In a phase I CARdinal-22 study, CD22-directed chimeric antigen receptor (CAR) T-cell therapy (CAR22) was highly active in patients who relapsed after CD19-directed CAR T-cell therapy (CAR19) or had CD19-negative large B-cell lymphoma. Patients with a complete response frequently had durable remissions. Similar clinical efficacy was observed between the two tested dose levels. However, because of the observed increase in toxicity at the higher dose level 2, the recommended phase 2 dose was reduced back to 1 × 10⁶ CAR-positive T-cells per kg.
At the maximum tolerated dose (i.e. the recommended phase 2 dose), the estimated 2-year survival was 52%, in stark contrast to the median overall survival (OS) of 6 months observed in patients who relapsed after CAR19. However, those who did not have a complete response after CAR22 had poor OS rates. The toxicity profile of CAR22 is favourable compared with other approved CAR T-cell therapies for relapsed or refractory large B-cell lymphoma. The findings are published by Dr. Matthew J. Frank, Prof. David B Miklos of the Stanford University in Stanford, CA, US and colleagues on 9 July 2024 in The Lancet.
The authors wrote in the background that the long-term follow-up of patients given commercially available CAR19 therapies, including axicabtagene ciloleucel, lisocabtagene maraleucel, and tisagenlecleucel, has shown durable responses in 30-50% of patients with relapsed or refractory large B-cell lymphoma. However, the outcomes of patients who relapse after CAR19 are poor. CD19 downregulation or loss has emerged as a mechanism of resistance against CAR19. CD22 is expressed in nearly all B-cell malignancies. Although CD22 has proven to be an effective therapeutic target for B-cell acute lymphoblastic leukaemia, no CD22-directed therapy is approved for use in large B-cell lymphoma.
In this single centre, open-label, dose-escalation phase I study, the CARdinal-22 investigators administered CAR22 intravenously at two dose levels (1 × 10⁶ and 3 × 10⁶ CAR22-positive T-cells per kg of body weight) to adult patients who relapsed after CAR19 or had CD19-negative large B-cell lymphoma. The primary endpoints were manufacturing feasibility, safety measured by the incidence and severity of adverse events and dose-limiting toxicities, and identification of the maximum tolerated dose (i.e. the recommended phase 2 dose). This study is active, but closed for enrolment.
From 17 October 2019 to 19 October 2022, a total of 41 patients were assessed for eligibility, one patient withdrew; 40 patients underwent leukapheresis and 38 (95%) had CAR T-cell products manufactured successfully. The median age was 65 years (range, 25–84 years), 17 (45%) were women, 32 (84%) had elevated pretreatment lactate dehydrogenase, 11 (29%) had refractory disease to all previous therapies. Patients had received a median of 4 lines of previous therapy (range, 3–8). Of the 38 patients treated, 37 (97%) had relapsed after previous CAR19.
The identified maximum tolerated dose was 1 × 10⁶ CAR T-cells per kg. Of 29 patients who received the maximum tolerated dose, no patients developed a dose-limiting toxicity or grade 3 or higher cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or immune effector cell-associated haemophagocytic lymphohistiocytosis-like syndrome.
The authors concluded that CD22 is an effective target for relapsed or refractory large B-cell lymphoma, particularly after CAR19. The findings show that even in cases of early relapse after initial CAR T-cell therapy, patients can have positive treatment outcomes after subsequent autologous CAR T-cell therapy. However, there are multiple unanswered questions, including the role of CAR22 in other lymphoma subtypes, the response rate of CAR22 in patients who are CAR T-naïve, and the role of co-administering adoptive cellular therapies that target multiple antigens simultaneously.
Based on these results, a multicentre study investigating CAR22 for patients with large B-cell lymphoma who have relapsed after CAR19 is actively enrolling. Furthermore, ongoing investigations are exploring the effect of residual CAR19 on CAR22 production and patient outcomes, along with CAR19 kinetics in these patients after CAR22 infusion, with findings expected to be reported in the future.
Drs. Maria-Luisa Schubert and Peter Dreger of the Department Medicine V, University of Heidelberg in Heidelberg, Germany wrote in an accompanied comment that it is mandatory validating CAR22 safety and efficacy in larger samples and outside of Stanford University. Additionally, the pitfalls of upscaling the production to cope with the needs of large clinical studies and eventual commercial demands must be managed. The results of the ongoing multicentre study in patients with large B-cell lymphoma refractory to CAR19 therapy should provide with informative answers.
However, novel questions arise regarding CAR22 beyond the setting of CAR19 therapy failure. These include its use earlier during the disease course and in patients who are CAR T-cell therapy-naïve, its synergies with other immunotherapeutics, the potential for a possible combination with CAR19 therapy and uncovering the cause that makes CAR22 much more effective than other CD22-based CAR T-cell therapy products.
Funding for this study was acknowledged from the US National Cancer Institute, National Institutes of Health, Stanford Cancer Institute, Leukemia & Lymphoma Society, Parker Institute for Cancer Immunotherapy, Lymph & Co, and the European Hematology Association.
References
Frank MJ, Baird JH, Kramer AM, et al. on behalf of the CARdinal-22 Investigator group. CD22-directed CAR T-cell therapy for large B-cell lymphomas progressing after CD19-directed CAR T-cell therapy: a dose-finding phase 1 study. The Lancet; Published online 9 July 2024. DOI: https://doi.org/10.1016/S0140-6736(24)00746-3
Schubert M-L, Dreger P. CD22 CAR T-cell therapy: new hope for patients with large B-cell lymphoma. The Lancet; Published online 9 July 2024. DOI: https://doi.org/10.1016/S0140-6736(24)00815-8