Although CAR-T cell therapies have significantly improved the treatment of B cell malignancies, many patients relapse even after achieving apparently complete responses. Researchers led by Ludwig MIT’s Michael Hemann reported in a December paper in Nature Communications their exploration of cancer cell-intrinsic mechanisms of resistance to the therapy in a preclinical model of B cell-acute lymphoblastic leukemia (B-ALL) using a novel CRISPR-Cas9 loss-of-function genetic screen. Combining gene expression and in vivo screening data obtained from relapsed B-ALL cells led to the identification of components of the IFNγR/JAK/STAT signaling pathway as key elements of a mechanism of CAR-T therapy resistance. Relapsed murine tumors exhibited heightened activity of this pathway. Functional studies identified a target of this pathway, Qa-1b—the murine homolog of Human leukocyte antigen E (HLA-E) —as essential to the observed resistance mechanism. Functional studies revealed that the mechanism involved cancer cells’ simultaneous interaction with both CAR-T cells and natural killer (NK) cells, with Qa-1b binding a receptor on CAR-T cells to inhibit their activity. NK cell depletion in mice abrogated the effect, significantly extending survival following treatment with CAR-T cell therapy. Ditto for antibodies that blocked Qa-1b interaction with its receptor. Michael and his colleagues note that their findings suggest an approach to improving CAR-T therapy for B-ALL that does not require modification of the CAR-T cells themselves.
Leukemia-intrinsic determinants of CAR-T response revealed by iterative in vivo genome-wide CRISPR screening
Nature Communications, 2023 December 5