Minerva Biotechnologies - Overcoming the Solid Tumor Barrier: MUC1*-Targeted CAR T bearing 1XX mutations overcomes exhaustion and enables killing of low antigen expressing cancer cells
Novel target, MUC1*, is a cancer-specific growth factor receptor that is expressed on the surface of 75% of solid tumors. In this study, we compared the efficacy, persistence and antigen sensitivity of three MUC1* CARs, all directed to the tumor by the same antibody fragment, but bearing different co-stimulatory domains and one construct bearing the 1XX mutations in the CD3ζ cytoplasmic domain.
We showed that in animal models, the MUC1* CAR-1XX increased CAR T-cell persistence and suppressed tumor recurrence by enabling the killing of low antigen-expressing cancer cells. 'These findings in stringent animal models are very encouraging for developing 1XX CAR T cells to treat solid tumors,' said Michel Sadelain, inventor of the 1XX technology. 'They further underscore the promise of targeting the cleaved form of MUC1 known as MUC1*."
The in vivo efficacy of MUC1* targeted CAR-1XX T cells against heterogeneous tumors comprising defined percentages of low vs high antigen expressing cancer cells predicts that a large patient population could be treated with MUC1* targeted CAR T immunotherapy.
Although MUC1 has been known for 30 years to be aberrantly expressed in 75% of solid tumors, no therapeutic targeting MUC1 has ever been Food and Drug Administration approved. Part of the problem is that the identification of exactly which form of MUC1 drives tumor growth and metastasis has been controversial. The development of a MUC1* antibody that selectively recognizes the cancer-associated growth factor receptor form, as described here, is an important advance.
Minerva has an FDA-approved IND for a MUC1*-CAR22 that persists longer in vivo enabling a more durable response in solid tumor treatment.
We thank Memorial Sloan Kettering Cancer Center for the license to 1XX technology.
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