Title: Investigating Immune cell fitness to determine patient response to Chimeric Antigen Receptor (CAR)T-Cell therapy
Funder: Health and Care Research Wales (Welsh Government)

Abstract: Chimeric Antigen Receptor (CAR)-T cells are at the forefront of cancer immunotherapy with great promise as treatments for haematological cancers including advanced diffuse large B-cell lymphoma (DLBCL). There are limited predictors of long-term response to CAR-T therapy which is extremely expensive despite relapse in 50-60% of recipients. Acute toxicity from cytokine release syndrome (CRS) and significant neurotoxicity impacting cognitive function means this treatment has a significant impact on quality of life for many patients and biomarkers to screen for patient suitability and the mechanisms underpinning this area lags behind. The functional and proliferative capacity of CAR-T cells appears to determine initial anti-tumour efficacy, but the longer term responses and underlying parameters constituting T- cell fitness remain undefined and may be influenced by both the characteristics of the patient´s own T-cells during the manufacturing process and immunological interactions with the tumour microenvironment after infusion into the patient. This precision medicine approach brings variation in both the patient cellular properties and a lack of effective standardization methods for manufacture which further exacerbates this issue. Some limited T cell fitness parameters have been explored individually (Activation, Proliferation, Exhaustion, Differentiation) in animal models and during manufacture, however the effects of the patient microenvironment and the screening of multiple biomarkers not been jointly studied before in primary patient samples obtained during CAR-T cell therapy. Our multidisciplinary team will explore fitness biomarker dynamics in patient samples serially before and after infusion to identify the best fitness biomarkers and timepoints for clinical monitoring compared to age matched healthy immune cell properties. This will include assessment of Telomere length, Immunosuppressive microenvironment cytokines within the peripheral blood, bone marrow and lymph sites, T cell sub-population analysis and metabolic function and homing capacities. We aim to develop a greater understanding of the interplay between CAR-T cells and the tumour microenvironment as a determinant of CAR-T cell efficacy and identify QA/QC parameters for academic/commercial manufacture of new CAR-T products. This feasibility study will prospectively profile distinct functional properties of CAR-T cells to refine a biomarker panel regarding CAR-T efficacy and persistence prior to development of a large scale CAR-T consortium funding bid linking the data to clinical outcomes with the goal of optimising and incorporating clinical assays that will a priori predict whether a patient will or will not respond to this high cost, high toxicity therapy. Our data will be fed into the commissioning pipeline for CAR-T therapies to help clinicians and policy makers map the best treatment pathway for lymphoma patients in Wales.

Lay abstract: Recent advances in cancer therapy have recognised that killer T cells within the body’s immune system can target cancer cells. A novel approach called chimeric antigen receptor (CAR)-T cell therapy which engineers killer T-cells from the blood of patients to kill the patient’s own tumour cells is provided on the NHS for some blood cancers and is being delivered to patients in Wales for the first time over the last year. While this remarkable therapy cures about half of patients with advanced lymphoma, the remaining 50% of patients relapse and die within 6 months (at a cost of up to £500,000 per patient) and there is currently no way of predicting which patients to treat. The reasons why CAR-T cell therapy fails is unclear but may involve the ‘fitness’ of the T cells being engineered as these patients tend to be heavily pre-treated with other chemotherapies. This could mean either that the CAR-T cells don’t expand inside the body or that they don’t last very long there. We will explore key immune T cell behaviours that are considered important for their anti-cancer activity: 1) Their ability to grow and divide before and after treatment 2) The ability to travel through the blood stream and reach the correct tumour site in the body 3) The types of killer T cells present in the CAR-T product and how they interact with the tumour and surrounding cells (microenvironment) after they are infused into the patient. We will compare how lymphoma patient immune cells differ to normal healthy immune cells along the treatment pathway to see if patients should have their cells preserved earlier for use at a later date. Our feasibility study aims to use excess patient samples at serial timepoints before and after CAR-T treatment to develop a panel of biomarkers which can identify which patients will produce effective CAR-T cell products and improve the quality of the killer T cells made. We will co-ordinate a multidisciplinary team of scientists, clinical colleagues and patient/public groups to develop and communicate our findings at a local and national level, increasing our potential for patient impact. Achieving these goals would greatly benefit patient outcomes and quality of life by tailoring the best treatment for the individual patient. This timely project has the potential to save a considerable amount of healthcare resources by providing quality data to map the best treatment pathway for lymphoma patients in Wales.

Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS;INFLAMMATORY AND IMMUNE SYSTEM