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Advances in T-Cell–Directed Immunotherapy for Adult Mature B-Cell Lymphoma: A Comprehensive Review of CAR T-Cell and Bispecific Antibody Therapies

Article information

Cancer Res Treat. 2025;57(4):905-922
Publication date (electronic) : 2025 June 26
doi : https://doi.org/10.4143/crt.2025.440
Jinchul Kim1orcid_icon, Seok Jin Kim,2,3orcid_icon
1Department of Hematology-Oncology, Inha University Hospital, Inha University College of Medicine, Incheon, Korea
2Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
3Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, Seoul, Korea
Correspondence: Seok Jin Kim, Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea Tel: 82-2-3410-1766 E-mail: kstwoh@skku.edu
Received 2025 April 23; Accepted 2025 June 25.

Abstract

B-cell lymphomas are a heterogeneous group of malignancies with a high relapse rate after conventional therapies. T-cell–mediated immunotherapies, notably chimeric antigen receptor (CAR) T-cell therapies and T-cell–engaging bispecific antibodies (BsAbs), have transformed treatment paradigms by harnessing the immune system to target malignant cells. This review analyzes the efficacy and safety profiles of several CD19-targeted CAR T-cell therapies and emerging CD20×CD3 BsAbs across various B-cell lymphoma subtypes. While these therapies have demonstrated high response rates and potential for durable remissions, challenges such as cytokine release syndrome, neurotoxicity, and infections remain significant. Understanding these mechanisms and managing adverse effects are crucial for optimizing clinical outcomes and guiding future research in personalized treatment strategies.

Keywords: B-cell lymphomas; CAR T-cells; Bispecific antibody

Introduction

B-cell non-Hodgkin lymphomas (B-NHLs) comprise a diverse group of malignancies, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), among others. Although these subtypes exhibit distinct clinical and pathological features, they share a common challenge: the propensity for relapse and poor outcomes in patients who fail to respond to initial chemoimmunotherapy [1-4]. This underscores the urgent need for effective therapeutic strategies beyond conventional cytotoxic regimens. The advent of T cell–directed immunotherapies has significantly reshaped the treatment landscape for relapsed or refractory (R/R) B-NHLs. In particular, chimeric antigen receptor (CAR) T-cell therapy and T cell–engaging bispecific antibodies (BsAbs) have emerged as transformative modalities. These therapies leverage the immune system to selectively target malignant B cells, offering renewed hope for patients with limited treatment options. Their capacity to induce durable remissions has established them as critical components in the management of R/R DLBCL and other B-NHL subtypes [4,5].

However, despite their promise, both CAR T-cell therapy and BsAbs present important limitations. CAR T-cell therapy requires an individualized and labor-intensive manufacturing process, involving autologous T-cell collection, genetic modification, and expansion prior to reinfusion. This process can result in treatment delays, which may be detrimental for patients with rapidly progressing disease [6,7]. Moreover, the high cost of these therapies poses accessibility challenges, and both modalities are associated with potentially serious toxicities—including cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) —which necessitate specialized management [8,9].

Given these considerations, a comprehensive evaluation of CAR T-cell therapies and BsAbs is essential to better understand their clinical utility, limitations, and opportunities for optimization. In this review, we aim to provide an in-depth analysis of the efficacy and safety profiles of these immunotherapeutic approaches in B-cell lymphomas. We will examine their mechanisms of action, clinical outcomes across various subtypes, and the spectrum of associated toxicities. By integrating current evidence and identifying key areas for future investigation, this review seeks to inform the evolving role of immunotherapy in B-cell lymphoma and support the development of more effective and personalized treatment strategies.

Targeted T-Cell Engagement: CARs vs. BsAbs in B-Cell Malignancies

CAR T-cell therapy involves the genetic modification of a patient’s T cells to express CAR—synthetic receptors that enable T cells to recognize and eliminate malignant cells in a major histocompatibility complex–independent manner (Fig. 1). All currently approved CAR T-cell therapies for B-NHLs target CD19, a surface antigen broadly expressed across mature B-cell malignancies. A typical CAR construct includes an extracellular antigen-recognition domain—commonly a single-chain variable fragment (scFv) derived from an antibody—connected via a hinge and transmembrane domain to intracellular signaling components. These intracellular elements consist of the CD3ζ signaling domain and one of two co-stimulatory domains, CD28 or 4-1BB, both of which are essential for T-cell activation, expansion, and persistence [10-12]. The selected co-stimulatory domain influences CAR T-cell phenotype and durability: CD28 is associated with effector memory differentiation and more rapid kinetics, whereas 4-1BB promotes central memory T-cell formation and prolonged persistence [10].

Fig. 1.

Structure and mode of action in CD19 chimeric antigen receptor (CAR) T cells.

In contrast, BsAbs are engineered to simultaneously engage two distinct antigens—typically CD20 on malignant B cells and CD3 on T cells—thereby directing cytotoxic T-cell activity toward tumor cells (Fig. 2). This dual engagement facilitates immunological synapse formation and triggers T-cell activation, cytokine release, and target cell lysis [13]. All BsAbs currently approved for B-NHLs employ this CD20×CD3 configuration. Structurally, BsAbs consist of two antigen-binding domains (Fab regions) and an Fc region, which can be engineered to enhance molecular stability and minimize off-target immune activation. Modifications to the Fc region, including mutations that promote correct heavy chain pairing, ensure the production of functional bispecific molecules while preventing the assembly of monospecific or mispaired antibodies [14,15]. The overall architecture—including domain arrangement, valency, and binding affinity—is critical to the therapeutic potency and safety profile of BsAbs.

Fig. 2.

Structure and mode of action in CD20×CD3 bispecific antibodies. APC, antigen-presenting cell.

Both CAR T-cell therapies and BsAbs represent major innovations in the treatment of B-NHLs, offering complementary approaches with distinct advantages and limitations. CAR T-cell therapy provides a highly personalized and potentially curative option, albeit with manufacturing complexity and logistical challenges. BsAbs, in contrast, offer an “off-the-shelf” therapeutic solution with immediate availability and broader accessibility. A thorough understanding of their structural design and mechanisms of action is essential for optimizing clinical application and guiding future developments in B-cell lymphoma immunotherapy.

Efficacy of CD19 CAR T Cells across B-Cell Lymphoma Subtypes

1. Axicabtagene ciloleucel: a paradigm-shifting therapy in B-cell lymphoma subtypes

Axicabtagene ciloleucel (axi-cel) has demonstrated substantial efficacy in R/R large B-cell lymphoma (LBCL), particularly among patients who have failed multiple prior lines of therapy [16]. In the 5-year follow-up of the pivotal ZUMA-1 trial, axi-cel achieved an overall response rate (ORR) of 83% and a complete response (CR) rate of 58% [17]. The median duration of response (DOR) was 11.1 months, and the 5-year overall survival (OS) rate reached 43%, highlighting its potential to induce durable remissions in a subset of patients. Supporting these findings, a multicenter real-world analysis from the U.S. Lymphoma CAR T Consortium reported a comparable 5-year OS of 40% and lymphoma-specific survival of 53% [18]. Notably, nearly one-third of patients remained alive and in remission at 5 years, underscoring the curative potential of axi-cel even outside the clinical trial setting.

Axi-cel has also shown impressive outcomes as a second-line treatment for R/R LBCL [19]. In the phase 3 ZUMA-7 trial, axi-cel significantly outperformed standard of care (SOC)—chemoimmunotherapy followed by high-dose chemotherapy and autologous stem cell transplant (ASCT) in eligible patients. Extended analysis revealed a median event-free survival (EFS) of 8.3 months with axi-cel, compared to 2.0 months for SOC (p < 0.001) [20]. Median OS was not reached in the axi-cel arm versus 31.1 months for SOC (p=0.03), reinforcing its role as a curative-intent option for early-relapsing or refractory disease (Table 1).

Efficacy of CD19 CAR T cells and CD20×CD3 bispecific antibodies

In indolent B-cell lymphomas, axi-cel has also demonstrated high efficacy. The phase 2 ZUMA-5 trial in patients with R/R FL reported an ORR of 94% and a CR rate of 79% [21]. With a median follow-up of 41.7 months, the median progression-free survival (PFS) was 40.2 months, reflecting sustained clinical benefit [22]. Updated analyses extended the median PFS to 57.3 months, with over half of patients maintaining response at 5 years, emphasizing the long-term disease control and potentially curative outcomes axi-cel offers in indolent lymphomas [23].

2. Tisagenlecleucel: efficacy across relapsed B-cell lymphoma settings

Tisagenlecleucel (tisa-cel) has shown meaningful clinical activity as a third-line or later therapy in patients with R/R LBCL (Table 1). In the pivotal phase 2 JULIET trial, tisa-cel achieved an ORR of 52% and a CR rate of 40% in a heavily pretreated population [24]. The median PFS was 5.9 months, and the 24-month PFS rate was 33%, underscoring the potential for durable remissions in select patients [25]. Tisa-cel was also evaluated as a second-line treatment in the phase 3 BELINDA trial, which compared it with standard salvage therapy followed by high-dose chemotherapy and ASCT in patients with early-relapsing or refractory LBCL [26]. However, the study did not meet its primary endpoint of improved EFS, failing to demonstrate superiority over standard care. These results emphasize the importance of patient selection and timing of CAR T-cell therapy in the second-line setting. In FL, tisa-cel has also shown promising efficacy. The phase 2 ELARA trial reported an ORR of 86% and a CR rate of 69% in patients with R/R FL [27]. Updated results from 2024, with a median follow-up of 29 months, demonstrated a 24-month PFS rate of 57% and an OS rate of 88%, with no new safety signals [28]. Notably, comparisons between ELARA and real-world data showed a 1.9-fold higher CR rate and a 1.4-fold higher 12-month PFS rate with tisa-cel, along with an 80% reduction in the risk of death compared to usual care, reinforcing its clinical benefit in this setting [29].

3. Lisocabtagene maraleucel: broad efficacy across B-cell lymphoma subtypes

Lisocabtagene maraleucel (liso-cel) has demonstrated robust clinical efficacy across a range of R/R B-NHLs. In the pivotal TRANSCEND NHL 001 trial, which enrolled heavily pretreated patients with R/R LBCL, liso-cel achieved an ORR of 73% and a CR rate of 53% [30]. The median DOR was 23.1 months, and the median PFS was 6.8 months, with a 2-year OS rate of 50.5%, underscoring its potential for durable remission in this high-risk population [31]. In the second-line setting, the phase 3 TRANSFORM trial evaluated liso-cel in patients with primary refractory LBCL or those who relapsed within 12 months of first-line therapy. The trial demonstrated a significant improvement in EFS with liso-cel compared to SOC therapy, which included high-dose chemotherapy and ASCT. The median EFS was 10.1 months with liso-cel versus 2.3 months with SOC (hazard ratio, 0.34; 95% confidence interval, 0.22 to 0.51; p < 0.0001), establishing liso-cel as a superior option in this setting [32].

In FL, the phase 2 TRANSCEND FL trial reported impressive outcomes in both third- or later-line and second-line settings. In the later-line cohort, liso-cel achieved an ORR of 97% and a CR rate of 94%. In the second-line setting, all responses were complete, yielding a CR rate of 96% [33]. At the 12 months, DOR rates were 82% and 90% in ≥ third-line and second-line groups, respectively, with corresponding PFS rates of 81% and 91%. Updated 2-year data presented at ASH 2024 confirmed sustained benefit, with 24-month PFS rates of 72.5% and 82.6%, respectively, in these cohorts [34,35]. Liso-cel has also shown promising activity in MCL. In the MCL cohort of the TRANSCEND NHL 001 trial, patients who had received at least two prior lines of therapy, including a Bruton tyrosine kinase (BTK) inhibitor, achieved an ORR of 85% and a CR rate of 68%. The median DOR was 13.3 months, suggesting meaningful durability of response in this challenging population [36].

4. Brexucabtagene autoleucel: a breakthrough in R/R MCL

Brexucabtagene autoleucel (brexu-cel) is a CD19-directed CAR T-cell therapy that has demonstrated high efficacy in R/R MCL (Table 1), including patients with prior exposure to BTK inhibitors. The pivotal phase 2 ZUMA-2 trial established its role in this setting, reporting an ORR of 93% and a CR rate of 67% among patients who had received multiple prior therapies, including a BTK inhibitor and anti-CD20 monoclonal antibody [37]. The median DOR was 28.2 months, underscoring its potential to induce long-term remission in a population with historically poor outcomes. Subsequent data from ZUMA-2 cohort 3 evaluated brexu-cel in BTK inhibitor–naïve patients, showing similarly encouraging results: an ORR of 91%, a CR rate of 73%, and a 12-month OS rate of 90% [38]. These findings suggest that brexu-cel may also be effective earlier in the treatment course, expanding its therapeutic utility. Real-world studies have further validated the efficacy of brexu-cel in routine clinical practice. A multicenter analysis conducted by the U.S. Lymphoma CAR T Consortium included patients with high-risk features often excluded from clinical trials. This cohort demonstrated an ORR of 90% and a CR rate of 82%, with 6- and 12-month PFS rates of 69% and 59%, respectively [39]. These real-world data confirm the durability and consistency of brexu-cel’s benefit across a broader, more diverse patient population.

5. Emerging innovations in CD19 CAR T-cell therapy for B-cell lymphomas

Recent advancements in CD19-directed CAR T-cell therapy have led to the development of several next-generation candidates aimed at improving efficacy, minimizing toxicities, and addressing resistance mechanisms. These novel approaches are redefining the landscape of immunotherapy for B-cell lymphomas beyond currently U.S. Food and Drug Administration–approved treatments. Anbalcabtagene autoleucel (anbal-cel) incorporates dual gene silencing of prog-rammed death-1 (PD-1) and TIGIT—two key immune checkpoint receptors—designed to mitigate T-cell exhaustion and enhance antitumor activity within the immunosuppressive tumor microenvironment (TME). In a phase 2 study, anbal-cel demonstrated promising clinical activity in patients with R/R LBCL, with high response rates and durable remissions [40]. WZTL-002, a third-generation CAR T-cell therapy, integrates both CD28 and Toll-like receptor 2 (TLR2) co-stimulatory domains to augment T-cell activation while potentially reducing cytokine-mediated toxicity. In the phase 1 ENABLE-1 trial, WZTL-002 showed a favorable safety profile, with no grade ≥ 3 CRS and only one case of grade 1 ICANS (3%). Clinical efficacy was also encouraging, with CR rates of 52% in the dose-escalation cohort and 56% at the recommended phase 2 dose. These findings suggest that incorporating TLR2 may support outpatient administration by enhancing safety without compromising therapeutic activity [41]. An innovative CD19 CAR construct, 19(T2)28z1XX, was developed through selective mutagenesis of two out of three immunoreceptor tyrosine-based activation motifs, creating a more controlled activation signal. In a clinical study involving R/R DLBCL, 19(T2)28z1XX therapy achieved an ORR of 88% and a CR rate of 75%, even at the lowest tested dose (25×106 CAR T-cells). Toxicity was minimal, with only 4% of patients experiencing grade ≥ 3 CRS and 7% experiencing ICANS. Responses were durable, with most responders remaining in remission beyond 12 months [42]. Next-generation products such as rapcabtagene autoleucel (YTB323) and GLPG5101 have been designed to preserve early memory T-cell phenotypes while significantly reducing manufacturing times. YTB323 is produced using the T-Charge platform in less than 2 days and demonstrated an ORR of 88% and a CR rate of 65% in a phase 2 study of R/R DLBCL. Importantly, severe CRS and ICANS rates were low at 6% and 3%, respectively [43]. Similarly, GLPG5101, developed using a decentralized 7-day fresh product workflow, showed an ORR of 88% and a CR rate of 83% across multiple B-NHL subtypes in the ongoing ATALANTA-1 trial [44]. Both therapies demonstrated robust in vivo expansion and long-lasting responses, particularly in patients achieving early CR and measurable residual disease negativity. These emerging therapies highlight the evolving potential of CD19 CAR T-cell therapy to deliver more potent, durable, and accessible treatment options for patients with B-cell lymphomas. By addressing key barriers such as immune evasion, toxicity, and manufacturing logistics, next-generation CAR T-cell therapies may further expand their role in routine clinical practice. Continued clinical evaluation will be critical to define optimal strategies for their use and integration into current treatment algorithms.

6. Advances in allogeneic CD19 CAR T-cell therapies

Allogeneic CD19-directed CAR T-cell therapies are emerging as promising alternatives to autologous products, with the potential to address key challenges such as prolonged manufacturing timelines, inconsistent product quality, and limited scalability. These “off-the-shelf” therapies offer the advantage of immediate availability and standardized manufacturing, and recent clinical trials have demonstrated encouraging efficacy and safety. Cemacabtagene anseqedleucel (cema-cel), formerly ALLO-501A, is an allogeneic CAR T-cell product evaluated in a phase 1 trial involving patients with R/R LBCL who were naïve to CAR T-cell therapy [45]. Cema-cel demonstrated an ORR of 58% and a CR rate of 42%. Among patients achieving a CR, the median DOR was 23.1 months. CAR T-cell expansion was observed post-infusion, with persistence detectable up to four months. Importantly, the therapy showed a favorable safety profile, with no cases of graft-versus-host disease, grade ≥ 3 CRS, or neurotoxicity. CTX112 is a next-generation, CRISPR-Cas9–engineered allogeneic CAR T-cell therapy incorporating multiple targeted gene edits, including disruption of TRAC (T cell receptor alpha constant), B2M (beta-2 microglobulin), TGFBR2 (transforming growth factor beta receptor II), and ZC3H12A (zinc finger CCCH-type containing 12A, encoding Regnase-1) [46]. These modifications are designed to improve immune evasion, enhance antitumor function, and increase cell persistence. Early clinical data revealed an ORR of 67% and a CR rate of 44%, with some responses maintained for over one year. Enhanced expansion and in vivo persistence were attributed to the disruption of TGFBR2 and Regnase-1, key regulators of T-cell exhaustion and immune suppression. CB-010, assessed in the ongoing ANTLER trial, is another allogeneic CAR T-cell product engineered to knock out PD-1 expression, thereby augmenting T-cell effector function [47]. In this trial, CB-010 achieved an ORR of 94% and a CR rate of 69% in patients with R/R B-NHLs, underscoring the therapeutic benefit of immune checkpoint disruption in enhancing CAR T-cell efficacy. Collectively, these investigational therapies illustrate the rapid progress of allogeneic CD19 CAR T-cell platforms. By employing sophisticated gene-editing strategies to optimize cell function, persistence, and safety, these approaches are redefining the therapeutic potential of off-the-shelf CAR T-cell products for B-cell malignancies. Continued clinical validation is essential to determine their long-term efficacy, scalability, and role in future treatment algorithms.

Efficacy of BsAbs across B-Cell Lymphoma Subtypes

1. Mosunetuzumab: A CD20×CD3 BsAb for FL

Mosunetuzumab is a humanized IgG1-based CD20×CD3 BsAb that has demonstrated clinical efficacy in patients with B-NHLs, particularly FL (Table 1). In a pivotal single-arm phase 2 trial that enrolled 90 patients with R/R FL, mosunetuzumab was administered intravenously in 21-day cycles with a step-up dosing (SUD) strategy during cycle 1 to mitigate CRS: 1 mg on cycle 1 day 1 (C1D1), 2 mg on C1D8, 60 mg on C1D15 and cycle 2 day 1 (C2D1), followed by 30 mg on day 1 of subsequent cycles [48]. Among patients who had received at least two prior lines of therapy—including anti-CD20 therapy—mosunetuzumab achieved an ORR of 80% and a CR rate of 60%. An updated analysis with a median follow-up of 37.4 months showed a 3-year PFS rate of 43.2% [49]. These results led to the regulatory approval of mosunetuzumab for R/R FL after two or more prior lines of therapy in 2022. More recently, subcutaneous administration of mosunetuzumab as a first-line treatment in patients with high-tumor-burden FL yielded a best ORR of 95% and a CR rate of 80% [50]. At a median follow-up of 10.6 months, the estimated 12-month PFS rate was 88%. The treatment was well tolerated, with no neurotoxicity and only low-grade CRS events reported. In a phase 1/2 trial involving patients with R/R DLBCL, mosunetuzumab monotherapy demonstrated an ORR of 42% and a CR rate of 23.9% [51]. This cohort included heavily pretreated individuals, 29.5% of whom had received prior CAR T-cell therapy. The median PFS was 3.2 months, with a median time to first response of 1.4 months. In an updated analysis, responses remained consistent, with a median DOR of 10.6 months among patients who achieved CR [52].

2. Epcoritamab: a subcutaneously administered CD20×CD3 BsAb

Epcoritamab is a humanized IgG1-based CD20×CD3 BsAb administered following a SUD schedule of 0.16 mg on day 1 and 0.8 mg on day 8, followed by full-dose 48 mg weekly. In the EPCORE NHL-1 trial, which enrolled 157 patients with R/R LBCL and a median of three prior lines of therapy, patients received a median of five treatment cycles. At a median follow-up of 10.7 months, epcoritamab demonstrated an ORR of 63% and a CR rate of 39% [53,54]. Among patients with prior CAR T-cell therapy, the ORR and CR rate were 54% and 34%, respectively. With extended follow-up (median, 25.1 months), the CR rate remained durable at 40.1%, and the estimated 24-month duration of CR was 64.2% [55]. While the median PFS in the overall population was 4.4 months, patients who achieved CR experienced significantly improved outcomes, with estimated 24-month PFS and OS rates of 65.1% and 78.2%, respectively. In the FL cohort, 128 patients who had received at least two prior lines of therapy—including an anti-CD20 monoclonal antibody and either an alkylating agent or lenalidomide—were treated with epcoritamab. After a median follow-up of 17.4 months, the ORR was 82%, with a CR rate of 62.5% [54]. The median PFS was 15.4 months, while the median DOR, duration of CR, and OS had not yet been reached at the time of analysis.

3. Odronextamab: a CD20×CD3 BsAb across B-cell lymphomas

Odronextamab is an IgG4-based CD20×CD3 BsAb administered at doses ranging from 0.1 to 320 mg weekly for the first 9 weeks, followed by dosing every other week until disease progression. In the phase 1 ELM-1 trial, which included 145 patients with R/R B-cell NHL, clinical activity was observed at doses ≥ 80 mg in patients with DLBCL and ≥ 5 mg in those with FL [56]. The median number of prior therapies was three, and 41% of the 85 DLBCL patients had previously received CAR T-cell therapy. In the DLBCL cohort, ORR were similar between CAR T-exposed and CAR T-naïve patients, with ORRs of 33% and 39%, respectively, and a CR rate of 24% in both groups. Among FL patients, 78% achieved an objective response, including a 63% CR rate. The phase 2 ELM-2 trial evaluated odronextamab in multiple disease-specific cohorts using a revised step-up dosing regimen to mitigate CRS. The regimen began with 0.7 mg split across cycle 1 days 1 and 2, followed by stepwise dose escalation to 160 mg on C2D1. Treatment was continued at 160 mg weekly through cycle 4, then increased to 320 mg every 2 weeks until progression or unacceptable toxicity. In the DLBCL cohort (n=127), odronextamab yielded an ORR of 52% and a CR rate of 31.5%, with a median DOR of 10.2 months and median duration of CR of 17.9 months [57]. A dedicated analysis of the CAR T-exposed DLBCL subgroup from ELM-1 confirmed sustained efficacy, with an ORR of 48.3% and a CR rate of 31.7% in 60 heavily pretreated patients [58]. In the FL cohort of ELM-2, patients received an initial step-up dose (0.7/4/20 mg) during cycle 1, followed by 80 mg on days 1, 8, and 15 of cycles 2 through 4. Among 128 patients with R/R FL, the ORR was 80.5%, with a CR rate of 73.4%. Responses were durable, with a median DOR of 23 months, median duration of CR of 25 months, and a median PFS of 20.7 months. The 2-year PFS rate was 46.1% [59]. In the phase 3 OLYMPIA-1 trial for high-risk FL, odronextamab monotherapy in the safety lead-in cohort resulted in a 100% CR rate among response-evaluable patients at Week 12. No dose-limiting toxicities, nor any grade ≥ 2 CRS or ICANS events, were reported [60]. Additionally, in the marginal zone lymphoma (MZL) cohort of ELM-2, odronextamab achieved an ORR and CR rate of 79.3% [61]. Responses were durable, with a 36-month DOR of 72.4% and a 36-month PFS rate of 69.4%. No cases of ICANS or grade ≥ 3 CRS were observed.

4. Glofitamab: a 2:1 CD20×CD3 BsAb with durable activity in B-NHLs

Glofitamab is a T cell–engaging BsAb featuring a unique 2:1 configuration that enables bivalent binding to CD20 and monovalent binding to CD3, enhancing T cell recruitment and cytotoxicity. It has been evaluated in the pivotal, phase 1/2 NP30179 trial in patients with R/R B-NHLs. In the phase 1 dose-escalation portion (0.005-30 mg every 14 or 21 days following obinutuzumab pretreatment), glofitamab demonstrated an ORR of 61% and a CR rate of 49% in 171 patients with B-NHLs [62]. In the phase 2 expansion cohort of 155 patients with R/R LBCL, the ORR was 52%, with 39% achieving CR—most within 42 days of treatment initiation [63]. Notably, CR rates were similar among patients who had relapsed after CAR T-cell therapy (35% CR). The 12-month PFS and OS rates were 37% and 50%, respectively, with durable remissions and rare relapses following CR. In an updated analysis with over three years of follow-up, the median duration of CR was 29.8 months. Among patients who achieved a CR at the end of treatment, the 2-year PFS and OS rates were 57% and 77%, respectively [64]. Circulating tumor DNA analysis confirmed sustained molecular remission, and no new safety signals—including CRS or ICANS—were reported with longer follow-up. In the NP30179 trial cohort of R/R MCL (n=60), glofitamab achieved an ORR of 85.0% and a CR rate of 78.3% [65]. With a median follow-up of 17.2 months, the median duration of CR was 15.4 months, and 59.6% of CRs were ongoing at the data cutoff. The estimated 12-month CR duration and PFS rates were 71.0% and 66.6%, respectively. Particularly in patients refractory to prior BTK inhibitor therapy, the ORR and CR rates were 74.2% and 71.0%, respectively. Glofitamab is currently being further evaluated in the ongoing phase 3 GLOBRYTE study in patients with R/R MCL.

5. Emerging CD20×CD3 BsAbs in B-cell lymphomas

Several emerging CD20×CD3 BsAbs are currently under investigation for their therapeutic potential in B-cell lymphomas. Plamotamab, a humanized BsAb comprising an anti-CD20 Fab and an anti-CD3 scFv with an engineered Fc domain to eliminate FcγR binding, has demonstrated clinical activity in heavily pretreated patients with R/R DLBCL and FL. In a phase 1 trial, plamotamab achieved an ORR of 47.4% and a CR rate of 26.3% in DLBCL, and an ORR of 100% with a CR rate of 50% in FL. Importantly, patients with prior CAR-T therapy also responded, with an ORR of 46.2% [66]. IGM-2323 (imvotamab) is a first-in-class IgM-based BsAb that incorporates ten high-affinity CD20-binding domains into an IgM framework. This unique configuration enhances avidity for target cells, enabling robust T cell–mediated cytotoxicity even in cells with low CD20 expression, while also supporting complement-dependent cytotoxicity. In a phase 1 dose-escalation study involving patients with R/R NHL, IGM-2323 demonstrated a 35% ORR among 23 patients with either indolent or aggressive B-NHLs [67]. Ongoing phase 2 randomized trials in DLBCL and FL are evaluating two dose regimens (arm A: 15/100 mg vs. arm B: 15/300 mg) to identify the optimal therapeutic dose. GB261 is a novel CD20×CD3 BsAb designed to retain Fc effector functions, thereby expanding its mechanisms of tumor cell killing through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. In a phase 1/2 trial of 47 patients with R/R B-NHLs treated with doses ranging from 1 to 300 mg, GB261 achieved an ORR of 73% and a CR rate of 46% [68]. At the 100 mg dose level, all five evaluable patients responded, including 80% with CR. Responses were rapid, with a median time to response of 1.3 months. The pharmacokinetic profile showed an effective half-life of 2-3 weeks, supporting dosing intervals of every 3-4 weeks. These results highlight its potential efficacy in heavily pretreated populations. MBS303, a CD20×CD3 BsAb with a 2:1 binding configuration, has also shown encouraging safety and efficacy in a phase 1 dose-escalation study [69]. Among patients with R/R B-NHLs receiving doses ≥ 9 mg, the ORR was 71% with a CR rate of 43%. Notably, in the FL subgroup treated at 9 mg, both the ORR and CR rate reached 100%.

6. Emerging CD19×CD3 BsAbs in B-cell lymphomas

CD19, a widely expressed pan-B-cell antigen, is the target of all currently approved CAR T-cell therapies for B-cell NHL, as well as agents like tafasitamab and loncastuximab tesirine for R/R DLBCL [70,71]. However, CD19 expression is more variable in malignant cells than CD20, contributing to antigen loss in ~30% of patients who relapse after CAR T-cell therapy [72]. Recently developed CD19×CD3 BsAbs show encouraging early efficacy and favorable safety profiles, potentially filling treatment gaps in R/R B-cell lymphoma, including cases previously treated with CD19- or CD20-directed therapies.

In a first-in-human phase 1 trial, AZD0486—a novel fully human CD19×CD3 BsAb engineered for low-affinity CD3 binding to reduce cytokine release—showed promising efficacy and tolerability in R/R DLBCL, including CAR T-exposed patients [73]. Among 40 patients treated at doses ≥ 2.4 mg, the ORR was 43% with a CR rate of 33%. In CAR T-naïve patients receiving 7.2 mg, ORR and CR reached 80%; in CAR T-exposed patients, 36% and 29%, respectively. Treatment was well tolerated, with manageable and reversible CRS and ICANS. Another investigational BsAb, RO7227166, targets CD19 and 4-1BB and is under phase 1 evaluation in combination with glofitamab [74]. Preliminary results from 56 efficacy-evaluable patients with R/R DLBCL showed an ORR of 67% and CR rate of 39%, without new safety concerns.

Safety Profiles of CAR T-Cell Therapies and CD20×CD3 BsAbs

1. Cytokine release syndrome

CRS is a common and significant adverse effect associated with T-cell–redirecting therapies used in the treatment of B-cell lymphoma [75,76]. It arises from rapid T-cell activation and subsequent cytokine release, leading to systemic inflammation. Clinically, CRS can range from mild symptoms such as fever and fatigue to life-threatening complications including hypotension and multi-organ failure. Effective recognition and management of CRS are critical to ensuring the safe and effective use of these therapies.

In phase 3 trials of CAR T-cell therapy as a second-line treatment for R/R LBCL, axi-cel induced CRS in 92% of patients, primarily grade 1-2, with 6% experiencing grade ≥ 3 events [19]. In contrast, tisa-cel caused CRS in 61.3% of patients in the BELINDA trial, with 5.2% experiencing grade ≥ 3 events [26]. The TRANSFORM trial showed that liso-cel led to CRS in 49% of patients, mostly grade 1-2, with only 1% experiencing grade 3 events [32]. Similarly, in the phase 2 PILOT study of liso-cel in transplant-ineligible R/R LBCL patients, grade 3 CRS occurred in only 1.6% of patients (n=61) (Table 2) [77]. For third- or later-line treatment of LBCL, the ZUMA-1 trial reported that axi-cel induced CRS in 93% of patients, again mostly grade 1-2 (37% grade 1, 44% grade 2), with 13% experiencing grade ≥ 3 events [16]. In the JULIET trial, tisa-cel was associated with CRS in 58% of patients, including 36% with grade 1-2 and 22% with grade 3-4 events [24]. The TRANSCEND NHL-001 study showed that liso-cel led to CRS in 42% of patients, with the majority being grade 1-2 (40%) and only 2% experiencing grade 3-4 CRS [30].

Safety profiles of CAR T-cells and bispecific antibodies

In R/R FL, CRS is a common adverse event with CAR T-cell therapy, though its incidence and severity vary by product. In ZUMA-5, axi-cel induced CRS in 78% of patients, predominantly grade 1-2 (72%), with 6% experiencing grade ≥ 3 events, including one fatal case [21]. The ELARA trial of tisa-cel, which enrolled a more heavily pretreated and high-risk FL population (median of four prior therapies; 62.9% with progression of disease within 24 months), reported CRS in 49% of patients—all grade 1-2 [27]. In the phase 2 TRANSCEND FL study, liso-cel was associated with a CRS rate of 58%, with only 1% of patients experiencing grade 3 events [33]. In R/R MCL, CRS occurred in 91% of patients, with most events being grade 1-2 (76%) and 15% grade 3-4 after brexu-cel therapy in the ZUMA-2 trial [37]. More recently, liso-cel was approved for R/R MCL based on the TRANSCEND NHL 001 study, which showed a markedly lower CRS profile, with only 1% of patients experiencing grade 3-4 CRS [36]. Across various lymphoma subtypes, liso-cel appears to be associated with a consistently lower incidence and severity of CRS compared to axi-cel and tisa-cel. In both LBCL and FL, liso-cel demonstrated reduced rates of CRS and fewer high-grade events. Additionally, patients with FL generally experienced milder CRS across all CAR T-cell therapies, suggesting that disease biology and tumor burden may significantly influence both the incidence and severity of CRS in CAR T-cell treatment.

In the context of BsAbs for R/R LBCL, CRS is a commonly reported adverse event but is generally less frequent and severe than with CAR T-cell therapies. In the phase 2 EPCORE NHL-1 study, epcoritamab induced 49.7% of CRS with most events being low grade (32% grade 1, 15% grade 2, and 2.5% grade 3) [53]. Glofitamab, administered intravenously over 12 fixed-duration cycles following pretreatment with obinutuzumab to mitigate CRS risk, resulted in CRS in 63% of 154 patients. Most events were low grade (47% grade 1, 12% grade 2), with 3% grade 3 and 1% grade 4 events [63]. In the phase 2 ELM-2 study of odronextamab, CRS occurred in 55% of 141 patients, with nearly all events being grade 1-2, except for a single case of grade 3 CRS [78]. Mosunetuzumab was associated with a lower CRS incidence in LBCL, occurring in 26.1% of patients—20.5% grade 1, 3.4% grade 2, and 2.3% grade 3—with no grade 4 or 5 events reported [51].

In R/R FL, mosunetuzumab led to CRS in 44% of 90 patients, mostly grade 1-2 (42%), with grade 3 and 4 events each occurring in 1% of patients [48]. Epcoritamab, approved for continuous therapy in R/R FL, showed a higher CRS rate of 67% among 128 patients, with the vast majority being grade 1-2 (65%) and 2% grade 3 events [54]. In R/R MCL, glofitamab remains the most extensively studied BsAb. In a cohort of 37 patients receiving obinutuzumab pretreatment at two different doses, CRS events were mostly low grade. Notably, grade ≥ 3 CRS occurred less frequently in the cohort pretreated with 2,000 mg of obinutuzumab (9.5%) compared to the 1,000 mg cohort (25%) [79].

CRS with BsAbs typically occurs early in treatment, most commonly during the SUD phase. Compared to CAR T-cell therapies, the incidence and severity of CRS with BsAbs are generally lower [80]. This favorable safety profile is largely attributed to mitigation strategies, including SUD protocols and pretreatment with agents such as obinutuzumab, which help temper the initial immune activation and reduce CRS risk.

2. Neurotoxicity

Neurotoxicity is a notable adverse event associated with T-cell–mediated therapies, commonly termed ICANS. This complication typically arises within days to weeks following treatment and can range from mild cognitive disturbances to severe manifestations such as cerebral edema and seizures. Although the precise pathophysiology remains unclear, it is thought to involve inflammatory cytokine release, blood-brain barrier disruption, and immune cell infiltration into the central nervous system [81]. In prior phase 3 trials evaluating CAR T-cell therapy as second-line treatment for R/R LBCL, tisa-cel was associated with neurological complications in 10.3% of patients, with only 1.9% experiencing grade ≥ 3 events [26]. Liso-cel had a 12% incidence of neurotoxicity, which was mostly low grade (grade 1: 5%, grade 2: 2%, grade 3: 4%) [32]. In the phase 2 PILOT study involving transplant-ineligible patients, liso-cel showed a low incidence of neurologic events (4.9%) and no grade 4 toxicities among 61 treated patients [77]. In contrast, axi-cel demonstrated a significantly higher rate of neurotoxicity. In the ZUMA-7 trial, 60% of patients experienced neurologic events, with 21% being grade ≥ 3 [19]. Similarly, in third- or later-line treatment trials for LBCL, axi-cel had a higher rate of grade ≥ 3 neurotoxicity (28%) compared with tisa-cel (12%) and liso-cel (10%) [16,24,30].

Neurotoxicity has also been a notable concern in R/R indolent B-cell lymphoma, particularly with axi-cel. In the ZUMA-5 trial, neurologic adverse events occurred in 59% of patients (87 of 148), including 56% of those with FL and 71% with MZL [21]. Grade 1-2 events were observed in 40% of patients, while 19% experienced grade 3-4 events. The median onset was 7 days, with a median duration of 14 days for FL and 10 days for MZL. Conversely, liso-cel showed a much lower neurotoxicity profile in the phase 2 TRANSCEND trial, with any-grade events reported in 15% of patients, predominantly grade 1 (12%) and grade 3 in only three patients. The median onset was 8.5 days, and median duration was 3.5 days [33]. Similarly, the ELARA trial evaluating tisa-cel in FL reported any-grade neurologic events in 37.1% of patients, with ICANS occurring in only 4.1% within 8 weeks post-infusion [27]. Three patients developed grade ≥ 3 events, including one case of grade 4 ICANS. The median time to onset was 9 days, with resolution typically within 2 days. In R/R MCL, the pivotal phase 2 ZUMA-2 study found that brexu-cel caused neurotoxicity in 62% of patients, with grade 3-4 events in 31% [37]. By comparison, liso-cel in R/R MCL was associated with grade 3-4 neurologic events in only 9% of patients [36]. Overall, neurotoxicity is more frequent and severe with axi-cel and brexu-cel, particularly in R/R LBCL and MCL. Axi-cel consistently shows higher rates of neurological complications across different lymphoma subtypes, whereas liso-cel exhibits the lowest incidence and severity. Moreover, these events tend to be more common and serious in aggressive lymphomas such as LBCL and MCL compared to indolent B-cell lymphomas.

Neurologic adverse events associated with BsAbs are generally infrequent and milder compared to those seen with CAR T-cell therapy. Notably, BsAb-related neurotoxicity has not been linked to circulating BsAb molecules, activated T cells, or proinflammatory cytokines in the cerebrospinal fluid. While brain cells express CD19—the target of CAR T-cell therapies—they do not express CD20, the target of CD3×CD20 BsAbs [82]. This likely contributes to the lower incidence and severity of BsAb-induced neurotoxicity [80]. Reported neurologic events in BsAb trials have mostly consisted of mild symptoms such as headache and dizziness, with ICANS-like presentations occurring in only 1%-8% of cases. In third- or later-line treatment of LBCL, the phase 2 EPCORE NHL-1 trial reported ICANS in 6.4% of patients receiving epcoritamab (n=157), including grade 1 (4%), grade 2 (1%), and one grade 5 event (1%) [53]. Glofitamab was associated with ICANS in 9% of patients (n=154), with 6% experiencing grade 1-2 events and 3% having grade ≥ 3 events [63]. Mosunetuzumab induced ICANS in two patients (1.1% each), presenting as grade 1 confusion and attention disturbance; no grade ≥ 3 neurologic events were reported [51]. In a trial of odronextamab for R/R LBCL, no ICANS events were observed among 141 patients [78]. In patients with R/R FL, mosunetuzumab was associated with neurologic events in 5% of cases, all of which were grade 1-2 [48]. Epcoritamab induced ICANS in 6% of 128 R/R FL patients, again all grade 1-2 [54]. Odronextamab had a single case of grade 2 ICANS reported with the 0.7/4/20 mg step-up dosing schedule [59]. In R/R MCL, glofitamab given after pretreatment with two different doses of obinutuzumab (n=37) resulted in ICANS in 13.5% of patients, all grade 1-2 [79].

3. Infections

Infections associated with T-cell–mediated therapies for B-cell lymphomas span a wide clinical spectrum, from mild to potentially life-threatening. These include bacterial, fungal (notably Pneumocystis jirovecii), and viral pathogens such as cytomegalovirus, hepatitis viruses, respiratory viruses, and others. Heavily pretreated patients—often receiving CAR T-cell therapy as third-line or later treatment—are particularly susceptible to opportunistic infections. Clinical trials have consistently reported a notable incidence of severe (grade 3 or 4) infectious complications in this setting (Table 2). In the ZUMA-1 trial, 30 patients (28%) developed grade ≥ 3 infections, primarily lung infections and bacteremia, during the extended follow-up period [15]. Similarly, the JULIET trial documented grade 3 or 4 infections in 20% of patients, with 6% experiencing infections concurrently with CRS [23]. In the TRANSCEND NHL-001 study, 33 patients (12%) experienced grade ≥ 3 infections, including severe bacterial infections (4%), fungal infections (1%), and viral infections (1%) [29]. The use of CAR T-cell therapy in the second-line setting has also been associated with notable infection risks. In the ZUMA-7 trial, 17% of patients experienced grade ≥3 infections [20], while the TRANSFORM trial reported a similar incidence at 15% [32]. In the PILOT trial, grade 3 or higher infections occurred in 7% of patients (four individuals) [77].

The use of CAR T-cell therapy in indolent B-cell lymphomas warrants careful consideration, given the need to balance therapeutic benefits against potential risks, particularly infections. Among the available products, tisa-cel demonstrated a favorable safety profile in the ELARA trial, with only 5.2% of patients experiencing grade ≥ 3 infections within 8 weeks post-infusion [27]. In contrast, axi-cel in the ZUMA-5 trial was associated with a higher rate of severe infections, reported in 18% of patients (26 individuals), including pneumonia in 10 patients (7%) [21]. Similarly, liso-cel in the TRANSCEND FL trial showed grade ≥ 3 infections in 10.3% of patients [33].

In R/R MCL, infection remains a significant concern during CAR T-cell therapy. The ZUMA-2 trial reported a high incidence of grade ≥ 3 infections in 32% of patients, with pneumonia being the most frequent (9%) [37]. Notably, two grade 5 infection-related adverse events occurred—organizing pneumonia and Staphylococcus bacteremia—both associated with conditioning chemotherapy. In the MCL cohort of the TRANSCEND NHL-001 trial, grade ≥ 3 infections were observed in 13 patients (15%), including one death due to coronavirus disease 2019 (COVID-19) pneumonia and another due to cryptococcal meningitis [36].

Given the need for continuous administration, BsAbs also carry a significant risk of infectious complications in patients with R/R LBCL, with infection rates comparable to those seen with CAR T-cell therapies (Table 2). In clinical trials, grade ≥ 3 infections occurred in 14.6% of patients treated with epcoritamab, out of an overall infection rate of 45.2% [53]; in 15% of patients receiving glofitamab, among 59 patients with infections (38%) [63]; and in 12.5% of those treated with mosunetuzumab [51]. In contrast, odronextamab was associated with a notably higher rate of severe infections. In the ELM-2 trial, 37% of patients (52 individuals) experienced grade ≥ 3 infections, including 16 fatal (grade 5) cases (11%). COVID-19 infections were reported in 23 patients (16%), with six resulting in death (4%) [78]. In R/R FL, mosunetuzumab was associated with grade ≥ 3 infections in 13 patients (14%), with common etiologies including urinary tract infections, COVID-19 pneumonia, and Epstein-Barr virus viremia [48]. Notably, no infection-related grade 5 (fatal) adverse events were reported. In the EPCORE NHL-1 trial involving patients with FL, infections occurred in 17 patients (13%) treated with epcoritamab, with six fatal cases (5%) due to COVID [54]. For R/R MCL, glofitamab treatment was associated with four deaths attributed to COVID-19–related pneumonia [79].

Combination Strategies with T-Cell–Redirected Immunotherapies

Several pharmacologic and biologic partners are under investigation to enhance CAR T-cell activity and durability. Immune checkpoint blockade has produced mixed but informative results. Pembrolizumab “add-back” in patients who relapsed after CD19 CAR T therapy led to re-expansion of circulating CAR T cells and clinical benefit in one-third of cases [83]. Conversely, initiating anti–programmed death-ligand 1 therapy before infusion reduced severe CRS but was less effective than post-infusion dosing [84].

Dual-targeting strategies—particularly layering CD20-directed agents onto CD19 CAR T cells—are gaining traction. In the phase 2 ZUMA-14 study, rituximab plus axi-cel achieved an ORR of 88% and CR of 65% in R/R DLBCL, with two-thirds of responders remaining in remission at 17 months [85]. Trials are now expanding this approach using other CD20 antibodies and CD3×CD20 bispecifics to prevent antigen escape and improve molecular clearance. Small-molecule partners offer additional refinement. BTK inhibitors like ibrutinib and newer agents enhance CAR T proliferation and persistence, with combination regimens showing ORRs over 80% in CLL and MCL and reduced CRS severity [86,87]. Bridging radiotherapy before CD19 CAR T infusion has also shown promise, yielding a 100% response rate and fewer grade ≥ 3 CRS/ICANS events in R/R DLBCL [88]. Collectively, these combinations—checkpoint inhibitors, antibody or BsAb co-targeting, BTK inhibitors, and radiotherapy—are expanding the therapeutic index of CAR T therapy across B-cell lymphomas.

Among CD20-directed BsAb combinations, adding chemotherapy remains the most advanced strategy. Mosunetuzumab with CHOP in untreated DLBCL achieved ORR 88%, CR 85%, and 2-year PFS of 65%, with mostly grade 1-2 CRS [89]. Epcoritamab combined with full-dose R-CHOP produced ORR 100%/CR 76% in fit patients, while R-mini-CHOP still achieved CR 85% in frail patients [90,91]. Glofitamab plus R-CHOP yielded ORR 93%/CR 84% in early-phase studies [92]. In the transplant-ineligible salvage setting, epcoritamab plus GemOx achieved ORR 85%/CR 61%, though with some fatal adverse events [93]. The phase 3 STARGLO trial showed that adding glofitamab to GemOx improved CR rate by 33% and prolonged OS compared to rituximab-GemOx [94].

Polatuzumab vedotin has become a key BsAb partner. Mosunetuzumab-polatuzumab achieved ORR 62%/CR 50% in R/R LBCL and ORR 55%/CR 45% in frail frontline patients, with manageable CRS and ICANS [95,96]. Glofitamab-polatuzumab showed ORR 78%/CR 56% in heavily pretreated DLBCL/high-grade B-cell lymphoma, with 59% of CRs durable at 12 months [97]. A “chemo-light” rituximab-polatuzumab-glofitamab regimen is under study in older untreated patients [98]. Epcoritamab plus polatuzumab-R-CHP in EPCORE-NHL-5 achieved ORR 100%/CR 88.6% with fixed-duration treatment [99].

BTK inhibitors are also being tested for synergy with BsAbs via TME modulation. Trials are evaluating glofitamab with pirtobrutinib, acalabrutinib, or ibrutinib in MCL (NCT05833763, NCT06054776). In DLBCL, EPCORE-NHL-5 is assessing epcoritamab with lenalidomide with or without ibrutinib; the lenalidomide-only arm has shown a 58% CR rate [100]. Interim results from the GPL regimen—glofitamab, poseltinib, and lenalidomide—reported ORR 89.3%/CR 42.9% in 28 heavily pretreated R/R DLBCL patients, including prior CAR T recipients. Six-month OS and PFS were 81% and 55%, respectively, with a low incidence of high-grade CRS, highlighting the potential of BTK-enhanced CD20-targeted T-cell engagement [101]. Together, these findings support that rationally combining BsAbs with chemotherapy, antibody–drug conjugates, or BTK inhibitors can deepen responses and potentially prolong durability. Ongoing trials will clarify optimal sequencing and patient selection.

Mechanisms of Resistance and Strategies to Improve CAR T-Cell and BsAb Therapies in B-Cell Lymphomas

The long-term success of this cellular immunotherapy is often compromised by the emergence of resistance, and durable responses remain a significant challenge for many patients. Overcoming this requires a comprehensive understanding of key barriers, including CAR T-cell dysfunction, global immune dysregulation, and intrinsic tumor resistance. CAR T-cell exhaustion—a functional decline resulting from chronic antigen exposure—is marked by upregulation of inhibitory receptors such as PD-1, TIM-3, and LAG-3, along with diminished proliferative capacity and impaired cytotoxic activity [102]. Clinical studies have demonstrated that CAR T cells from non-responders express higher levels of these exhaustion markers [103]. Several strategies are under investigation to reverse or prevent exhaustion. For instance, epigenetic modulators like the BET inhibitor JQ1 have been shown to restore CAR T-cell function [104]. Other promising approaches include multi-antigen targeting CAR T-cells combined with immune checkpoint blockade [105], modulation of exhaustion-related signaling pathways [106,107], and enhancement of co-stimulatory signaling [108]. The immunosuppressive TME further limits CAR T-cell efficacy by impairing trafficking, upregulating immune checkpoints, and inducing dysfunction through chronic interferon-γ signaling [109]. Suppressive components such as myeloid-derived suppressor cells, regulatory T-cells, and tumor-associated macrophages have been linked to inferior responses. Strategies to overcome TME-mediated suppression include engineering CAR T-cells to secrete cytokines (e.g., interleukin [IL]-7, IL-12, IL-15, IL-18) [110], employing Toll-like receptor agonists to boost immune recruitment [111], and modifying co-stimulatory domains to mitigate Treg activity [112]. Targeting these barriers may improve CAR T-cell performance and clinical outcomes.

B-cell lymphomas employ multiple mechanisms to evade CAR T-cell cytotoxicity, most notably antigen loss via mutation [72], alternative splicing [113], epigenetic silencing [114], trogocytosis [115], and lineage switching [116]. Strategies to address antigen-negative relapse include dual-antigen targeting CAR T-cells [117], sequential targeting (e.g., CD22 after CD19 CAR T-cell therapy), and pharmacologic agents that restore antigen expression [118]. Resistance may also involve defects in apoptotic pathways, such as FAS mutations or deletions, which correlate with poor outcomes [119]. Targeting apoptosis regulators—for example, using the BCL2 inhibitor venetoclax—may enhance CAR T-cell activity and reduce exhaustion [120]. Resistance to BsAbs also arises primarily through antigen escape mechanisms, including complete loss of CD20 expression via alternative mRNA splicing [121]. T-cell exhaustion also contributes to resistance, with non-responders to glofitamab exhibiting increased intra-tumoral PD1 gene signatures [122]. Moreover, CD3×CD20 BsAbs activate all CD3-positive cells unselectively, including potentially immunosuppressive regulatory T cells. TME immunosuppression also significantly affects efficacy; patients with high baseline immunosuppressive markers, such as intra-tumoral C-reactive protein, IL-6, and IL-8, exhibit reduced responses to glofitamab [122]. Further translational research is necessary to establish strategies to overcome resistance to BsAbs. Insights gained from CAR T-cell approaches—such as dual targeting, modulation of T-cell exhaustion, and TME modification—should inform future approaches to enhance BsAb efficacy and improve therapeutic outcomes.

Conclusion

CAR T-cell therapies and BsAbs have transformed the therapeutic landscape for R/R B-cell lymphomas, offering renewed hope to patients with limited treatment options. These immunotherapies have demonstrated impressive efficacy across multiple subtypes, including DLBCL, FL, and MCL, with encouraging rates of complete and durable responses. Despite these advances, challenges remain. Toxicities such as CRS, ICANS, and infection risk necessitate vigilant monitoring and proactive management. Moreover, the complexity of CAR T-cell manufacturing and the associated costs continue to limit widespread access, underscoring the need for more efficient and scalable solutions. Looking ahead, the focus must shift toward optimizing these therapies—enhancing safety profiles, streamlining production, and refining patient selection to maximize outcomes. Promising avenues include next-generation constructs, combination strategies, and personalized approaches informed by deeper biological insights.

Importantly, CAR T cells and BsAbs should not be viewed as competing modalities but rather as complementary tools in the therapeutic arsenal. CAR T-cell therapy offers the potential for long-term remission or cure, while BsAbs provide off-the-shelf availability with manageable toxicity, serving as a bridge, alternative, or adjunct in various clinical scenarios. Harnessing their synergistic potential through integrated treatment strategies may be key to achieving durable disease control and advancing personalized care in B-cell lymphoma.

Notes

Author Contributions

Conceived and designed the analysis: : Kim J, Kim SJ.

Collected the data: Kim J, Kim SJ.

Contributed data or analysis tools: Kim J, Kim SJ.

Performed the analysis: Kim J, Kim SJ.

Wrote the paper: Kim J, Kim SJ.

Conflicts of Interest

Conflict of interest relevant to this article was not reported.

Funding

This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (RS-2020-KH088685). This work also received support from the National Research Foundation of Korea (NRF) grant, funded by the Korean government (MSIT) (RS-2024-00345897), as well as the Industrial Technology Innovation Program (RS-2024-00403681), funded by the Ministry of Trade, Industry & Energy of the Republic of Korea.

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Fig. 1.

Fig. 1.

Structure and mode of action in CD19 chimeric antigen receptor (CAR) T cells.

Fig. 2.

Fig. 2.

Structure and mode of action in CD20×CD3 bispecific antibodies. APC, antigen-presenting cell.

Table 1.

Efficacy of CD19 CAR T cells and CD20×CD3 bispecific antibodies

Drug name CAR T-cell
 Bispecific antibodies
Axi-cel Liso-cel Tisa-cel Brex-cel Epcoritamab Glofitamab Odronextamab Mosunetuzumab
Structure CD19-targeting CAR T-cell with CD28 co-stimulatory domain CD19-targeting CAR T-cell with 4-1BB co-stimulatory domain CD19-targeting CAR T-cell with 4-1BB co-stimulatory domain CD19-targeting CAR T-cell with CD28 co-stimulatory domain IgG1 DuoBody 1:1 CD20×CD3 IgG1 2:1 CD20:CD3, silenced Fc IgG4 1:1 CD20×CD3, null Fc Humanized IgG1 1:1 CD20×CD3
Indication 2nd line LBCL 2nd line LBCL r/r LBCL r/r MCL r/r LBCL r/r LBCL r/r LBCL r/r LBCL
r/r/ LBCL r/r LBCL r/r FL r/r FL r/r FL r/r FL
r/r FL r/r MCL
No. of patients 180 92 93 74 157 154 127 88
111 269 97 128 128 90
124 88
CR rate (%) 65 74 40 68 39 39 31 24
58 53 68 63 73 60
79 72
PFS (mo), median 14.7 NR 5.9 25.8 4.4 4.9 NR 3.2
5.9 6.8 NR 15.4 20.7 17.9
57.3 15.3
Reference ZUMA-7 TRANSFORM JULIET ZUMA-2 EPCORE-NHL-1 - ELM-2 -
ZUMA-1 TRANSCEND ELARA EPCORE-NHL-1 ELM-2
ZUMA-5 TRANSCEND
FDA approval date Apr 1, 2022 Jun 24, 2022 Aug 30, 2017 Jul 24, 2020 May 19, 2023 Jun 15, 2023 NA NA
Oct 18, 2017 Feb 5, 2021 May 27, 2022 Jun 26, 2024 NA Dec 22, 2022
Mar 5, 2021 May 30, 2024

CAR, chimeric antigen receptor; CR, complete response; FDA, U.S. Food and Drug Administration; FL, follicular lymphoma; LBCL, large B-cell lymphoma; MCL, mantle cell lymphoma; NA, not available; NR, not reported; OR, odds ratio; PFS, progression-free survival; r/r, relapsed/refractory.

Table 2.

Safety profiles of CAR T-cells and bispecific antibodies

Type Drug name CRS (%) Neurotoxicity (%) G3/4 infections (%) Reference
CAR-T 2nd line LBCL
 Axi-cel 92 60 17 ZUMA-7
 Liso-cel 49 12 15 TRANSFORM
 Liso-cel for SCT-ineligible patients 38 31 7 PILOT
≥ 3rd line LBCL
 Axi-cel 93 64 28 ZUMA-1
 Tisa-cel 58 21 20 JULIET
 Liso-cel 42 30 12 TRANSCEND
r/r indolent BCL
 Axi-cel 78 59 18 ZUMA-5
 Liso-cel 58 15 10.3 TRANSCEND
 Tisa-cel 49 37.1 5.2 ELARA
r/r MCL
 Brexu-cel 91 62 32 ZUMA-2
 Liso-cel 61 31 15 TRANSCEND
BsAb ≥ 3rd line LBCL
 Epcoritamab 49.7 6.4 14.6 EPCORE NHL-1
 Glofitamab 63 9 15 -
 Odronextamab 55 0 37 ELM-2
 Mosunetuzumab 26 2.3 12.5 -
r/r FL
 Mosunetuzumab 44 5 14 -
 Epcoritamab 67 6 13 EPCORE NHL-1

Grade 3 infections are defined per Common Terminology Criteria for Adverse Events v5.0 as severe infections requiring intravenous antibiotics or hospitalization; grade 4 infections are life‑threatening and may require urgent intervention. Reported values reflect the percentage of patients experiencing ≥ grade 3 infections within each pivotal study. Axi-cel, axicabtagene ciloleucel; BCL, B-cell lymphoma; Brexu-cel, brexucabtagene autoleucel; CAR, chimeric antigen receptor; CRS, cytokine release syndrome; FL, follicular lymphoma; LBCL, large B-cell lymphoma; Liso-cel, lisocabtagene maraleucel; MCL, mantle cell lymphoma; r/r, relapsed/refractory; SCT, stem cell transplant; Tisa-cel, tisagenlecleucel.