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The CD19/CD22-directed bispecific CAR T-cell therapy CAR2219 induced high response rates, including complete responses (CRs), in patients with relapsed/refractory large B-cell lymphoma (LBCL), according to findings from a prospective, single-arm, single-center, phase 2 trial (NCT06081478) presented at the 2025 ESMO Congress.¹

At a median follow-up of 4.2 months after CAR2219 infusion, among 31 treated patients, the best overall response rate (ORR) was 100%. The CR rate was 67.7% (95% CI, 48.6%-83.3%), and the partial response (PR) rate was 32.3%. Early responses were reported; at 4 weeks post-infusion, the ORR was 93.5%, and the CR rate was 61.3%.

A subgroup analysis of CR rates showed the efficacy of this therapy across most prespecified subgroups. However, male patients (n = 14), those with bulky disease of at least 5 cm in diameter (n = 8), and those with double-expressor or double-hit lymphoma (n = 12) had the most inferior CR rates compared with the rest of the population, of 50.0% (95% CI, 23.0%-77.0%), 37.5% (95% CI, 8.5%-75.5%), and 50.0% (95% CI, 21.1%-78.9%), respectively.

What was the rationale for investigating CAR2219 in relapsed/refractory LBCL?

The addition of CAR T-cell therapy to the LBCL treatment paradigm has improved the overall prognosis of this population. For example, findings from a 2023 SEER database analysis of 41,219 patients with diffuse LBCL (DLBCL) showed improved overall survival (OS) outcomes in the post-CAR T-cell therapy approval era vs the pre-approval era (HR, 0.951; 95% CI, 0.913-0.990; P = .014).²

“There is a significant difference between those two eras, indicating the benefit brought by the CAR T-cells to [patients with] DLBCL, especially those with relapsed or refractory disease,” presenting author Liang Wang, MD, PhD, contextualized.

Wang is an associate professor in the Department of Hematology at Beijing Tongren Hospital Capital Medical University in China.

However, Wang noted that there is still room for improvement, citing an exploratory long-term survival assessment of the phase 1/2 ZUMA-1 trial (NCT02348216) that showed that axicabtagene ciloleucel (Yescarta) elicited a median lymphoma-related event-free survival (EFS) of 5.7 months (95% CI, 3.1-13.9) and a 5-year EFS rate of 30.3% (95% CI, 21.5%-39.6%).³

CAR2219 is composed of a single-chain variable fragment derived from an anti-CD22 monoclonal antibody fused to a second single-chain variable fragment derived from an anti-CD19 monoclonal antibody.¹ Investigators used parallel truncated EGFR expression to detect the expression efficiency of CAR T cells.

“Previous studies have also found that anti-EGFR antibodies may help to eliminate the CAR T cells in case of severe adverse effects [AEs],” Wang added.

What was the design of the phase 2 study investigating CAR2219 in relapsed/refractory LBCL?

Patients in this trial underwent peripheral blood mononuclear cell collection. Bridging therapy prior to CAR2219 infusion was permitted at the choice of the treating physician. Patients then received a 3-day lymphodepletion regimen consisting of cyclophosphamide at 250 mg/m² per day plus fludarabine at 25 mg/m² per day, followed by CAR2219 infusion at 2 x 10⁶ cells/kg. Patients who responded to CAR2219 were allowed to receive maintenance therapy with agents such as PD-1 inhibitors 1 month after infusion.

Best ORR at 3 months post-infusion served as the trial’s primary end point. Secondary end points included best CR rate, progression-free survival (PFS), OS, and AEs.

A previously conducted retrospective study evaluated the use of bridging therapy with mitoxantrone liposome plus dexamethasone and polatuzumab vedotin (MPD) with or without rituximab prior to CAR T-cell therapy in patients with LBCL. All patients in that study (n = 10) received 1 cycle of MPD. The median number of prior lines of therapy was 3 (range, 2-5), 7 patients had refractory disease, and the median ECOG performance status before bridging therapy was 2 (range, 1-4). AEs associated with bridging therapy were grade 4 neutropenic fever (n = 2) and COVID-19 infection (n = 1). An efficacy evaluation prior to CAR T-cell infusion showed a disease control rate of 100% (CR, n = 1; PR, n = 5; stable disease [SD], n = 4), relief of lymphopenia-related symptoms, and a median ECOG performance status improvement to 1 (range, 1-2). All patients who received bridging therapy went on to receive subsequent CAR T-cell therapy infusion.

“Thus, we think the MPD regimen was an effective and tolerable regimen,” Wang reported.

What were the baseline characteristics of the population enrolled inthe trial of CAR2219 in relapsed/refractory LBCL?

Patients enrolled in the phase 2 trial had stage I (6.5%; n = 2), II (6.5%; n = 2), III (13%; n = 4) or IV (74%; n = 23) disease. Most patients had tumor bulk less than 5 cm (74%; n = 23), had refractory disease (74%; n= 23), had an International Prognostic Index score of greater than 2 (71%; n = 22), and had received more than 2 prior lines of therapy (55%; n = 17). Only 2 patients did not receive bridging therapy. Among those who did receive bridging therapy, this treatment resulted in CR (3.4%; n = 1), PR (31%; n = 9), SD (62.1%; n = 18), and progressive disease (3.4%; n = 1). Prognostic markers included double-expressor or double-hit lymphoma (39%; n = 12), p53-positive disease (42%; n = 13), disease invasion of more than 2 extranodal sites (55%; n = 17), lactate dehydrogenase levels above the upper limit of normal (61%; n = 19), and lymphoma present in the bone marrow (13%; n = 4).

What additional efficacy findings were seen with CAR2219 in relapsed/refractory LBCL?

At the median follow-up, the median PFS and OS were not reached. The estimated 6-month PFS and OS rates were 83% and 87.1%, respectively. At the data cutoff, 93.5% of treated patients were still alive. Among the 2 deaths that were reported, 1 was attributed to lymphoma progression, and the other was attributed to non-lymphoma causes.

In total, 90% of patients had peak CAR T-cell expansion between days 10 and 14 post-infusion. The median peak CAR T-cell count was 2.35 x 10⁸ cells per liter. CAR T cells were detectable after 3 months in most patients. Additionally, interleukin-6 concentration peaked between days 4 and 7 post-infusion; this level also rebounded after the use of tocilizumab.

Wang highlighted the case of a heavily pretreated male with DLBCL who had progressed on prior PD-1–directed therapy and went on to receive CAR2219. This patient had disease progression at 1 month post-infusion but had CAR T-cell expansion in both blood and neck lymphoma tissue.

“Thus, we think the exhausted CAR T cells may contribute to disease progression,” Wang contextualized.

This patient achieved a CR 2 months after reuse of a PD-1 inhibitor.

“Until now, this patient has been lymphoma free for more than 1 and a half years, and we can detect the CAR T cells in his peripheral blood,” he added.

What was the safety profile of CAR2219 in relapsed/refractory LBCL?

Overall, Wang explained that CAR2219 was well tolerated in most patients, and investigators reported no AE-related deaths. In total, 74% of patients (n = 23) had grade 1/2 cytokine release syndrome (CRS), with no grade 3 or higher CRS reported. The rate of any-grade immune effector cell–associated neurotoxicity syndrome (ICANS) was 6% (n = 2), and 3% of patients (n = 1) had grade 3 ICANS. Other AEs included neutropenia (any-grade, 93%, n = 29; grade ≥ 3, 90%, n = 28), thrombocytopenia (77%, n = 24; 45%, n = 14), and anemia (71%, n = 22; 32%, n = 10).

Wang noted that the patient with grade 3 ICANS was transferred to the intensive care unit, where he recovered after receiving high-dose steroids, plasma exchange, and cerebrospinal fluid exchange.

“The role of post-infusion maintenance therapy, especially using PD-1 inhibitors or other small molecule agents, needs to be further investigated,” Wang concluded.

Disclosures: Wang had no financial relationships to disclose. He reported that the present trial was supported by grants from the National Natural Science Foundation of China and the National Science and Technology Major Project of China.

References

1. Wang L, Liu X-D, Cong J, et al. CD19/CD22 bispecific CAR-T cell therapy for relapsed/refractory large B-cell lymphoma: a prospective, single-arm, single-center, phase II clinical trial. Presented at: 2025 ESMO Congress; October 17-25, 2025; Berlin, Germany. Abstract 1240O.
2. Wasifuddin M, Ilerhunmwuwa NP, Becerra H, et al. Survival trends in diffuse large B-cell lymphoma (DLBCL) in the CAR-T cell therapy era vs pre-CAR-T cell therapy era in the United States: a population-based study. Blood. 2023;142(suppl 1):3765. doi:10.1182/blood-2023-181377
3. Neelapu SS, Jacobson CA, Ghobadi A, et al. Five-year follow-up of ZUMA-1 supports the curative potential of axicabtagene ciloleucel in refractory large B-cell lymphoma. Blood. 2023;141(19):2307-2315. doi:10.1182/blood.2022018893