CD22-Directed CAR T-Cell Therapy Achieves Complete Remission in CD19-Directed CAR T-Cell Refractory Follicular and Mantle Cell Lymphoma
Authors: Kramer Anne Marijn , Srinagesh Hrishikesh , Su Yi-Jiun , Hamilton Mark P. , Levine Kendall , Migliore Eleonora , DeNoble Kimi , Brown Annie K. , Cunanan Kristen , Agarwal Neha , Lohman Claire , Mavroukakis Sharon , Bharadwaj Sushma , Arai Sally , Johnston Laura , Lowsky Robert , Meyer Everett H. , Negrin Robert S. , Rezvani Andrew R. , Shizuru Judith , Mikkilineni Lekha , Hosoya Hitomi , Shiraz Parveen , Sidana Surbhi , Weng Wen-Kai , Kennedy Vanessa E. , Smith Melody , Dahiya Saurabh , Davis Kara L. , Ramakrishna Sneha , Schultz Liora Michal , Tunuguntla Ramya , Feldman Steven A. , Muffly Lori , Mackall Crystal L. , Miklos David B. , Frank Matthew J. 
Published: December 2024

Introduction
CD19-directed chimeric antigen receptor T cells (CAR19) achieve high response rates in patients with relapsed/refractory (r/r) mantle cell lymphoma (MCL) and Follicular Lymphoma (FL). However, their use can be associated with significant toxicity, including cytokine release syndrome (CRS) and neurotoxicity, and concern for relapse. In a Phase 1 clinical trial (NCT04088890), 38 participants with LBCL who relapsed after CAR19 therapy were treated with CD22-directed CAR T-cells (CAR22). The ORR and CR rates were 68% and 53%, respectively (Frank MJ, et al., Lancet 2024). Based on these results, CAR22 has been granted Breakthrough Therapy Designation (BTD) by the FDA for the treatment of CAR19-resistant LBCL. Here, we hypothesize that CAR22 will be an effective treatment for r/r MCL and FL, particularly in those who have progressed after CAR19.
Methods
This ongoing single-institution academic Phase 1b clinical trial is evaluating a CAR22 construct incorporating the m971 CD22 single chain variable fragments and 41BB/CD3z, as previously reported. Primary outcome measures are manufacturing feasibility, maximum tolerated dose (MTD) and overall response rate (ORR). Secondary outcome measures are Progression Free Survival (PFS), Overall Survival (OS) and Duration of Response (DOR).
Eligible patients in the FL cohort were ≥18 years old, had histologically-confirmed R/R FL after ≥ 2 lines of systemic therapy, or relapsed or progressive disease within 24 months of initiation of the initial course of chemotherapy (POD24). Prior therapy must have included an anti-CD20 monoclonal antibody combined with systemic therapy. Eligible patients in the MCL cohort were ≥18 years old, had histologically-confirmed R/R MCL after ≥ 2 lines of prior therapy, including a BTKi, alkylating agent, and CD20-targeted agent. All patients had measurable disease at time of CAR-T infusion. Participants with prior CAR were ≥30 days post-CAR infusion and had ≤5% circulating CAR positive cells.
Results
As of July 1st 2024, 6 patients were enrolled on trial and here we report on the first 4 consecutive patients treated with a single infusion of autologous 1 × 106 CAR+ T cells/kg. Two patients had MCL (leukemic subtype; n=1, TP53 mutation; n=1), and two patients had high-risk FL. Median age was 70 years (48-77), 3 were female and the median number of prior lines of therapy was 4 (1-5), including CAR19 therapy in 3 out of 4 patients. CAR22 was well tolerated, without any reported &gt;grade 2 nonhematologic adverse events. All 4 patients had grade 2 Cytokine Release Syndrome (CRS), with a median time to CRS onset of 2 days (1-9) and time to resolution of 1 day (1-4). One patient exhibited biphasic CRS, with a second CRS recrudescence at day 5, lasting for 7 days. CRS was treated with tocilizumab and steroids. Notably, we observed no neurotoxicity (ICANS) or Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome (IEC-HS). At Day 28 post-infusion ORR was 100% (CR, n=3; Radiographic PR, yet MRD-negative by Clono-Seq in MCL patient, n=1) . Circulating CAR22 cells demonstrated robust expansion at day 14 (peak range, 47-1586 cells per microliter) by serial flow cytometric evaluation of peripheral blood (CAR-FACS). Outcomes for additional patients will be reported at the meeting.
Conclusion
Here, we report initial safety and antitumor activity of CAR22 for R/R FL and MCL. CAR22 therapy resulted in 100% ORR in the first 4 consecutive patients treated without significant toxicity. Further accrual is ongoing and will include patients with FL, MCL, Hairy cell leukemia, Lymphoplasmacytic lymphoma, Burkitt lymphoma, and Marginal zone lymphoma. This trial is registered on clinicaltrials.gov as #NCT06340737.