Post-infusion CAR Treg cells identify patients resistant to CD19-CAR therapy
Good et al. Nat Med (2022)
Axi-cel is a chimeric antigen receptor (CAR) T cell therapy that involves programming a patient’s own T cells to express a receptor that targets a unique cancer specific protein. Over half of axi-cel-treated patients with large B cell lymphoma fail to benefit from treatment and two-thirds develop neurologic toxicities, which can be fatal. Understanding the therapy-intrinsic factors that maximize tumor response and minimize toxicity is critical to a successful cancer treatment.
Good et al. at Stanford School of Medicineused a 37-marker mass cytometry to identify biomarkers associated with disease progression or severe neurotoxicity by profiling post-infusion CAR T cells from 31 patients with large B cell lymphoma treated with axi-cel. The authors identified two effector CAR T cell metaclusters associated with response, both of which expressed CD57 and had lower than average expression of inhibitory proteins, like PD-1. Surprisingly, they also discovered a metacluster associated with progressive disease characterized by high expression of markers typically found on immunosuppresive regulatory T cells (Tregs), including Helios, CD25, CTLA-4, and TIGIT. This CAR Treg metacluster finding was validated in a prospective cohort of 31 patients with large B cell lymphoma treated with axi-cel at the authors’ institution.
This manuscript highlights the utility of mass cytometry to identify markers indicative of disease progression and neurotoxicity in patients with large B cell lymphoma. Importantly, Good and colleagues identified a novel population of CAR T cells that may be fine-tuned, either at the time of infusion or after, to potentially maximize the anti-tumor effect or minimize neurotoxicity.
Reference citation: Good Z, Spiegel JY, Sahaf B et al. Post-infusion CAR TReg cells identify patients resistant to CD19-CAR therapy. Nat Med 28, 1860–1871 (2022). doi: 10.1038/s41591-022-01960-7