Optimisation and deployment of a quiescence factor dose delivery system to enhance long-term maintenance and efficacy of T cell therapies

Cell therapy with T cells expressing gene-engineered chimeric antigen receptors (CAR) specific for cancer-associated antigens is transforming the way we treat patients with blood cancers, including myeloma. A critical issue limiting efficacy of cell therapies is that durable responses are limited by poor maintenance and survival of transferred cells resulting in treatment failure and myeloma relapse. There is a need to develop methods to enhance the persistence of CAR T cells for development of therapeutic products with long-lived efficacy.

Long-term maintenance of T cell responses is dependent upon maintaining a pool of stem cell-like memory/progenitor T cells which are long-lived and self-renew, but do not engage in effector functions. Our prior BBSRC-funded work has revealed that the transcription factor BACH2 is required for the differentiation of long-lived stem/memory CD8+ T cells. However, conventional high-level overexpression of BACH2 locks T cells in a stem/memory differentiation state unable to engage in effector functions and mediate anti-tumour responses in vivo.

To surmount this issue, we have recently developed an approach to deliver dose-adjusted expression of BACH2 at low levels to tumour-reactive T cells, which enhances stem/memory differentiation without compromising effector function. We find that dosed expression of BACH2 to tumour-reactive T cells results in marked improvements to persistence, efficacy and function in murine pre-clinical cell therapy models. With this proposal, we aim to configure dose-optimised BACH2 delivery for deployment in CAR T cell therapy of multiple myeloma using a novel CAR targeting SEMA4A, to optimise quiescence factor dosage for optimal function of anti-SEMA4A CAR T cells in vivo, and to test the safety and efficacy of the new product in widely established pre-clinical models of multiple myeloma.

Our proposed work is organised into three Aims:

Aim 1. Defining the optimal dose for quiescence factor delivery in anti-SEMA4A targeting CAR T cells

Aim 2. Defining efficacy and toxicity of BACH2 dose-optimised SEMA4A CAR T cell therapy in murine pre-clinical multiple myeloma models

Aim 3. Development, pre-clinical efficacy and safety evaluation of a lentiviral vector system for dosed quiescence factor co-delivery with CARs into human T cells

Follow-on funding will be a critical step in translating our BBSRC-funded discoveries through commercialisation of this technology for the benefit of patients and society.