Patients with large B-cell lymphoma (LBCL) treated with a CD22-targeted chimeric antigen receptor (CAR) T-cell therapy had durable clinical responses, despite prior disease progression on CD19-targeted CAR T-cell therapy. These results, from a phase I clinical trial at the Stanford Cancer Institute in California, were published in The Lancet.1
“There are currently no U.S. Food and Drug Administration-approved drugs that target CD22 for the treatment of lymphoma. This study shows that CD22 is an effective therapeutic target for lymphoma. This is also the first study to show that patients with LBCL who have progressed after an initial CAR T-cell therapy can respond durably to a subsequent CAR T-cell therapy that targets an alternative tumor antigen,” said study author Matthew Frank, MD, PhD, assistant professor of medicine in the Division of Blood and Marrow Transplantation and Cellular Therapy at Stanford University.
Historical long-term follow-up indicates that patients with relapsed or refractory (R/R) LBCL treated with CD19-directed CAR T-cell therapies axicabtagene ciloleucel, lisocabtagene maraleucel, or tisagenlecleucel experience a 30% to 50% durable response rate.2-5 Unfortunately, patients with relapsed LBCL do poorly, with only a median six-month overall survival (OS).
Loss of downregulation of CD19 expression on lymphoma cells is a common mechanism of progression after CD19+ CAR T-cell therapy, and prior patient studies consistently showed that patients with LBCL did not have durable remissions after receiving a second CD19 CAR T-cell therapy if they had progressed after an initial CD19 CAR T-cell therapy.
“Our hypothesis for this study is that we could overcome this mechanism of resistance by using a CAR T-cell therapy that targeted a different antigen, namely CD22,” Dr. Frank said.
Dr. Frank and his colleagues conducted a dose-escalation study using a second-generation CAR T-cell therapy containing a fully humanized CD22 (m971) single-chain variable fragment as well as a 4-1BB costimulatory domain, and CD3 zeta activation domain (CAR22), in 41 adults with R/R LBCL that progressed after CAR19 therapy or with CD19-negative disease.5 Patients were recruited between October 2019 and October 2022. Forty patients underwent leukapheresis, and CAR T-cell therapy was successfully manufactured and administered in 38 patients. Median patient age was 65 (range = 25-84), and 17 (45%) were women. Thirty-seven patients (97%) had relapsed after CD19, and the median time from CAR19 infusion to CAR22 infusion was 212 days. Patients had received a median of four prior therapies.
The overall response rate was 68% with a complete response (CR) rate of 53%. The response rates were similar between dose level 1 and dose level 2. Of the 20 patients with a CR, three patients (15%) experienced disease relapse.
The median duration of response was 27.8 months. The median progression-free survival for all patients was 3.0 months, and the median OS was 14.1 months. There were no significant differences in survival or response duration among different disease groups by previous CAR19 response or time until relapse to CAR19.
“This study shows that a CD22-targeting CAR T-cell therapy, which has now been given the name firicabtagene autoleucel (firi-cel), was highly effective in very heavily treated patients with LBCL,” Dr. Frank said.
The most common grade 3 or higher adverse events were hematologic events, including neutropenia in 100% of patients, thrombocytopenia in 63%, and anemia in 61%. Recovery to grade 2 or lower cytopenias occurred within the first 60 days after infusion in most patients. After the CAR22 CAR T-cell infusion, infections occurred in 16 (42%) patients, and only two were grade 3 or higher.
Thirty-six (95%) patients developed cytokine release syndrome (CRS), and only one patient, at dose level 2, had grade 3 CRS. Twenty-four patients (63%) had a monophasic CRS event with a median time of onset of one day after infusion, and that lasted for a median of two days. Twelve patients (32%) developed a second onset biphasic CRS event after the initial CRS resolution.
Four patients developed immune effector cell-associated neurotoxicity syndrome (ICANS) after CAR22 infusion (two with grade 1 and two with grade 2). The median time to the initial onset of ICANS was seven days, and all ICANS events resolved in one day in three patients and in two days in one patient. ICANS was managed with tocilizumab and glucocorticoids.
“Neurotoxicity was extremely rare with only four patients out of 38 developing grade 1 or 2 neurotoxicity, which resolved within one or two days,” Dr. Frank said. “Given how heavily treated these patients were, we were not surprised to see that patients took time to recover blood counts. Infections were also common but manageable.
“Frankly, everything about this trial was surprising,” Dr. Frank concluded. “We were surprised to observe both how effective this CAR-T therapy was and surprised to see the lack of significant CAR-T–related toxicities. We were treating patients with high-risk LBCL who had run out of effective treatment options. … Nearly 30% of patients had never achieved a CR to any prior line of therapy. To see two-thirds of these patients respond and more than half have a CR was well beyond what we expected to see.”
The study had several limitations, one of which was that a small proportion (n=14) of patients received bridging therapy, which may have had additional benefits beyond CAR22. The results of the study may not be generalizable to all patients who relapse after CAR19, given the study’s inability to address the expression concentrations of CD22 on CAR19-refractory LBCL. The exploratory analysis was also limited by the small number of patients.
Currently, Cargo Therapeutics is conducting a pivotal phase II trial of firi-cel in patients who have progressed after CD19 CAR T-cell therapies.6
Any conflicts of interest declared by the authors can be found in the original article.
References
- Frank MJ, Baird JH, Kramer AM, et al. 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. Lancet. 2024;404(10450):353-363.
- Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386(7):640-654.
- Kamdar M, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399(10343):2294-2308.
- Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380:45-56.
- ClinicalTrials.gov. NCT04088890. Autologous CD22 CAR T cells in adults w/ recurrent or refractory B cell malignancies. July 25, 2024. Accessed Aug. 8, 2024. https://www.clinicaltrials.gov/study/NCT04088890.
- ClinicalTrials.gov. NCT05972720. A phase 2 study of firi-cel in patients with relapsed/refractory large B-cell lymphoma (FIRCE-1). June 13, 2024. Accessed Aug. 8, 2024. https://www.clinicaltrials.gov/study/NCT05972720.
