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Background Chimeric antigen receptor T cell therapy targeting B cell maturation antigen on multiple myeloma is quick but not long-lasting responses. In vitro trimer-BB6 CAR T cells were more flexible and produced more synapses than monomer-BB/u03b6 CAR T cells. CAR T cells were quickly internalized, and BCMA on MM cells was rapidly digested by trogocytosis. We investigated whether non-functional CAR T cells play a role in tumor formation since BCMA can be re-expressed during progression and persistent CAR T cells may not shield patients from relapse. Although CAR T cell-MM cell interactions triggered the BCMA pathway, we did not find increased tumor formation in vitro or in vivo, we did not find enhanced tumor formation in vitro or in vivo. Our report sheds light on the underlying causes of CAR T cell failure in MM when targeting BCMA and can inform the design of new treatment protocols.
Source link: https://europepmc.org/article/MED/36323436
Pre- and post-B-cell maturation antigen-specific CAR T therapy was used by multiple investigators in the tumor microenvironment of myeloma patients' pre- and post-B-cell maturation antigen-specific CAR T therapy. Longer PFS was correlated with an elevated number of CLEC9A+ dendritic cells, CD27+TCF1+ T cells with varying T-cell receptors, and the emergence of T cells with marrow-residence genes. The emergence of new dominant clones in primary response reveal stemlike genes, and tumor recurrence was traced to the emergence of new dominant clones. These results reveal a dynamic interplay between endogenous T, CAR T, myeloid/DC, and tumor compartments that can influence response sensitivity following CAR T therapy in myeloma. Following CAR T therapy, a high-dimensional review of the TME was done to find characteristics of immune and tumor cells that correlate with survival, as well as other intervention plans to increase outcomes following CAR T therapy.
Source link: https://europepmc.org/article/MED/36026513
CAR T cells from GPRC5D-targeted CAR T cells are demonstrated to be highly effective in a BCMA antigen escape model, according to preclinical reports. Methods of Administration In this phase I dose escalation study, we administered a GPRC5D-targeted CAR T-cell therapy at four dose levels to patients with acutely treated multiple myeloma, as well as patients with relapse after BCMA CAR T-cell therapy. Responders included those who had recently received BCMA drugs; responses were observed in 7 of ten such patients in the entire cohort; and in 3 of 6 such patients who received 25 to 150 6 cells. GPRC5D is a novel immunotherapeutic target in multiple myeloma, according to the findings of this review.
Source link: https://europepmc.org/article/MED/36170501
According to reports, there is a need to expand and maintain BCMA expression on MM cells in patients undergoing BCMA-CAR T-cell therapy. In pre-clinical studies, we used all-trans retinoic acid to raise BCMA expression on MM cells and improve the efficacy of BCMA-CAR T-cells. ATRA treatment has resulted in an increase in BCMA transcripts by quantitative PCR and a rise in BCMA protein expression by flow cytometry in MM cell lines and primary MM cells, according to our results. Following ATRA treatment, Analyses with super-resolution microscopy confirmed increased BCMA protein expression and revealed an even distribution of non-clustered BCMA molecules on the MM cell membrane. In vitro and in vivo, combined cell culture treatment of MM cells with ATRA and the ostensible antise inhibitor cren. . . cestat has also improved BCMA expression and the efficacy of BCMA-CAR T-cell therapy.
Source link: https://europepmc.org/article/MED/36047086
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