhaps no surprise, therefore, that the major side effect of these therapies is undirected immune activation causing severe inflammation in multiple tissues.
This fellowship aims to explore the possibility of targeting the blockade of these restricting brakes to within the actual tumour-reactive immune cells, examining the idea that this will localise their effects, enhancing anti-cancer activity whilst limiting more widespread toxicities. We hope that this will inform the next generation of clinical trials improving both survival and quality of life for patients with cancer.
Technical Summary
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.
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.