Posted: Wednesday, August 23, 2023
How can a chimeric antigen receptor (CAR) T-cell therapy hone in solely on multiple myeloma cells that express high quantities of CD229, a signaling lymphocyte-activation molecule family member, when healthy cells express the same molecule, albeit in lower amounts? That important question is the focus of preclinical work by Erica R. Vander Mause, PhD, of the University of Maryland School of Medicine (UMSOM), Baltimore, and colleagues. In Science Translational Medicine, they explained that their use of affinity tuning meant lower frequencies of CD229 CAR T cells targeting healthy lymphocytes—and thus potentially reduced toxicity for patients.
In employing affinity tuning, the team tested 305 single amino acid substitution variants to isolate the CAR T-cell sequence that would best ignore healthy cells, thereby potentially reducing on-target, off-tumor toxicity. Simultaneously, this approach would increase the selectivity of CD229 CAR T cells for multiple myeloma cells.
“We screened variant binding domains using solid-phase binding assays and biolayer interferometry and determined the cytotoxic activity of variant CAR T cells against multiple myeloma cells and healthy lymphocytes,” the investigators explained further. Ultimately, they “identified a CD229 CAR-binding domain with micromolar affinity that, when combined with overexpression of c-Jun, confers antitumor activity comparable to parental CD229 CAR T cells but lacks the parental cells’ cytotoxic activity toward healthy lymphocytes in vitro and in vivo.”
“Clinical studies are currently being initiated at University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer and partnering institutions to investigate, as a first step, the safety and efficacy of CD229-targeted CAR T cells for the treatment of multiple myeloma and possibly also other malignancies,” stated study coauthor Djordje Atanackovic, MD, of UMSOM, in an institutional press release.
Disclosure: The study authors’ disclosure information can be found at science.org.