Significant changes in the treatment landscape of diffuse large B cell lymphoma (DLBCL), the most common form of non-Hodgkin’s lymphoma, has led to an explosion of research and development in this disease setting, says GlobalData. According to the leading data and analytics company, there are over 255 products currently in clinical trials for the treatment of DLBCL. However, there is still a high level of unmet need in this disease and the pathway to regulatory approval will be steep for these agents.

Avigayil Chalk, PhD, Oncology & Hematology Analyst at GlobalData, comments: “Three autologous anti-CD19 CAR T-cell therapies, Gilead’s Yescarta, Novartis’ Kymriah, and BMS’ Breyanzi have gained FDA approval for the treatment of relapsed or refractory DLBCL. This success has particularly fuelled research in the field of gene-modified cell therapies, with 96 agents of this class currently being trialled.

“However, personalized manufacture, high price, and the requirement for specialist medical centres are major limitations of the currently approved CAR-Ts. Pipeline gene-modified cell therapies will either have to demonstrate superior efficacy to currently approved CAR-Ts or address one of these limitations to gain approval in this competitive setting.”

Among the novel gene-modified cell therapies in the DLBCL pipeline are allogeneic CAR natural killer (CAR-NK) and allogeneic CAR T-cell therapeutics. GlobalData believes these allogeneic agents may have a distinct advantage over autologous therapies in the pipeline.

Chalk continues: “The lack of personalized manufacture required for allogeneic therapeutics allows up-scaling of production, which drives price down, increases the number of patients that can be treated and reduces the time to therapy initiation. Allogeneic agents have shown very promising efficacy in early phase DLBCL trials, clinical data due to be reported during 2023-2025 will be crucial for determining the future outlook and potential of these agents. The originality of the target antigen or targeting more than one antigen may also be key to the success of an agent, as this may allow for treatment of patients who have relapsed following traditional CAR-T therapy.”

There are two monoclonal antibodies (mAbs) and two antibody-drug conjugates (ADCs) with regulatory approval for the treatment of DLBCL, and many more mAb-based products in late-stage clinical trials. Currently, a Rituxan/biosimilar rituximab combination is the standard of care in the first-line setting, driving remission in 60% of patients. It is likely that Roche’s ADC, Polivy will be added to the therapy in patients with high-risk disease, based on recently published data from the POLARIX study.

Chalk adds: “MAb-based agents will be competing fiercely against each other, and against gene-modified cell therapies. While mAbs are expected to dominate in the first-line setting, the refractory and relapsed setting pipeline is a hotbed of competition, and it’s expected that many of the agents will never make it to market. Therefore, agents will have to outperform each other for efficacy and ease of production. Innovation and investment are expected to continue to transform patients’ outlook in a disease setting that historically offered limited treatment options.”