In this issue of Blood Advances, Pophali et al1 demonstrate the efficacy and safety of CD19-directed chimeric antigen receptor (CAR) T-cell therapy in patients with heavily pretreated relapsed and refractory (R/R) T-cell/histiocyte rich large B-cell lymphoma (THRLBCL). In this real-world registry study, 58 patients who received CAR T-cell therapy demonstrated a 2-year progression-free survival (PFS) of 29% with an acceptable safety profile, underscoring the benefit of cellular therapy in this rare, hard-to-treat, and aggressive lymphoma.
THRLBCL is a rare and aggressive subtype of diffuse large B-cell lymphoma (DLBCL), characterized by a distinctive histological pattern of sparse population of clonal B cells within a background of abundant reactive T cells and histiocytes.2 The treatment for R/R THRLBCL has traditionally followed the management algorithms such as those used in other DLBCL subtypes; however, R/R THRLBCL frequently exhibits a poorer response to these standard therapies, with lower overall survival and PFS rates. The dense T-cell microenvironment is believed to contribute to an immunosuppressive milieu, potentially hindering therapeutic efficacy.2,3
Although CD19-directed CAR T-cell therapy has transformed the outcomes for patients with R/R DLBCL, prospective pivotal studies enrolled very few patients with this subtype to make meaningful conclusions on efficacy of CARs in THRLBCL.4-6 Published case series of patients with R/R THRLBCL have shown a discouraging lack of response, with early treatment failure in the majority of patients after CAR T-cell infusion.3,7
Pophali et al present a registry analysis of 58 patients with heavily pretreated R/R THRLBCL treated with CD19-directed CAR T-cell therapy. This registry study evaluates, to our knowledge, the largest cohort of R/R THRLBCL to date and thus provides a glimpse into the overall efficacy and safety of using cellular therapy as well as a more comprehensive account of the outcomes of patients with THRLBCL treated with CAR T-cell therapy. The majority of patients had early-relapsed disease, 20% had marrow involvement, and approximately one-third had a prior autologous transplant. Patients had a median of 3 prior lines of therapy, and axicabtagene ciloleucel was the most common construct administered. The median follow-up was 23 months after CAR T-cell infusion. The overall response rate and complete response rate were 50% and 28%, respectively. The 2-year overall survival and PFS were 42% (95% confidence interval [CI], 27-57) and 29% (95% CI, 17-43), respectively. Grade ≥3 cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome occurred in 7% and 15% of patients, respectively.
The study is limited by its retrospective nature, lack of central pathologic review, and absence of correlative studies. However, the sheer number of patients evaluated in this registry deserves a mention, given the lack of cellular therapy outcome data in this rare population. Overall, the responses to CAR T-cell therapy as well as PFS are modest and notably lower than those for DLBCL, not otherwise specified.4-6 Despite these inherent and observed limitations, it is important to underscore that the responses are durable, without excessive toxicity, and contrary to prior published dismal outcomes. These results provide hope for treating patients with THRLBCL with CAR T cells and the ability to overcome some of the inherent challenges related to THRLBCL. The key challenge moving forward is to enhance these response rates and maximize the therapeutic potential of CAR T cells in this difficult-to-treat lymphoma.
These findings prompt several critical questions for future research. First, why CAR T cells may not elicit a robust response in this subtype remains understudied. The unique tumor microenvironment consisting of dense infiltrates of benign T cells and histiocytes in THRLBCL may pose barriers to the efficient trafficking and persistence of CAR T cells within the tumor microenvironment. Furthermore, the immunosuppressive microenvironment of THRLBCL, characterized by regulatory T cells and myeloid-derived suppressor cells, may dampen the efficacy of CAR T-cell therapy.
Should we perhaps consider using a different CAR construct that might be more effective in targeting the unique biology of THRLBCL? The current constructs may not fully address the nuances of this lymphoma's microenvironment. Innovative designs such as engineering CAR T cells to target multiple antigens simultaneously to address tumor heterogeneity and reduce the risk of antigen escape or using gene editing technologies (eg, CRISPR) to knock out inhibitory receptors or genes that suppress CAR T-cell function, thereby enhancing their efficacy, could potentially yield better outcomes.
Overcoming the unique immunosuppressive microenvironment by combining CAR T-cell therapy with other treatments such as immune checkpoint inhibitors (eg, antiprogrammed death protein 1/programmed death-ligand 1) merits exploration. Could combining these therapies help sustain and bolster the responses, making them even more durable? This combinatorial approach might be a key to overcoming the resistance mechanisms inherent to THRLBCL, and a clinical trial investigating this question is currently underway (NCT05934448).
Understanding the biology of responders vs nonresponders is crucial. By dissecting the molecular and cellular differences between these groups, we can gain insights into why certain patients benefit from CAR T-cell therapy, whereas others do not. This knowledge will be instrumental in tailoring treatments and developing more effective strategies.
Given the rarity of THRLBCL, clinical trials are understandably limited, which poses a significant hurdle to advancing research. However, the hope instilled by this registry study's findings emphasizes the importance of continued clinical investigation. Building a multi-institutional consortium might be a crucial step forward, given the challenges of conducting prospective trials in this rare lymphoma. It is incumbent upon clinical investigators to design and conduct studies that explore new avenues for improving responses and ultimately achieving cures for patients with this aggressive lymphoma.
In conclusion, although the current results are promising, the journey to optimized CAR T-cell therapy for THRLBCL is just beginning. The path forward involves a multifaceted approach, including innovative CAR designs, combination therapies, and a deeper understanding of lymphoma biology. With these efforts, we can aspire to turn the tide against this formidable lymphoma and offer new hope to patients.
Conflict-of-interest disclosure: M.K. reports research support/funding from Novartis; consultancy fees from AbbVie, AstraZeneca, Celgene/Bristol Myers Squibb, BeiGene, and Genentech; is a member of the speaker's bureau for Seagen; and serves on data monitoring committees for Celgene and Genentech.
