A single viral step can strip donor T-cells of their identity-tagging receptors, turning them into ready-made cancer killers that any patient can receive off the shelf. This matters because current CAR T-cell therapy—a treatment that re-engineers a patient’s own immune cells to attack tumours—requires a bespoke, weeks-long manufacturing process that fails about 10% of the time and costs a fortune. Using donor cells would eliminate the need for each patient to undergo leukapheresis, guarantee product quality, and allow economies of scale in manufacturing. If the TCR-KDEL platform works in this early clinical test against advanced B-cell malignancies, it could slash production time from weeks to days and dramatically lower the cost of CAR T-cell therapy. That would broaden access to a treatment currently limited to well-resourced centres and wealthy health systems. The approach is not limited to one cancer target—success here would open the door to cheaper, faster, more reliable cell therapies for a range of tumour types.
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Chimeric Antigen Receptor (CAR) T-cell therapy has recently been approved in the USA and Europe for the treatment of relapsed B-cell malignancies, with potential further application in a broad range of tumour types. Currently, most CAR T-cell products are generated as autologous bespoke products for each patient. This has several disadvantages: each patient must undergo leukapheresis; production failure rate is ~10%; product quality is not guaranteed; there is a 3-4 week lag time to treatment; and economies of manufacturing scale cannot be applied. A potential solution is allogeneic CAR T-cells from healthy donors, which could be manufactured in advance, quality-checked and cryopreserved for timely administration to any potential patient. However, unrelated donor CAR T-cells would cause severe or fatal graft-versus-host-disease (taGvHD) mediated by the T-cell receptor (TCR) of donor T-cells. To deliver allogeneic CAR T-cells, TCR signalling must be prevented. To date, allogeneic CAR T-cell strategies have used genome-editing to delete the TCR. Indeed, we were the first to describe clinical use of anti-CD19 CAR T-cells generated from allogeneic TALEN-edited cells. While some clinical efficacy has been seen, a complex multi-stage manufacturing process is required, with highly stringent depletion of TCR positive T-cells. This difficult manufacture obviates much of the advantage in terms of practicality / cost of goods for allogeneic cells. We have since developed an alternative platform for allogeneic CAR T-cell manufacturing without genome-editing. By co-expressing a TCR-specific single-chain variable fragment with a Golgi retention signal (TCR-KDEL) along with the CAR, TCR-negative CAR T-cells can be generated with a single viral transduction. Further, additional co-expression of a GMP compliant marker gene facilitates facile highly stringent selection of TCR-negative, CAR-positive cells in a single sorting step. With this grant, we propose to test the TCR-KDEL allogeneic CAR T platform in patients with advanced B-cell malignancies, using a next-generation CD19 CAR (CAT19) currently in several studies at our centre. While we do not expect TCR-KDEL usage to be limited to CD19 CAR, testing with CAT19 allows direct comparison with ongoing autologous CAR studies, and acts as a 'proof of concept' for potential future studies. We anticipate our approach could reduce cost and broaden access to CAR T-cell therapy.
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