Researchers from The University of Texas MD Anderson Cancer Center have identified three distinct subgroups of patients with large B-cell lymphoma (LBCL) who demonstrate significantly different responses to CD19 chimeric antigen receptor (CAR) T cell therapy. The findings, published in Cancer Cell, represent the largest study of its kind and offer new insights to guide precision medicine approaches for lymphoma treatment.
The study analyzed samples from 232 patients with LBCL to create "LymphoMAPs" that provide detailed information about the tumor microenvironment and its relationship to clinical outcomes. Researchers profiled over 1.8 million cells, approximately 10 times more than previous lymphoma studies of this type.
"This study marks a pivotal step in refining precision medicine for patients with large B-cell lymphoma by accounting for the non-malignant cells that surround and interact with the malignant B-cells," said corresponding author Michael Green, Ph.D., 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."
Three Distinct Tumor Microenvironments
The research team profiled single cells from 232 biopsy samples from 217 newly diagnosed and previously treated lymphoma patients. To validate their findings, researchers integrated the data with published results from the ZUMA-7 Phase III clinical trial, which examined the effectiveness of axicabtagene ciloleucel (axi-cel) compared to standard-of-care therapy in patients with relapsed/refractory diffuse large B-cell lymphoma.
Through this analysis, researchers identified three primary types of lymphoma microenvironments with distinct CAR-T response patterns:
The fibroblast/macrophage group consists of patients with tumors depleted of T cells and containing a high abundance of cancer-associated fibroblasts. These patients demonstrate mixed responses to CAR-T therapy but still significantly benefit compared to chemotherapy as a group.
The lymph node group includes patients with tumors containing many T cells supported by non-hematopoietic cells normally found within lymph nodes that support T cell health. This subgroup shows the greatest benefit from CD19 CAR-T cell therapy.
The T cell exhausted group comprises patients with tumors containing mostly CD8 exhausted T-cells and activated macrophages. Researchers found these patients had no significant benefit from CAR-T therapy and are in need of alternative therapeutic options.
Clinical Implications and Future Directions
The findings address a critical clinical challenge in CAR-T therapy. While three CAR-T cell therapies are approved for patients with LBCL and have shown promising results, less than half of patients achieve long-lasting responses, highlighting the need to understand factors influencing treatment outcomes.
"The underlying biology clearly supports the association with CAR T cell outcomes and highlights opportunities for interventions using targeted therapies that are either already in the clinic or in the late stages of preclinical development," Green said. "These insights bring us closer to optimizing therapies for all patients, ensuring more effective, individualized care."
The research team believes there are opportunities to target key biological pathways in tumors from the T cell exhausted group to improve outcomes for these patients who do not benefit from current CAR-T approaches.
Advancing Precision Medicine
Using insights from this study, MD Anderson researchers plan to collaborate with other academic cancer centers and pharmaceutical companies to advance clinical trials focused on targeted therapies for patients in subgroups with poorer outcomes. The work represents a significant step toward biology-driven treatment selection in lymphoma care.
The study's comprehensive approach to profiling the tumor microenvironment provides a framework for understanding how non-malignant cells surrounding lymphoma cells influence treatment response, potentially transforming how clinicians approach treatment decisions for patients with large B-cell lymphoma.
