Precision targeting of mTOR in conventional and MHC class I-restricted anti-tumour CD4+ T cells

Adoptive immunotherapy is an emerging therapy that has provided exciting preliminary results in some cancer patients. The protocols involve removing immune cells called T cells from patients and then reprogramming them to attack cancer cells. However, early results show that not all patients will respond to the treatment or will later relapse, meaning either that the T cells don't work or that the cancer changes and evades the immune attack. In our laboratory, we are developing methods to broaden the immune attack by including other immune cells. In this project, we will evaluate how modifying a subset of immune cells called CD4+ T cells can improve their ability to target cancer cells following infusion and then, keep working to ensure that the cancer cannot regrow. We intend to use this knowledge to design new approaches for adoptive immunotherapy in patients.

Although adoptive transfer of CD8+ T cells engineered to express tumour-specific TCR or chimeric antigen receptors can successfully induce remissions in patients with cancer, other patients fail to respond or respond only transiently. Recent work from the host laboratory has focused upon the concept that adoptive transfer of multiple T cell populations (heterogeneous in terms of subset, functional state and persistence) will better protect against immune escape than transfer of uniform populations of CD8+ T cells. In this proposal, I am seeking to extend this 'multiplex' T cell approach by exploring how gene modification of antigen recognition and functional state can be used to exploit the anti-tumour functions of CD4+ T cells. I will test the hypothesis that precision up- or downward tuning of mTOR complex 1 (mTORC1) in CD4+ T cells bearing conventional or MHC Class I-restricted TCR can be exploited (1) to enhance their effector functions within tumour microenvironments, and (2) to increase their potential for self-renewal, thus enabling long-term immune surveillance. By introducing positive or negative regulators of mTORC1 into tumour-specific murine CD4+ T cells and using tractable tumour models, I will determine the effects of mTORC1 tuning upon Th differentiation, functional plasticity and self-renewal. Knowledge regarding how mTORC1 up- or down-regulation will impact upon Th function and persistence will be used to devise appropriate delivery systems for manipulation of CD4+ T cells for future clinical use.

Although there is huge interest in using TCR- or CAR-modified T cells to treat patients with cancer, a major challenge in the UK is to develop infrastructure and skills so that greater number of patients can gain access to these novel treatments. By providing me with skills in the relevant technologies, my project will align with the MRC's aim to strengthen the research base in a strategically important area.

An MRC Clinical Training Fellowship will equip me to pursue career development as a Clinician Scientist and to foster future translation of T cell therapies into the clinic. Both the Chakraverty and Stauss host laboratories have patented technologies relating to genetic manipulation of therapeutic T cells and are developing these for clinical use, for example through Wellcome Trust Pathfinder Awards, by interaction with UK Cell Therapy CATAPULT or through UCL partnerships with the commercial sector (e.g. Cell Medica). I will therefore gain a better understanding of how basic research findings can be developed as commercial assets in order to allow their wider application. Furthermore, by interacting with researchers who are running early phase clinical studies of TCR- and CAR-based T cell therapies at UCL, I will also improve my understanding of issues relating to trial regulation, cell manufacture and governance.

By applying the knowledge and skills derived from this fellowship, I will hope to contribute to a growing pool of UK clinical researchers adept at developing innovative T cell therapies that can be rapidly developed for application in patients.