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bioRxiv · 10.1101/2024.09.27.615167

A balanced CAR-T cell metabolism driven by CD28 or 4-1BB co-stimulation correlates with clinical success in lymphoma patients

Cook, M.·Flaherty, K.·Papa, S.·Benjamin, R.·Schurich, A.
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Abstract

Chimeric antigen receptor (CAR) T cell therapy has led to unprecedented success in treating relapsed/refractory diffuse large B cell lymphoma (DLBCL). The most common CAR-T cell products currently in the clinic for DLBCL differ in their co-stimulation moiety, containing either CD28 or 4-1BB, which initiate distinct signalling pathways. Previous work has highlighted the importance of T cell metabolism in fuelling anti-cancer function. We have studied the metabolic characteristics induced by CD28 versus 4-1BB co-stimulation in patient CAR-T cells ex vivo. Our data show that in patients, CD28 and 4-1BB drive significantly divergent metabolic profiles. CD28 signalling endows T cells with a preferentially glycolytic metabolism supporting an effector phenotype and increased expansion capacity, while 4-1BB co-stimulation preserves mitochondrial fitness and results in memory-like differentiation. Despite this divergent programming, T cells in patients responding successfully to therapy were metabolically similar, irrespective of co-stimulator, suggesting that efficient fuelling of CAR-T cells in lymphoma requires a balanced metabolism. In contrast, CAR-T cells in non-responders were pushed to their metabolic extremes. One sentence summaryCD28 and 4-1BB signalling drive divergent metabolic profiles in patient CAR-T cells, however patients that respond to therapy have CAR-T cells that maintain metabolic balance.

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Cook, M., Flaherty, K., Papa, S., Benjamin, R., Schurich, A.. 2024-09-29. A balanced CAR-T cell metabolism driven by CD28 or 4-1BB co-stimulation correlates with clinical success in lymphoma patients. https://doi.org/10.1101/2024.09.27.615167

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