Engineered immune therapies such as chimeric antigen receptor T (CART) have led to major clinical benefits in myeloma patients. However, many of these patients develop recurrent cancer. The likelihood of achieving durable responses may depend on properties of immune cells before CARTs are administered, according to a new study led by researchers at Winship Cancer Institute of Emory University.
The study, “Changes in bone marrow tumor and immune cells correlate with durability of remissions following BCMA CAR T therapy in myeloma,” is the first to systematically examine the connection between distinctive cells formed in the bone marrow and the duration of response to immunotherapy. It was published in Blood Cancer Discovery and its findings were presented at the International Myeloma Society Annual Meeting in Los Angeles, held August 25-27, 2022.
“A key goal in the field is to identify the factors that influence the durability of response so that we can improve treatment accordingly,” says senior author Madhav Dhodapkar, MBBS, the Anise McDaniel Brock Chair and Georgia Research Alliance Eminent Scholar in Cancer Innovation, leader of the Cancer Immunology research program at Winship Cancer Institute, director of the Winship Center for Cancer Immunology and professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine.
The study found that patients with myeloma whose immune microenvironments had more diverse T cells and fewer myeloid cells in the bone marrow showed longer progression-free survival (PFS), the length of time during and after treatment that a patient lives with a disease without it getting worse. This study defined PFS as less or greater than six months. The tumor immune microenvironment contains numerous immune cells, including lymphocytes with tumor suppressing effects, such as CD8+ T cells and natural killer cells, and some tumor-promoting cells with immunosuppressive functions, such as regulatory T cells and myeloid-derived suppressor cells.
Two approved chimeric antigen receptor (CAR) T-cell therapies target the B-cell maturation antigen (BCMA)—a cell surface protein universally expressed on malignant plasma cells. But many people do not experience lasting responses after receiving CAR T-cell therapy.
“The challenge is that many of the responses to this therapy are not durable, and patients remain at risk for recurrence,” says Dhodapkar.
The study design
Dhodapkar and colleagues analyzed 28 pre- and post-treatment bone marrow samples from 11 patients who received, and responded to, CAR T-cell therapy in a previous phase 1 clinical trial. The researchers classified patients into a “long PFS” group—meaning 6 months or longer without recurrence—and a “short PFS” group, meaning 6 months or less until recurrence. They compared changes in patients’ immune cells and bone marrow between the short PFS and long PFS groups to determine which factors correlated with longer PFS.
The researchers found that the proportion of T cells in the bone marrow increased after treatment in patients with long PFS. This change was not found in those with short PFS. The researchers also identified higher proportion of myeloid cells and lower proportion of dendritic cells in patients with short PFS. Dhodapkar suggests that a higher proportion of myeloid cells may have promoted cancer growth and/or suppressed anti-tumor immunity.
The study also found that both CAR and non-CAR T cells from patients with long PFS were genetically distinct, with a lower number of immune checkpoint genes and other genes that indicate T-cell exhaustion than those from patients with a short PFS. T cells from patients with long PFS also had more genes associated with T cell retention in the bone marrow.
Acknowledging the study’s limitations, including its small sample size, Dhodapkar says its findings have broad implications for the CAR T-cell therapy field. “It emphasizes the importance of the patient’s preexisting immune microenvironment as a determinant of durable responses,” he says.
Additional Winship and Emory University researchers contributed to the research, including: Kavita Dhodapkar, MBBS, a research member at Winship Cancer Institute and the scientific director of Winship’s Immune Monitoring Shared Resource, professor in the Department of Pediatrics at Emory University School of Medicine, and director of the Pediatric Immuno-Oncology Program at the Aflac Cancer and Blood Disorders Center at Children's Healthcare of Atlanta; Kaushal Akhilesh, postdoctoral fellow; and Renee Julia Manalo, lead research specialist, Allison R. Carr and Samuel S. McCachren III from the Emory Department of Hematology and Oncology.
The study was supported with funding from the National Institutes of Health CA197603 (5R35CA197603), The Leukemia & Lymphoma Society and the Paula and Rodger Riney Foundation.