Patient Immune Cells Could Determine Durability of CAR T-Cell Therapies Approved to Treat Myeloma

Investigators announced 2 CAR T-cell therapies that target B-cell maturation antigen (BCMA) were approved to treat myeloma; however, the therapies may not be durable for all patients and could put some patients at risk for recurrence, according to investigators in a study published in Blood Cancer Discovery. The study authors noted that BCMA-targeted T-cell therapy was observed to increase the progression-free survival (PFS) of patients who had a diverse baseline T-cell repertoire in their tumor immune microenvironment, less immune cell exhaustion, and immune cell population changes.

“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,” said senior author Madhav Dhodapkar, MBBS, professor at the Emory University School of Medicine and the director of the Center for Cancer Immunology at the Winship Cancer Institute of Emory University, in a press release.

The team of investigators, comprised of senior author Dhodapkar, co-authors Kavita Dhodapkar, MD, of Emory University and Adam Cohen, MD, of the University of Pennsylvania, among other colleagues, conducted this study to understand factors that influence durable responses to BCMA-targeted T-cell therapy.

After identifying 11 patients with clinical responses from a previous BCMA-targeted CAR T-cell therapy trial, the investigators used single-cell approaches like CITE-Seq and transcriptomics to analyze 28 pre- and post-treatment bone marrow patient samples. Then they compared the bone marrow microenvironment of patients with short PFS at less than 6 months to patients with longer PFS at greater than 6 months.

Investigators identified that in long PFS patients, T cell proportions were found to increase while myeloid cell proportions decreased post-treatment. Further, high levels of myeloid cells might be a contributing factor to cancer recurrence, according to Dhodapkar.

Among short PFS patients, the investigators observed no changes in myeloid or T cell proportions after BCMA-targeted CAR T-cell therapy. Short PFS was also associated with more immune checkpoint genes and genes associated with T-cell exhaustion. Additionally, the investigators observed that the genes in long PFS patients expressed higher levels of bone marrow retention in post-treatment CAR and non-CAR T cells.

Based on the data from long PFS patients, the investigators observed baseline features such as high T-cell receptor diversity and expression interferon response genes—partnered with low expression of genes associated with epithelial-to-mesenchymal transition—were found to increase PFS.

“The study by Dhodapkar and colleagues provides the first hints (and data set) that endogenous immunity may play a role in sustaining antitumor responses that are initiated by direct antitumor CAR T cells,” wrote the study authors in Blood Cancer Discovery.

Additionally, the study was limited due to a small sample size. Further, investigators examined the bone marrow immune cells externally, which limited the potential to holistically understand the cells in their microenvironment.

In the future, the study authors noted that they would like to pursue similar analyses of bone marrow cells from patients receiving commercially available BCMA-targeted CAR T-cell therapies. They explained further that this additional data would allow them to hone in on those factors that remain most important for determining response durability, according to Cohen.

Reference

Specific components of the tumor immune microenvironment may affect the durability of responses to BCMA CAR T-cell therapy. American Association for Cancer Research. August 30, 2022. Accessed on August 31, 2022. https://www.eurekalert.org/news-releases/963287