Minerva Biotechnologies has published breakthrough research in the Journal for ImmunoTherapy of Cancer demonstrating that CAR-T cells targeting MUC1* with 1XX mutations overcome key barriers in solid tumor treatment. The study, titled "Effective CAR T cell targeting of a MUC1 cleavage product," reveals promising advances in addressing the persistent challenge of CAR-T cell exhaustion in solid tumor environments.
Novel MUC1* Target Shows Broad Therapeutic Potential
The research focuses on MUC1*, a cancer-specific growth factor receptor expressed on the surface of 75% of solid tumors. This represents a significant development in a field where, despite MUC1 being known for 30 years to be aberrantly expressed in three-quarters of solid tumors, no therapeutic targeting MUC1 has ever received Food and Drug Administration approval.
The identification challenge has centered on determining exactly which form of MUC1 drives tumor growth and metastasis. The development of a MUC1* antibody that selectively recognizes the cancer-associated growth factor receptor form represents an important advance in resolving this long-standing controversy.
Enhanced CAR-T Performance Through 1XX Technology
The study 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.
In animal models, the MUC1* CAR-1XX demonstrated increased CAR T-cell persistence and suppressed tumor recurrence by enabling the killing of low antigen-expressing cancer cells. This capability addresses a critical limitation in current CAR-T therapies, where cells often become exhausted and lose effectiveness against tumors with heterogeneous antigen expression.
"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*."
Clinical Translation and Patient Impact
The in vivo efficacy of MUC1* targeted CAR-1XX T cells against heterogeneous tumors comprising defined percentages of low versus high antigen expressing cancer cells predicts that a large patient population could be treated with MUC1* targeted CAR T immunotherapy.
Minerva Biotechnologies has secured FDA approval for an Investigational New Drug (IND) application for MUC1*-CAR22, which persists longer in vivo enabling a more durable response in solid tumor treatment. This regulatory milestone positions the company to advance toward clinical trials.
The technology development has been supported through a license agreement with Memorial Sloan Kettering Cancer Center for the 1XX technology, highlighting the collaborative nature of this therapeutic advancement.
Addressing Solid Tumor Treatment Challenges
The research addresses fundamental challenges in extending CAR-T cell therapy beyond hematologic malignancies to solid tumors. Traditional CAR-T approaches have struggled with the solid tumor microenvironment, where factors including antigen heterogeneity and T-cell exhaustion limit therapeutic efficacy.
The 1XX mutations in the CD3ζ cytoplasmic domain appear to enhance CAR-T cell function specifically in the challenging solid tumor context, potentially overcoming barriers that have limited previous approaches. The ability to target cancer cells with low antigen expression is particularly significant, as tumor heterogeneity often includes populations of cells with varying antigen levels.
