Abstract
Most solid tumors are comprised of multiple clones that express orthogonal antigens, suggesting that novel strategies must be developed in order to adapt chimeric antigen receptor (CAR) T-cell therapies to treat heterogeneous solid tumors. Here, we utilized a cocktail of low-molecular-weight bispecific adapters, each comprised of fluorescein linked to a different tumor-specific ligand, to bridge between an antifluorescein CAR on the engineered T cell and a unique antigen on the cancer cell. This formation of an immunologic synapse between the CAR T cell and cancer cell enabled use of a single antifluorescein CAR T cell to eradicate a diversity of antigenically different solid tumors implanted concurrently in NSG mice. Based on these data, we suggest that a carefully designed cocktail of bispecific adapters in combination with antifluorescein CAR T cells can overcome tumor antigen escape mechanisms that lead to disease recurrence following many CAR T-cell therapies. SIGNIFICANCE: A cocktail of tumor-targeted bispecific adapters greatly augments CAR T-cell therapies against heterogeneous tumors, highlighting its potential for broader applicability against cancers where standard CAR T-cell therapy has failed.
Highlights
Chimeric antigen receptor (CAR) T-cell therapies have recently demonstrated considerable potential in the treatment of a variety of hematopoietic cancers
Together with folate receptor alpha (FRa) that is overexpressed in approximately 40% of human cancers [27], these three tumor-enriched antigens allow for construction of a tumor model that should enable testing of the ability of a single CAR T cell to eradicate a heterogeneous tumor that has mutated to express multiple orthogonal antigens
In response to the antigenic heterogeneity that is believed to arise in almost all solid tumors, many laboratories have explored strategies to create a universal CAR T cell capable of recognizing different cancer cell clones that express unrelated tumor antigens [29,30,31,32]
Summary
Chimeric antigen receptor (CAR) T-cell therapies have recently demonstrated considerable potential in the treatment of a variety of hematopoietic cancers. 5), and upon treatment of refractory/recurrent multiple myeloma, an unrelated CAR T-cell preparation that recognizes B-cell maturation antigen has demonstrated an 89% overall response rate [6]. In the treatment of refractory non-Hodgkin's lymphoma, similar anti–CD19-specific CAR T cells have been shown to achieve a >80% response rates Based on these remarkable results, CAR T-cell therapies are rapidly emerging as one of the most promising developments in clinical oncology in many years.
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