Just in the last few years, we have seen the US Food and Drug Administration approval of several treatments that are not curative-intent therapies but are nonetheless very useful to have, perhaps especially in patients who are not proceeding to CAR T-cell therapy. In this category, we have regimens such as polatuzumab vedotin plus bendamustine and rituximab (Pola-BR); the CD19-directed monoclonal antibody (mAb) tafasitamab in combination with lenalidomide; and the CD19-targeted mAb loncastuximab tesirine, which is conjugated to the cytotoxic DNA-damaging agent pyrrolobenzodiazepine. Loncastuximab tesirine was granted accelerated approval for R/R DLBCL based on the LOTIS-2 trial, in which the overall response rate was close to 50% and, among responders, the median duration of response was approximately 13 months, which is durable in a very high-risk patient population. Although I do not necessarily believe that these options will be curative and you do have to be mindful of the toxicities that can develop, these are good options for disease control, and I am happy to have them.

In addition, many novel agents are in development. I have been pleasantly surprised by the data with bispecific mAbs in R/R DLBCL. In general, DLBCL is an aggressive, proliferative malignancy, and I just was not sure whether a bispecific mAb approach would achieve significant disease control, but these treatments clearly do. Data for the bispecific mAbs odronextamab, glofitamab, and epcoritamab look promising, and I am excited to see those move forward in DLBCL.

There is also a lot of novel drug development with ADCs and small-molecule–targeted agents. And some of the innovative cellular therapy strategies with dual-targeting and off-the-shelf CAR T-cell therapies could really be a substantial leap forward, assuming that they show good clinical activity and that the manufacturing process is straightforward. We will be quite busy for the next 10 years or so in lymphoma research. It is an exciting time to be a lymphoma investigator, as there are many treatments emerging and many promising agents in development.

Large-cell lymphoma is a disease that is very often chemotherapy resistant, and the promise held by immunotherapy in this space continues to be really exciting. The bispecific antibodies have demonstrated excellent activity and certainly offer a time to treatment and a convenience factor in terms of their off-the-shelf access that is lacked by autologous CAR T-cell therapy. There are a number of bispecific antibodies that are in development, including mosunetuzumab, glofitamab, epcoritamab, and odronextamab. Each bispecific antibody appears to have a somewhat different profile in terms of activity and toxicity.

Regarding toxicity, we are focused largely on the rate of cytokine release syndrome. The goal is to find the sweet spot of maximizing activity and tolerability, trying to strike the perfect balance. Ongoing clinical trials are also assessing whether these therapies will be used as monotherapy or in the context of combination regimens. Moreover, these treatments are being investigated for a spectrum of BCL, not just DLBCL, and response rates have also been high in most of the indolent BCLs such as follicular lymphoma, not just in large-cell lymphoma. But there continues to be a significant focus on DLBCL because the unmet need is still so great.

The anti-CD19 mAb tafasitamab and the ADCs loncastuximab tesirine and polatuzumab vedotin are the newest drugs in our armamentarium. The next group of drugs—which I think are the most exciting—are the bispecific antibodies, of which there are 4 that are under advanced development, as noted by Dr Matasar: mosunetuzumab, odronextamab, glofitamab, and epcoritamab. These all target CD20 and CD3, but there are differences in their design, so they are all slightly different molecules. We are seeing promising response rates in patients who have relapsed after CAR T-cell therapy, although responses appear to be better in those who have not received CAR T cells. Follow-up is limited, however, so we do not know about durability quite yet. 

There are also some newer CAR T-cell strategies that are exciting, including some autologous CAR T cells that target CD19 or multiple tumor antigens, as well as some bispecific CAR T-cell therapies that are in development. For example, the ALEXANDER trial is evaluating a CD19/22 dual-targeting CAR T-cell therapy in combination with pembrolizumab, and the preliminary data look promising. There are also emerging off-the-shelf cellular immunotherapies that are exciting and may avoid the logistics and delay the collecting of T cells needed for CAR T-cell therapy from patients who are heavily treated with chemotherapy. For example, the allogeneic CAR T-cell agent ALLO-501A has demonstrated promising efficacy in patients with R/R LBCL in the ALPHA2 study. In addition, there are some CAR natural killer agents that have shown promising results and are moving into advanced development. These have the appeal of being off-the-shelf products and do not necessarily carry the risk of graft-versus-host disease, which is a theoretical risk of the allogeneic CAR T-cell products. Finally, ADCs that target ROR1 are exciting. ROR1 is expressed in a number of B-cell malignancies, including mantle cell lymphoma and DLBCL, and there are some appealing phase 1 data.