Immune environment may dictate durability of response to CAR-T for multiple myeloma
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Prolonged responses to chimeric antigen receptor T-cell therapy for advanced multiple myeloma may depend on the composition of the patient’s post-treatment immune microenvironment, results from a retrospective study showed.
Patients with prolonged PFS after B-cell maturation antigen (BCMA)-targeted CAR-T had a higher proportion of T cells and a lower proportion of myeloid cells in the bone marrow than those who achieved shorter PFS, researchers from Emory University and University of Pennsylvania determined.
Patients with prolonged PFS had CAR T cells and other immune cells that exhibited lower genomic levels of cell exhaustion than those who had shorter PFS, according to the results, published in Blood Cancer Discovery and simultaneously presented at International Myeloma Society Annual Meeting.
Background
“Two CAR T-cell therapies targeting [BCMA] are now approved for the treatment of [multiple] myeloma, but the challenge is that many of the responses to this therapy are not durable and patients remain at risk for recurrence,” Madhav V. Dhodapkar, MBBS, professor at Emory University School of Medicine and director of Center for Cancer Immunology at Winship Cancer Institute of Emory University, said in an American Association for Cancer Research-issued press release. “A key goal in the field is to identify the factors that influence the durability of response so that we can improve treatment accordingly.”
Methodology
Dhodapkar and colleagues analyzed 28 pre- and post-treatment bone marrow samples from 11 patients who received BCMA-directed CAR T cells as part of a previous phase 1 trial and responded to therapy.
The investigators analyzed bone marrow samples using numerous single-cell methods, including CITE-Seq, transcriptomics, mass cytometry and T-cell receptor sequencing.
Researchers classified patients into a “long PFS” group — meaning PFS of 6 months or longer — and a “short PFS” group, meaning PFS of 6 months or less.
Investigators compared changes in immune cell composition and bone marrow microenvironment between the short PFS and long PFS groups to determine factors that correlated with prolonged response to therapy.
Key findings
Presence of hyperexpanded clones with exhaustion phenotype, as well as BAFF-positive/PD-L1-positive myeloid cells in the marrow, appeared associated with shorter PFS after CAR T-cell therapy.
Increased proportion of CLEC9A-positive dendritic cells, CD27-positive/TCF1-positive T cells with diverse T-cell receptors, and emergence of T cells that expressed bone marrow-residing genes correlated with longer PFS.
Clinical implications
Many prior studies have focused on how features of CAR T cells affect treatment durability. This study is unique in that it focused on how other immune cells in the tumor microenvironment may affect responses after therapy, Dhodapkar 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,” he said in the press release.
Dhodapkar acknowledged study limitations, including its small sample size, and noted larger independent studies should be conducted to confirm his group’s findings.
“Our analysis of responding patients receiving an experimental BCMA-specific CAR T-cell therapy suggests that durable responses may depend not just on properties of CAR T cells but also on endogenous T-cell states and properties of the [tumor microenvironment], including the myeloid/[dendritic cell] compartment and tumor cells themselves,” Dhodapkar and colleagues wrote.
The analysis by Dhodapkar and colleagues was the first to “systematically examine the hematopoietic cell lineages associated with duration of response to BCMA-targeted CAR T cells in the [tumor microenvironment],” Charlotte E. Graham, MRCP, FRCPath, PhD, and Marcela V. Maus, MD, PhD, both from Harvard Medical School and the cellular immunotherapy program at Mass General Cancer Center, wrote in an accompanying commentary.
“The authors show that endogenous T cells, myeloid cells and dendritic cell populations may influence or be associated with the duration of response to BCMA CAR T cells,” Graham and Maus wrote. “This implies that response is not just a direct interaction between effector and target cells, but rather that a favorable [tumor microenvironment] is required for sustained anti-tumor activity.”
Further study is needed “to delineate the mechanisms by which endogenous bone marrow immune cells could impact on BCMA CAR T cell function,” Graham and Maus said.
References :
- Dhodapkar KM, et al. Blood Cancer Discov. 2022;doi:10.1158/2643-3230.BCD-22-0018.
- Graham CE, et al. Blood Cancer Discov. 2022;doi:10.1158/2643-3230.BCD-22-0126.
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Dhodapkar KM, et al. Blood Cancer Discov. 2022;doi:10.1158/2643-3230.BCD-22-0018.
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