Understanding molecular determinants of immune evasion to CAR-T cells at single clone resolution
Mark Dawson
PhDThe University of Melbourne
Project Term: July 1, 2023 - June 30, 2026
Cellular immunotherapies such CAR-T cells are now firmly established as major pillars of anti-cancer therapy particularly in B-cell malignancies. However, despite their remarkable success in mediating an objective clinical response in up to 90% of patients, long-term durable remissions remain confined to only a minority of patients. It is now increasingly apparent that genetic evolution through the acquisition of new mutations cannot solely explain the molecular basis for therapeutic resistance. Therefore, to meet our ambition of precision medicine we need a better understanding of both the genetic and non-genetic mechanisms of malignant clonal dominance and therapeutic adaptation. To address this important challenge, we have developed new ex vivo and in vivo (mouse models) of resistance to CAR-T therapy. These will be coupled to a synthetic clone tracing strategy termed SPLINTR (Single-cell Profiling and LINeage Tracing) using expressed barcodes. In this proposal we will use SPLINTR in our models to uncover the clone intrinsic properties of cancer cells that enable them to evade these pioneering cellular immunotherapies. This research will deliver a blueprint around which future clinical trial strategies could be enabled to improve outcomes with these ground-breaking therapies.
Anti-cancer cellular immunotherapies such as CAR-T cells have resulted in durable and curative responses in thousands of patients who have failed conventional therapeutic approaches. CAR-T cells are made by collecting T cells from the patient and re-engineering them to produce proteins on their cell surface called chimeric antigen receptors (CAR), this in turn enables the CAR-T cells to to detect and attach to tumour specific proteins and kill the cancer cells. Despite the success of CAR-T cells in inducing clinical remission, durable responses and cures are limited to a small fraction of the overall number of patients who receive them highlighting the enduring challenge of acquired resistance which limits the utility of these therapies in the vast majority of cancer patients. Most patients who relapse after an initial clinical response, do so within the first 12-18 months of treatment.
It is now becoming increasingly apparent that acquired mutations, in response to therapeutic pressure exerted by CAR-T cells, is unlikely to be the main driving force for resistance within this timeframe. This fact has brought to the fore the importance of understanding non-genetic mechanisms of therapeutic adaptation to anti-cancer immune surveillance. Using cutting-edge single cell technologies that we have developed, we will study this clinical problem in innovative and clinically relevant biological models’ systems. Our ambition is to use these insights to design and develop novel therapeutic approaches to curtail and overcome these resistance mechanisms and improve outcomes for patients with various B-cell malignancies treated with CAR-T cells.