CD22-Directed CAR T-cell Therapy Overcomes CD19 Relapse in LBCL With High CR Rates

Matthew J. Frank, MD, PhD

Use of CD22-directed chimeric antigen receptor (CAR) T-cell therapy was found to be safe and feasible following relapse on CD19-directed CAR T-cell therapy for patients with heavily pretreated large B-cell lymphoma (LBCL), according to the results of a single-institution phase 1 trial (NCT04088890). Additionally, patients demonstrated high overall response rates (ORRs), and complete responses (CRs) were found to be durable in these patients.¹

“A single infusion of CAR22 produced high response rates in heavily pretreated large B-cell lymphoma patients who relapsed after CAR19,” lead study author Matthew J. Frank, MD, PhD, assistant professor of medicine, Division of Bone Marrow Transplant & Cellular Therapy, Stanford Cancer Institute, said in a presentation during the 2023 Tandem Meetings: Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR.

CD19-directed CAR T-cell therapy has led to significant responses for patients with relapsed/refractory LBCL, but if relapse occurs, patients tend to have a very poor prognosis and many demonstrate CD19 loss or reduced expression.

“There is a paucity of therapies that are given with curative intent after chronic relapse,” Frank said. “Given the poor prognosis of those patients relapsing after carnitine therapies, there's an urgent unmet need for novel therapies.”

CD22 is of interest as a target for CAR T-cell therapy as it can be found on the surface of malignant B cells in 95% of B-cell acute lymphoblastic leukemias (ALLs) and LBCLs. High response rates have already been seen with CD22-directed CAR T-cell therapy in patients with heavily pretreated ALL.

The dose-escalation phase 1 study of the autologous CD22-directed CAR T-cell therapy enrolled adult patients with B-cell non-Hodgkin lymphoma and B-cell ALL. At the Tandem Meetings, Frank presented on the results of the LBCL cohort.

All patients in the cohort had relapsed/refractory LBCL, which included diffuse LBCL not otherwise specified, transformed follicular lymphoma, marginal zone lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, primary mediastinal B-cell lymphoma, and those with secondary central nervous system involvement. Additionally, patients were refractory to CD19-directed CAR T-cell therapy or had CD19-negative disease plus any CD22 expression. If the patients had received prior CAR T-cell therapy, they were required to have at least 30 days since their prior infusion and have less than 5% circulating CAR-positive cells in the peripheral blood by flow cytometry.

Patients received 1 of 2 doses of the CD22-directed product: 1 x 10⁶ (dose level 1) or 3 x 10⁶ (dose level 2). Prior to infusion, patients received lymphodepleting chemotherapy with intravenous fludarabine 30 mg/m² and cyclophosphamide 500 mg/m².

The primary end points of the study were manufacturing feasibility, the recommended phase 2 dose, safety, and toxicities. Secondary end points included investigator-assessed ORR, duration of response, progression-free survival (PFS), overall survival (OS), CAR T associated toxicity, CD22 antigen expression, CAR-positive cell levels in the blood, and serum cytokine profiling.

Of 41 enrolled patients, the CAR T-cell product was successfully manufactured for 38 (95%), as 2 had insufficient T cells for leukapheresis. The median time from leukapheresis to infusion was 18 days.

Participants who received CAR T-cell therapy had a median age of 65 years (range, 25-84), had an ECOG performance status of 0 or 1, and had received a median of 4 prior lines of therapy (range, 3-8). The most common disease type was diffuse LBCL (74%) followed by transformed follicular lymphoma (21%). Thirty-nine percent of patients had non–germinal center B-cell like disease and 18% had double-hit status. Ninety-seven percent of patients had previously received a CD19-directed CAR T-cell therapy and 18% had undergone prior autologous hematopoietic stem cell transplant. Twenty-nine percent did not achieve a CR to any prior line of therapy.

Overall patients had a median follow-up of 18.4 months (range, 1.5-38.6), at which point the ORR was 68% and the CR rate was 53%. The median PFS was 2.9 months (95% CI, 1.7-not reached [NR]) and the median OS was 22.5 months (95% CI, 8.3-NR).

At dose level 1 (n = 29), patients were followed for a median of 14.1 months (range, 1.5-38.6) and showed an ORR of 66% and a CR rate of 52%. The median PFS was 3.0 months (95% CI, 1.6-NR) and the median OS was NR (95% CI, 8.3-NR).

At dose level 2 (n = 9), the median follow-up was 27.1 months (range, 24.7-33.5) and the ORR was 78% with a CR rate of 56%. The median PFS was 2.6 months (95% CI, 1.3-NR) and the median OS was 22.5 months (95% CI, 5.5-NR).

CRs were considered to be durable as only 1 of the 20 patients who achieved a CR had relapsed as of the data cutoff. All patients who progressed on treatment had done so by month 3.

Cytokine release syndrome was observed in 95% of patients, with grade 1 events reported in 37%, grade 2 in 55%, and grade 3 in 3%. Neurologic events of grade 1 severity were seen in 8% of patients and at grade 2 severity in 5%. Additionally, hemophagocytic lymphohistiocytosis-like toxicity was reported in 18% of patients.

One patient in dose level 2 died of sepsis at day 40, and 1 patient developed treatment-related myelodysplastic syndrome/acute myeloid leukemia without evidence of LBCL relapse 11 months after receiving the CD22-directed treatment.

The recommended phase 2 dose was determined to be dose level 1.

Previously published data shared the experience for the first 3 treated patients.² All had high-risk features and had received at least 5 prior treatment lines, including prior CD19-directed CAR T-cell therapy. One of the patients had received 2 prior CAR T-cell therapies, with the second targeting both CD19 and CD20. All 3 achieved a CR, with patient 3 achieving a CR as early as day 28. CRs were maintained for over 3 years.

Frank also noted that “the expansion of CAR22 is 10-fold higher and had longer persistence than CAR19.”

The agent is being investigated further in a planned multicenter phase 2 trial in patients who have relapsed after CD19-directed CAR T-cell therapy. The trial is expected to open this summer.

References

1. Frank MJ, Sahaf B, Baird J, et al. CD22 CAR T cell therapy induces durable remissions in patients with large B cell lymphoma who relapse after CD19 CAR T cell therapy. Presented at: 2023 Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; February 15-19, 2023; Orlando, FL. Abstract 2.

2. Baird JH, Frank MJ, Craig J, et al. CD22-directed CAR T-cell therapy induces complete remissions in CD19-directed CAR-refractory large B-cell lymphoma. Blood. 2021;137(17):2321-2325. doi:10.1182/blood.2020009432