TIME and space predict response to CAR T-cell therapy in lymphoma

“CD19-directed chimeric antigen receptor (CAR)-modified T-cell therapy represents a new paradigm for the treatment of patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL), however, durable remissions are observed in less than half of treated patients,” says Dr. Alexandre Hirayama, an Assistant Professor in the Clinical Research Division and co-first author with Dr.Jocelyn Wright on a new article recently published in HemaSphere, identifying factors that predict response to CAR T-cell therapy in LBCL patients. 

Most LBCLs start as a fast-growing mass in the lymph nodes, with symptoms including swollen lymph nodes, unexplained fever, night sweats, and weight loss. First-line treatment options include radiation and chemotherapy with or without rituximab, a monoclonal antibody that binds CD20 on the surface of LBCL cells that flags them to be destroyed by the patient’s immune system. Up to 40% of LBCL patients, however, will relapse or have disease that becomes refractory to initial therapy. For these R/R-LBCL patients, the prognosis is poor and median life expectancy is 6 months. Stem cell transplant has been the standard of care for nearly 30 years for R/R LBCL patients but only one in four are transplant eligible and about 40% of these patients will ultimately relapse after transplantation. For R/R LBCL transplant-ineligible patients, curative treatment options have remained limited until the development of CAR T-cell therapy over the last decade.

Since 2017, three CD19-directed CAR T-cell therapies have been approved in the US to treat R/R-LBCL. CD19-targeted CAR T cells can induce prolonged remissions in patients with R/R-LBCL, often with minimal long-term toxicities, and are thought to be curative for a subset of people. However, CAR T cells are not a silver bullet and long-term remission is not universal. In fact, the factors that determine whether CAR T-cell therapy is going to be successful are poorly understood. Loss of CD19 expression on LBCL cells and dysfunction of infused CAR T cells have been reported by other investigators. “Suppressive factors in the tumor immune microenvironment (TIME) are a potential mechanism of failure. Characteristics of the tumor immune microenvironment before and after CD19 CAR T-cell therapy have just begun to be explored,” Dr. Hirayama explains. “No studies have comprehensively examined the impact before or after CAR T-cell infusion of the distribution, adjacencies, spatial relationship, and spatial transcriptional profiles of distinct subsets of immune, stromal, and tumor cells on outcomes of CD19 CAR T-cell therapy for LBCL.” 

In their recent article, Dr. Hirayama and colleagues performed gene expression profiling and multiplex immunohistochemistry on biopsies collected before beginning CD19 CAR T-cell therapy to identify correlates of response. They identified specific macrophage and T cell gene signatures and distinct morphologic patterns of immune cell infiltration and fibrosis in patients who had a complete response. Notably, the proximity of PD-L1⁺ macrophages and tumor cells to PD-1⁺ T cells was particularly associated with inferior outcomes. “Our findings support further investigation of the spatial topography of the TIME as a predictor of response to CD19 CAR T-cell immunotherapy for R/R-LBCL,” says Dr. Hirayama and suggest that modifying the tumor immune microenvironment may improve CAR T-cell therapy efficacy in the future.

This work was enabled by investigators from across different divisions at Fred Hutch and programs at the Cancer Consortium who established a fruitful collaboration. Looking to the future, Dr. Hirayama says: “we will use new technologies such as co-detection by indexing (CODEX) multiplexed imaging, which allows deep cellular profiling with spatial relationships with a single slice of tissue, and Xenium, which enables high-throughput subcellular mapping of hundreds to thousands of RNA targets alongside multiplexed protein in the same tissue section, to study in detail the TIME in patients undergoing CAR T-cell therapy.”

The spotlighted research was funded by National Institutes of Health, Life Discovery Fund, the Bezos family,Fred Hutch Immunotherapy Integrated Research Center, Lymphoma Research Foundation, Juno Therapeutics, NanoString Technologies, and the CLEARbridge Foundation.

 Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Drs. Cameron Turtle, Cecilia Yeung, Kikkeri Naresh, David Maloney and Jordan Gauthier contributed to this work.”

Hirayama AV, Wright JH, Smythe KS, Fiorenza S, Shaw AN, Gauthier J, Maloney DG, Naresh KN, Yeung CCS, Turtle CJ. 2024. PD-L1⁺ macrophage and tumor cell abundance and proximity to T cells in the pretreatment large B-cell lymphoma microenvironment impact CD19 CAR-T cell immunotherapy efficacy. HemaSphere. Aug; 8(8): e142.