CAR-T cells: Beyond CD19
CAR-T cells are a new and exciting drug class in which treatment involves the use of transformed immune cells for cancer therapy. A patient’s T- cells are removed, transduced and expanded ex vivo. The genetically modified T- cells are infused back to the patient where they bind and kill their cancer cell target. The basic principle of CAR-T cell design involves recombinant receptors (CARs) that combine antigen-specific binding and T-cell activating functions. The success of this technology for the treatment of leukemia and lymphoma has led to the recent approvals of KymriahÔ (Novartis ) and YescartaÔ (Kite). With improvements in T-cell engineering and the identification of new cancer targets, there is now promise to expand this approach to treat other cancers including multiple myeloma (MM).
Here we highlight an article from Norris Lam, Leah Alabanza, Nathan Trinklein, Ben Buelow and James N. Kochenderfer in which they describe the design, construction and testing of CARs with 4 different single fully-human heavy-chain-only variable domains (FHVH) with specificity to the B-cell maturation antigen (BCMA). BCMA is expressed in MM and CAR-T cells specific for BCMA have been shown to have activity against MM. Replacement of the standard single-chain variable sequence with the FHVH should result in reduced immunogenicity, because the CAR has been designed to minimize the number of junctions and incorporates no linkers, thereby eliminating these as immunogenic targets.
The FHVH CARs were used to transduce T-cells and shown to express BCMA on the cell surface. T-cells expressing FHVH CAR specifically recognized the B-cell maturation antigen (BCMA) expressed on target cells as evaluated in an in vitro functional assay measuring interferon gamma release. Further, the authors report that BCMA-specific CARs led to tumor eradication in a mouse tumor model.
Please click to view the article, entitled “T Cells Expressing Anti-B-Cell Maturation Antigen (BCMA) Chimeric Antigen Receptors with Antigen Recognition Domains Made up of Only Single Human Heavy Chain Variable Domains Specifically Recognize BCMA and Eradicate Tumors in Mice”, published in Blood 2017 130:504.
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