From the Journals

New CAR T-cell therapy eliminates MM and tumor propagating cells without fratricide in lab study



Researchers have developed chimeric antigen receptor (CAR) T cells expressing a fully human antibody against CD229, a surface antigen that shows universal and strong tumor expression in patients with multiple myeloma (MM). These cells proved to be active in vitro and in vivo against MM plasma cells, memory B cells, and MM-propagating cells, according to a report in Nature Communications.

Histopathologic image of multiple myeloma. Smear preparation of bone marrow aspirate stained with May-Grünwald-Giemsa procedure. Wikimedia Commons/KGH/Creative Commons License

This research is important because most MM patients eventually succumb to the disease and previously developed CAR T cells targeting B-cell maturation antigen (BCMA) on MM cells have shown high-response rates but limited durability.

Previous research showed that CD229/LY9 is a potential target for CAR T-cell therapy in MM because of its strong and homogeneous expression on the bulk of tumor cells, as well as chemotherapy-resistant myeloma progenitors; its absence from most normal cells; and dependence of MM cells on CD229 for their survival, according to Sabarinath V. Radhakrishnan, MD, of the University of Utah, Salt Lake City, and colleagues.

Using primary CD138+ tumor cells from three patients with plasma cell leukemia, a highly aggressive form of MM, which all showed high expression of CD229, the researchers found that CD229 CAR T cells exhibited high cytotoxic activity against these cells. In addition, when assessing two MM cell lines, U-266 and RPMI-8226, expressing different levels of CD229, they found that CD229 CAR T cells efficiently killed both cell lines in vitro.

“We do not observe fratricide during CD229 CAR T-cell production, as CD229 is downregulated in T cells during activation. In addition, while CD229 CAR T cells target normal CD229high T cells, they spare functional CD229neg/low T cells. These findings indicate that CD229 CAR T cells may be an effective treatment for patients with MM,” the authors concluded.

The study was funded by several nongovernmental organizations and the National Cancer Institute. Three of the authors are inventors on PCT application US2017/42840 “Antibodies and CAR T Cells for the Treatment of Multiple Myeloma” describing the therapeutic use of CD229 CAR T cells.

SOURCE: Radhakrishnan SV et al. Nat Commun. 2020 Feb 7;11(1):798. doi: 10.1038/s41467-020-14619-z.

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