Anti-CD22 CAR T-cell therapy a ‘promising option’ for advanced B-cell malignancies
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An investigational chimeric antigen receptor T-cell therapy appeared safe and demonstrated antitumor activity among patients with relapsed or refractory B-cell malignancies, according to results presented at TCT Meetings Digital Experience.
The novel autologous CAR T-cell therapy, which targets the CD22 protein on the surface of cancer cells, was manufactured onsite by researchers at Stanford University using the CliniMACS Prodigy (Miltenyi Biotec) automated cell processing system.
CD22 is expressed on the surface of most B-cell malignancies — including large B-cell lymphoma and acute lymphoblastic leukemia — according to Matthew J. Frank, MD, PhD, assistant professor of medicine in the division of blood and marrow transplantation and cellular therapy at Stanford University.
“[Although] CD19-targeting CAR T-cell therapies have improved outcomes for patients with ALL and lymphoma, the majority of patients will relapse, often with mutations in CD19 or lower/loss of expression of CD19,” he told Healio. “Based on promising results seen in pediatric patients with relapsed or refractory B-cell ALL who received this CD22-targeting CAR-T therapy, we chose to evaluate the same therapy in adult patients with leukemia and lymphoma.”
Frank and colleagues presented initial findings of a phase 1, single-institution, dose-escalation trial that evaluated their novel CD22 CAR T-cell therapy.
The trial included nine adults (median age, 64 years; range 39-76; 66% men) with relapsed or refractory large B-cell lymphoma who had received a previous infusion of CD19-directed CAR T cells. The study also included six patients (median age, 43.5 years; range, 23-62; 50% men) with relapsed or refractory B-cell ALL, all of whom had undergone allogeneic hematopoietic stem cell transplant and two of whom had received CD19-directed CAR T cells.
Patients in both cohorts received a median six (range, 4-8) previous lines of therapy.
The CAR used in the study comprised an m971 CD22 single-chain variable fragment and 41BB/CD3z endodomains integrated within autologous T cells through lentiviral transduction.
Prior to infusion, study participants underwent lymphodepletion with 30 mg/m2 fludarabine and 500 mg/m2 cyclophosphamide. Patients with large B-cell lymphoma received the CD22 CAR T cells at a dose of either 1 × 106 cells/kg (n = 3) or 3 × 106 cells/kg (n = 6), whereas all those with large B-cell lymphoma received the 1 × 106 cells/kg dose.
The ability to successfully manufacture CAR T cells for each patient served as one of the study’s primary objectives, along with establishing a recommended phase 2 dose for patients with large B-cell lymphoma and safety.
Secondary objectives included investigator-assessed overall response rate and duration of response.
The manufacturing rate was 100% for patients enrolled in the study, with a median time from leukapheresis to infusion of 16 days.
All but one patient experienced cytokine release syndrome (CRS); however, most cases were grade 1 or grade 2. One patient with large B-cell lymphoma developed grade 3 CRS.
Median time to onset of CRS was 0 days (range, 0-2), with a median duration of 3 days (range, 0-23).
Researchers observed no cases of grade 3 or higher neurotoxicity. Two patients with large B-cell lymphoma experienced grade 1 or grade 2 immune effector cell-associated neurotoxicity syndrome, one at day 1 and the other at day 23. In both cases, the condition lasted for 1 day.
The only nonhematologic treatment-related adverse event was one case of grade 3 E. coli infection at day 63 after infusion.
Efficacy results for patients with large B-cell lymphoma showed an ORR of 78% and complete response rate of 56%, with median follow-up of 7 months (range, 1.2-14.7).
Three patients with large B-cell lymphoma who received the lower dose of CAR T cells remained in remission more than 6 months after infusion. Median duration of response was 12.9 months (range, 9.6-13.7) for those who received 1 × 106 cells/kg and 1.3 months (range, 0-4.1) for those who received 3 × 106 cells/kg.
All six patients with ALL had a complete response to therapy at median follow-up of 7.7 months (range, 5.3-14.5). Five of these patients were minimal residual disease negative at the initial 28-day follow-up. However, all but one patient with ALL experienced disease relapse by the data cutoff, with a median duration of response of 3.8 months (range, 1.7-5.2)
Subsequent assessment by flow cytometry showed three patients with ALL had downregulated or no expression of CD22, which led to disease progression.
Frank said he sees a future role for CD22-directed CAR T cells for treatment of ALL and large B-cell lymphoma.
“The early response rates appear similar to the response rates seen in CD19 CARs for patients with both leukemia and lymphoma,” he told Healio. “Importantly, the response rates and complete response rates are similar in [patients with lymphoma] who are very heavily pretreated and have already relapsed after a prior CD19 CAR-T.”
CD22-directed CAR T cells could be used in place of CD19 CAR-T for patients who have low or no surface expression of CD19, Frank said.
“Additional trials will have to evaluate the sequencing of CD22-directed therapy,” he said. “For now, we are grateful we have a promising option for patients with CD19-negative disease or who relapse after CD19 CAR-T.”
The trial is still enrolling patients with certain types of large B-cell lymphoma and ALL. Further study of the CD22 CAR-T is justified given the “encouraging results” seen thus far, Frank said.
“I don't want to overstate our results, but we are hopeful that this could be a practice-changing therapy given the high response rates that appear to be durable, particularly in lymphoma,” he said.
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Frank MJ, et al. Abstract 79. Presented at: The 2021 TCT Meetings Digital Experience (virtual meeting); Feb. 8-12, 2021.
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