Pembrolizumab Plus CAR T-Cell Therapy in Rare B-Cell Lymphomas

Primary mediastinal B-cell lymphoma (PMBCL) is a rare subtype of non-Hodgkin lymphoma (NHL), representing 2-3% of cases, which occurs most commonly in young women. While PMBCL was previously considered a subtype of diffuse large B-cell lymphoma (DLBCL), PMBCL is now recognized by the World Health Organization as a unique entity with distinct clinical and biologic features. PMBCL also has features that overlap with classic Hodgkin lymphoma (cHL), including hallmark features of immune evasion.

Epstein-Barr virus positive (EBV+) diffuse large B-cell lymphoma (DLBCL) and T-cell histiocyte rich large B-cell lymphoma (THRLBCL) are also rare subtypes of aggressive B-cell NHL. EBV+ DLBCL was first described as a distinct entity among elderly patients with in situ hybridization demonstrating an association with EBV. More recently, this entity has been appreciated in younger, immunocompetent hosts as well, thus leading to the revised entity, EBV+ DLBCL not otherwise specified (NOS). Similarly, THRLBCL is an uncommon variant of DLBCL with distinct clinical and pathologic features. Despite differences between DLBCL and these three entities, they are generally treated with similar treatment approaches.

PMBCL has been found to have frequent genomic alterations at the 9p24.1 locus, resulting in overexpression of the PD-1 ligands, PD-L1 and PD-L2 and sensitivity to checkpoint blockade. This initial work was led by the lab of Margaret Shipp, MD. In addition to PMBCL, EBV+ DLBCL and THRLBCL have a biologic rationale to support the therapeutic role of checkpoint blockade. In EBV+ lymphomas, EBV viral proteins lead to the upregulation of PD-L1 expression. THRLBCL has also been found to rely on PD-1 signaling as an immune escape pathway. While checkpoint blockade is promising for patients with these lymphomas, the majority of patients do not respond to therapy and are in need of alternative therapeutic options.

More recently, anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has emerged as an effective treatment strategy for patients with relapsed/refractory large B-cell lymphoma. Although patients with PMBCL represent a small subset of patients in the initial trials of CAR T-cell therapy, responses have been seen and some patients experienced sustained remissions. A retrospective real-world study has also shown that axicabtagene ciloleucel is an active therapy for patients with relapsed/refractory PMBCL with efficacy and toxicity similar to those seen in prior studies in large B-cell lymphomas. While responses to CAR T-cell therapy are high, the majority of patients will ultimately relapse and novel strategies are needed. Additionally, although CAR T-cell therapy is FDA approved for patients with THRLBCL, it appears less active in this histologic subtype.

Given the potential for enhanced immune response, there has been interest in combining checkpoint blockade and CAR T-cell therapy. Studies have demonstrated increased PD-1 expression following CAR T-cell therapy, suggesting a potential mechanism of immune escape following treatment. It has been shown that PD-1 is upregulated on peripheral blood CAR T cells over time. Therefore, the combination of CAR T-cell therapy with checkpoint blockade offers the potential to enhance sensitivity to CAR T-cell treatment. The combination of checkpoint blockade and CAR T-cells has been examined in ZUMA-6, the phase 1/2 study of axicabtagene ciloleucel combined with the anti-PD-L1 antibody, atezolizumab, in patients with DLBCL. Although the combination was safe, efficacy outcomes of axicabtagene ciloleucel combined with atezolizumab appeared to be similar to those of patients treated with axicabtagene ciloleucel alone.

The combination of checkpoint blockade and CAR T-cell therapy, however, has not been examined in lymphomas known to have increased sensitivity to PD-1 inhibition, where we hypothesize that the synergistic potential might be greatest. We have therefore developed a phase 2 trial combining those two therapeutic modalities in these three histologic subtypes. In this multicenter trial, patients are treated with pembrolizumab bridging therapy and continue on pembrolizumab maintenance after CAR T-cell therapy for one to two years depending on response. We are grateful to have the opportunity to offer a clinical trial to patients with these rare histologic subtypes. This trial is currently enrolling at Dana-Farber Cancer Institute and Memorial Sloan Kettering Cancer Center, and more data is anticipated.

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