BsAbs before CD19 CAR-T: full speed ahead!

In this issue of Blood, Crochet and colleagues demonstrate the effectiveness of CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy in patients with large B-cell lymphoma (LBCL) who received prior bispecific antibody (BsAb) treatment targeting an alternate antigen.¹ 

CAR-T has transformed the treatment landscape of LBCL, achieving impressive and often durable responses in patients with relapsed/refractory (R/R) disease. More recently, BsAbs have emerged as a promising modality in the treatment of LBCL, leading to Food and Drug Administration approval of epcoritamab and glofitamab in the third-line setting, with several agents in clinical development.^2,3 Each of these T-cell-engaging therapies (ie, CAR-T and BsAbs) share similar though distinct features. In CAR-T, T cells are engineered to express a synthetic chimeric antigen receptor, which combines an antigen binding domain with the signaling domain of a T-cell receptor. Upon infusion, CAR T-cells bind to their target antigen leading T-cell activation and associated cytotoxicity. Similarly, BsAbs are engineered molecules designed to engage both T cells along with tumor cells and offer a complementary approach to CAR-T by redirecting cytotoxic T cells to tumor cells expressing specific antigens.⁴ Similarities in the mechanism of action of these T-cell-engaging therapies has raised concern that prior BsAb exposure may impair the effectiveness of subsequent CAR-T, potentially via immune-resistance mechanisms and T-cell exhaustion. Although multiple studies have demonstrated complete response rates of 27% to 35% when BsAbs are utilized after CAR-T in LBCL, there are limited data using BsAbs prior to CAR-T, and their potential impact on subsequent CD19 CAR-T efficacy is unknown.^2,3,5 

In this retrospective analysis, Crochet et al evaluated the safety and efficacy of CD19 CAR-T in 47 recipients of prior CD20- or CD22-targeting BsAb therapy, given as monotherapy or in combination, in LBCL. From this analysis, several key findings emerge, namely: (1) exposure to a prior BsAb does not appear to impact subsequent CAR-T efficacy; (2) response to a prior BsAb may not be predictive of one’s chance of responding to subsequent CAR-T; and (3) developing cytokine release syndrome (CRS) with prior BsAb therapy does not seem to predict subsequent CRS with CAR-T.

Importantly, only 55% of patients in the analysis received BsAb therapy as their last regimen prior to CAR-T, and the median time from last BsAb dose to leukapheresis was 51 days (range: 13-512). The authors found no difference in CAR-T outcomes among patients exposed to BsAb within 50 days of leukapheresis as compared with those with a greater washout period. The authors went on to compare CAR-T outcomes in BsAb-exposed patients to a matched historical control of BsAb-naïve patients and demonstrate similar 1-year progression-free and overall survival outcomes with comparable rates of both CRS and neurotoxicity in each group.

This analysis by Crochet and colleagues suggests that it is viable to sequence BsAb-based therapy either before or after CD19 CAR-T. Although these data do not inform optimal treatment sequencing, CAR-T currently remains a preferred option in appropriate patients with R/R LBCL based on long-term data indicating its curative potential.^6,7 Although BsAbs are “the new kids on the block” in R/R LBCL, more mature data are needed to better understand longitudinal outcomes and the potential for long-term benefit with these agents. Emerging prognostic biomarkers will also ideally aid in further refining treatment selection.

CAR-T involves a complex set of steps including insurance approval, leukapheresis, cell manufacturing, and possible bridging therapy, all which take time and risk decline in a subject’s performance status, possibly limiting their chances of durably benefiting from such treatment.⁸ Conversely, BsAbs are “off the shelf” and hold the promise of more timely access. When given the choice between CAR-T or BsAb therapy in a patient with LBCL in need of urgent third-line treatment, these data may increase clinicians’ comfort level using BsAb therapy and leaving CAR-T in reserve. This analysis provides some degree of reassurance that should CD19 CAR-T be needed, it will likely work similarly in BsAb-naïve and BsAb-exposed patients with LBCL.

This study has several caveats and limitations aside from its retrospective nature and small sample size. The median time from last BsAb dose and leukapheresis was 51 days (lower range of 13 days); therefore, it is imperative to examine shorter intervals to understand the potential impact of timing on CAR-T efficacy and safety. Similarly, 45% of subjects received at least 1 additional line of therapy after their BsAb and prior to CAR-T, clouding our interpretation of the true impact of BsAbs on CAR-T outcomes. Future work is needed to confirm these findings in a larger and more homogenous cohort and to determine if results differ based on a particular BsAb agent or CAR-T product. Notably, these findings are only germane to CD19 CAR-T use following BsAbs targeting alternate antigens (eg, CD20 or CD22), and future investigation is warranted to confirm if such conclusions remain true when employing agents targeting identical tumor antigens.

Despite these limitations, this study provides valuable insights into the use of BsAb therapy in LBCL and suggests that although the optimal treatment sequence is unknown, previous BsAb exposure does not appear to compromise subsequent CD19 CAR-T outcomes. Should these findings be confirmed, this will likely foster the expansion and broader incorporation of BsAb-based therapy into the LBCL treatment paradigm.

Conflict-of-interest disclosure: P.A.R. has served as a consultant and/or advisory board member for AbbVie, ADC Therapeutics, BeiGene, Bristol Myers Squibb (BMS), CVS Caremark, Genentech/Roche, Genmab, Intellia Therapeutics, Janssen, Kite/Gilead, Nektar Therapeutics, Novartis, Pharmacyclics, and Sana Biotechnology and has received honoraria from Adaptive Biotechnologies and institutional research support from AstraZeneca, BMS, Calibr, CARGO Therapeutics, Cellectis, CRISPR Therapeutics, Fate Therapeutics, Genentech/Roche, Kite Pharma, Novartis, and Xencor.