Study: New Factors Are Associated With Increased PFS from BCMA-Targeted T-Cell Therapy

Treatment with B-cell maturation antigen (BCMA)-targeted T-cell therapy increased the likelihood of longer progression-free survival (PFS) for individuals with myeloma whose tumor immune microenvironment had a more diverse baseline T-cell repertoire, distinct changes to immune cell populations, and fewer markers of immune cell exhaustion, according to the results of a study published in Blood Cancer Discovery.

“Two CAR T-cell therapies targeting the [BCMA] are now approved for the treatment of myeloma, but the challenge is that many of the responses to this therapy are not durable, and patients remain at risk for recurrence,” Madhav Dhodapkar, MBBS, a professor at the Emory University School of Medicine said in a statement. “A key goal in the field is to identify the factors that influence the durability of response so that we can improve treatment accordingly.”

In the study, investigators from Emory University and the University of Pennsylvania analyzed 28 pre- and post-treatment bone marrow samples from 11 individuals who had clinical responses to BCMA-targeted CAR T-cell therapy in a previously reported phase 1 clinical trial.

They analyzed samples by single-cell approaches, including CITE-Seq, transcriptomics, mass cytometry, and T-cell receptor sequencing. They compared the change in bone marrow between individuals with long and short PFS, which were defined as greater than 6 months or less than 6 months, respectively.

Investigators found that in individuals with long PFS, the proportion of T cells in bone marrow increased after treatment, while myeloid cell proportions decreased.

They noted that these changes were not observed among individuals with short PFS.

A high proportion of myeloid cells may have contributed to recurrence in the individuals with long PSF by promoting cancer growth and/or suppressing antitumor immunity, the investigators said.

Additionally, post-treatment CAR and non-CAR T cells from individuals with long PFS had a distinct genomic signature with a lower expression of immune checkpoint genes and other genes associated with T-cell exhaustion compared with those with short PFS, according to investigators.

Also, T cells from individuals with long PFS had higher expression of genes associated with bone marrow retention.

Investigators also found that baseline features, such as greater T-cell receptor diversity, higher tumor expression of interferon response genes and mature plasma genes, and lower tumor expression of genes associated with epithelial-to-mesenchymal transition, were associated with PFS.

“The major finding of this study is that the durability of response may be dependent on characteristics of non-CAR T cells and other immune cells in the tumor microenvironment,” Dhodapka said. “This finding has broad implications for the CAR T-cell therapy field, as it emphasizes the importance of the patient’s preexisting immune microenvironment as a determinant of durable responses.”

Investigators think that understanding the baseline factors that affect durable responses could help physicians identify individuals who would benefit from BCMA-targeted CAR T-cell therapy.

Furthermore, the results could introduce opportunities to study combination therapies that target cell types or specific markers associated with relapse.

Reference

Specific components of the tumor immune microenvironment may affect the durability of responses to BCMA CAR T-cell therapy. News release. American Association for Cancer Research. August 29, 2022. Accessed August 30, 2022. https://www.aacr.org/about-the-aacr/newsroom/news-releases/specific-components-of-the-tumor-immune-microenvironment-may-affect-the-durability-of-responses-to-bcma-car-t-cell-therapy/