CARs vs bispecifics: the race is on!

In this issue of Blood, Kim and colleagues report on a timely meta-analysis comparing the safety and efficacy of chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies for relapsed/refractory large B-cell lymphoma in the third-line setting and beyond.¹ Pooled complete remission and progression-free survival rates were significantly better for CAR T cells than for bispecific antibodies, although this greater efficacy came with an increased incidence of adverse events (including cytokine release syndrome, neurotoxicity, and infections) in the CAR T group (see figure).

The knowledge that CD19-targeting CAR T-cell therapy can potentially cure patients with relapsed/refractory large B-cell lymphoma approximately 40% of the time² with just one treatment motivates clinicians and patients to obtain CAR T-cell therapy, despite the known, often severe side effects that are usually reversible with optimal and immediate management. Axicabtagene ciloleucel,² tisagenlecleucel,³ and lisocabtagene maraleucel⁴ have been approved by the US Food and Drug Administration for relapsed/refractory large B-cell lymphoma in the third-line setting and beyond, whereas axicabtagene ciloleucel and lisocabtagene maraleucel are approved for the second-line setting as well. Unfortunately, factors such as disease kinetics, patient comorbidities, socioeconomic/geographic limitations, and resource allocations often make it difficult for CAR T-cell therapy to be used widely.

Bispecific antibodies are an off-the-shelf way to harness the body’s T-cell immune system to fight B-cell lymphoma in vivo without having to perform leukapheresis, ex vivo transduction of autologous T cells, and manufacturing of CAR T cells before the lymphoma can actually be treated (typically a 2- to 4-week process). Initial approvals of the CD20/CD3-targeting bispecific antibodies glofitamab⁵ and epcoritamab⁶ came in 2023 for diffuse large B-cell lymphoma as third-line or higher therapy or for patients ineligible for CD19-targeting CAR T-cell therapy. Mosunetuzumab⁷ and odronextamab⁸ have also shown success in relapsed/refractory large B-cell lymphoma, but are not yet approved. All these bispecific antibodies can be used more widely geographically but involve repeated injections or infusions, often indefinitely; can still cause cytokine release syndrome and other side effects; and have not yet demonstrated cure potential. To improve the efficacy of bispecific antibodies in large B-cell lymphoma, studies have now been designed to combine bispecifics with novel targeted therapies and/or chemoimmunotherapy, even in the first-line setting. These studies also are exploring the use of bispecific antibodies for a fixed duration. Likewise, efforts to further improve efficacy of CAR T-cell therapy with a more favorable safety profile have led to the development and exploration of novel CAR T-cell targets and costimulation methods. One particularly interesting approach is direct administration of vectors into the body with directed in vivo transduction and CAR T-cell formation to save time and costs while enhancing wider access to these products.^9,10 

Although Kim et al’s meta-analysis shows that CAR T-cell therapy in the third-line and beyond scenario has superior efficacy to bispecific antibody treatment with higher complete remission and progression-free survival rates, it comes with a greater incidence of grade 3 and higher adverse events. Because many patients still relapse, the race is on to come up with the optimal novel therapy/combination that will confer even higher cures rates with lower toxicity and global access for patients with this deadly disease.

Conflict-of-interest disclosure: T.S. is a speaker for Bristol Myers Squibb (BMS), AstraZeneca, and BeiGene; is an advisory board member for BMS, AstraZeneca, BeiGene, Gilead, and AbbVie; and has received has grant funding from BMS.