In the largest study of its kind, researchers from The University of Texas MD Anderson Cancer Center have identified three subgroups of patients with large B-cell lymphoma (LBCL) who have different levels of benefit from CD19-targeted chimeric antigen receptor (CAR) T cell therapy.
In the study, published by Li et al in Cancer Cell, researchers profiled samples from 232 patients with LBCL to create “LymphoMAPs” that provide detailed information about the environment surrounding lymphoma cells and how they relate to clinical data and patient outcomes. The findings offer new insights to guide physicians toward the best potential clinical pathways for patients based on the underlying biology of the tumors profiled.
"This study marks a pivotal step in refining precision medicine for patients with [LBCL] by accounting for the nonmalignant cells that surround and interact with the malignant B cells,” said corresponding study author Michael Green, PhD, Associate Professor of Lymphoma/Myeloma at MD Anderson. “By identifying the three patient subgroups that have significantly different outcomes following CD19 CAR T-cell therapy, we move toward enhancing treatment selection for clinicians and pave the way for biology-driven targeted therapies for patients who may not respond as well.”
There are three CAR T-cell therapies approved for patients with LBCL—lisocabtagene maraleucel, tisagenlecleucel, and axicabtagene ciloleucel—and these have had promising results for many patients. However, less than half of patients have long-lasting responses to CAR T-cell therapies, highlighting a need to understand the factors that influence outcomes.
Three Lymphoma Microenvironments Identified
Researchers profiled single cells from 232 biopsy samples from 217 newly diagnosed and previously treated patients with lymphoma. In total, researchers profiled over 1.8 million cells—approximately 10 times more than the previous largest study of lymphoma.
To validate these findings, researchers integrated the data with published results from the ZUMA-7 phase III clinical trial, which examined the effectiveness of axicabtagene ciloleucel compared to the standard-of-care therapy in patients with relapsed/refractory diffuse LBCL. Through this work, the researchers identified three primary types of lymphoma microenvironments in patients with LBCL that have different patterns of response to CAR T-cell therapy:
- The fibroblast/macrophage group consists of patients with tumors that are depleted of T cells and contain a high abundance of cancer-associated fibroblasts. These patients have mixed responses when treated with CAR T-cell therapy, but as a group still significantly benefit from the treatment compared to chemotherapy.
- The lymph node group consists of patients with tumors that have many T cells supported by nonhematopoietic cells normally found within lymph nodes that support T-cell health. These patients have the greatest benefit from CAR T-cell therapy.
- The T cell–exhausted group consists of patients with tumors that have mostly CD8-exhausted T-cells and activated macrophages. Researchers found these patients had no significant benefit from CAR T-cell therapy and therefore are in need of alternative therapeutic options. Researchers believe there are opportunities to target key biological pathways of these tumors to improve outcomes.
“The underlying biology clearly supports the association with CAR T-cell [therapy] outcomes and highlights opportunities for interventions using targeted therapies that are either already in the clinic or in the late stages of preclinical development,” Dr. Green said. “These insights bring us closer to optimizing therapies for all patients, ensuring more effective, individualized care.”
Using insights from this study, the authors plan to collaborate with other researchers to advance clinical trials focused on targeted therapies for patients in subgroups with poorer outcomes.
Disclosure: The research was funded by a philanthropic contribution from Beatriz and Ed Schweitzer and by the MD Anderson Lymphoid Malignancies Program. For full disclosures of the study authors, visit cell.com.
