T cell balancing act

The latest debate in CAR T is whether CD8+ or CD4+ cells play the bigger role

Among the improvements to next-generation CAR T cell therapies is the need to optimize the ratios of the different T cell subsets. While CD8+ T cells have grabbed most of the attention, a study from City of Hope suggests that for some cancers, companies should look to CD4+ cells instead.

The dominant hypothesis is that CD8+ T cells are the primary cytotoxic agents in CAR T therapies. CD4+ T cells have played a Cinderella role, perceived as helpers that boost the killing power of their CD8+ counterparts.

But a growing body of research suggests CD4+ cells can directly kill tumors as well, raising the question of what balance of the cell types will provide the best therapy.

Two studies came to opposite conclusions. While a University of Pennsylvania study in Nature Medicine found CD8+ T cells were more powerful, the City of Hope , published in JCI Insight, argued that CD4+ cells drive bigger, longer lasting responses. Both studies were published last month.

First-wave CAR T therapies Kymriah tisagenlecleucel from Novartis AG and Yescarta axicabtagene ciloleucel from Gilead Sciences Inc. contain undefined mixtures of T cell subtypes that vary from patient to patient. The composition reflects the ratios present in the patient’s leukapheresis

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