Targeting TF (CD142) as a new target for CAR-NK cell immunotherapy in multiple myeloma

Description

Multiple myeloma (MM) is a bone marrow-resident hematologic malignancy of plasma cells and the second most diagnosed blood cancer, after non-Hodgkin lymphoma. Despite the development of myeloma-targeted immunotherapies, MM remains largely incurable. The objective of this research is to evaluate tissue factor (TF, also known as coagulation factor III and CD142) as a new target in MM and generate preliminary data to justify the future conduct of an early phase clinical trial of tissue factor-recognizing chimeric antigen receptor-engineered natural killer (TF CAR-NK) cell therapy as monotherapy and in combination with immune checkpoint blockade therapy (ICBT) in patients with multiple myeloma (MM). Our findings along with those of another group, showed that TF could serve as a new and ideal therapeutic target in MM. This is because TF is expressed on MM cancer lines and MM tumor cells from patients, whereas TF is negative on normal cells (avoiding side effects on harming normal cells) circulating in the blood such as peripheral blood mononuclear cells nor on normal vascular endothelial cells, the inner layer of blood vessels. With our invention of a patent pending TF targeting chimeric antigen receptor modified natural killer (TF-CAR-NK) technology, we were able to evaluate TF as a new target in an innovative CAR-NK cell immunotherapy as monotherapy and in combination with ICBT (for example, anti-PD-1 blocking antibody) for treating MM in preclinical animal trials. Our results demonstrate that TF-CAR-NK cells alone are effective and safe in inhibiting MM tumor growth in mouse models of human MM, when combined with clinically approved anti-PD-1 antibody the combination therapy can achieve a stronger effect compared to anti-PD-1 and TF-CAR-NK alone. With the completion of this preclinical study, we offer an innovative, “off-the-shelf” allogeneic CAR-NK approach that targets a new surface molecule (TF), which could be a more ideal and safer target than current MM targets (e.g., CD38 and B cell maturation antigen, BCMA) and can overcome several limitations of current CAR-T cell therapy. After the successful completion of the translational research, our team of experts will translate the findings into a first-in-human clinical trial in patients with MM. If successful, the findings from this translational research award project may benefit the majority (up to 56%) of MM patients. These findings can also be extended to treat other TF-positive subtypes of plasma cell dyscrasia, such as monoclonal gammopathy of undetermined significance, asymptomatic myeloma, plasma cell leukemia, plasmacytoma and amyloidosis.