Todd Bradley, Ph.D.
Doctoral Research Faculty, Genomic Medicine Center, Children’s Mercy Research Institute

Immunotherapy has revolutionized cancer treatment, yet challenges persist, particularly in overcoming tumor resistance and relapse. Current approaches targeting single tumor antigens often falter when tumors evade immune surveillance by losing the targeted antigen. Our research addresses this hurdle by developing novel combinatorial immunotherapies that simultaneously target multiple tumor antigens.

Building upon our recent work developing bispecific therapeutic antibodies that targeted two tumor antigens on B cell lymphoma, we have engineered dual-targeted chimeric antigen T (CAR-T) cells capable of recognizing and eliminating B-cell malignancies, even in the case of single antigen loss. Our project aims to further develop and characterize these dual-targeted CAR-T cells laying the groundwork for future funding proposals to pave the way for clinical translation.

In our preliminary work, we found that tumor B cells that lacked CD20, that is a common target of immunotherapies, retained expression of another surface marker called CD74. Immunotherapies targeting B cell antigens CD20 or CD74, individually, are approved or in clinical development for targeting B-cell mediated cancers. We showed that bispecific antibodies that targeted both CD20 and CD74 simultaneously lead to killing of B cell tumors, even in tumors that have lost expression of CD20. CAR-T cells allow for direct killing of tumor cells, even in tumor cells with low antigen expression, and has demonstrated superior efficacy to bispecific antibody treatment in lymphoma. We have now engineered CAR-T cells that target both CD20 and CD74 simultaneously in the same CAR-T cells. The overall goal of our project is to determine if our novel dual-targeting CAR-T cells will have increased efficacy against tumor cells that have loss expression of the single CD19 or CD20 antigens, which are the targets of current immunotherapies. This study’s findings may have broader implications for enhancing the efficacy of CAR-T cell therapy in other B-cell malignancies and autoimmune diseases, offering potential new tools for patients facing treatment-resistant tumors. The successful testing of dual-targeted CAR-T cells in this pilot study will lay the groundwork for further development of more effective and durable treatments for patients with refractory B-cell malignancies.