Novel treatment target for lymphoma patients who relapse after CAR-T therapy

Feb 2023: The results of the trial demonstrated that a novel chimeric antigen receptor T-cell therapy elicited a response in adults with advanced large B-cell lymphoma who had relapsed following prior CAR-T.

According to statistics given during the Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, all but one of the 20 study patients who achieved an initial full response to therapy remained in remission as of the cutoff date.

“We never thought response rates would be this high,” Matthew Frank, MD, PhD, assistant professor of medicine in the division of blood and marrow transplantation and cellular therapy at Stanford University, told Healio. “It’s a very effective and safe CAR-T to give to patients who will largely have an unmet need.”

The CD22 protein on the surface of cancer cells is the target of an investigational autologous CAR T-cell treatment developed by Stanford University researchers. Using the CliniMACS Prodigy (Miltenyi Biotec) automated cell processing equipment, they produced the agent on-site over a 12-day period.

CD22-directed CAR-T resulted in a 70% complete response rate among 58 younger patients with relapsed or refractory B-cell ALL whose illness progressed following earlier CD19-directed CAR-T.

Frank stated, “Half of our patients still relapsed after using commercial CAR-T, and a common cause of relapse was downregulation or deletion of CD19.” We anticipated responses by using a different antigen that appeared promising for youngsters.

Frank and coworkers tested their novel CD22-targeted CAR T-cell treatment in a phase 1, single-institution, dose-escalation study.

The trial enrolled 38 persons (median age, 65 years; age range, 25-84; 55% men) with relapsed or refractory large B-cell lymphoma whose disease progressed after prior CD19-directed CAR-T therapy or had CD19-negative disease.

All patients except one who were treated during the trial had previously received CD19-directed CAR T-cell therapy. Participants underwent lymphodepletion prior to receiving a single infusion of CD22 CAR T cells at a dosage of either 1 x 106 cells/kg (n = 29) or 3 x 106 cells/kg (n = 9).

The primary outcomes of this study were feasibility, safety, and the recommended phase 2 dose. Secondary objectives included overall response rate as determined by the investigator, duration of response, PFS, OS, and CAR-T-associated toxicity. At a cutoff date of December 27, 2022, the median follow-up period was 18.4 months (range: 1.5-38.6).

36 people were diagnosed with cytokine release syndrome. The only grade 3 adverse event occurred in the group receiving the highest dose. In the higher-dose group, grade 2 CRS occurred significantly more frequently (78% vs. 48%).

Five patients (13%) had neurotoxicity syndrome associated with immune effector cells. During the trial, no cases of severe ICANS (grade 3 or above) were reported.

Five patients, including three of the nine who received the larger dose, were diagnosed with CAR-associated hemophagocytic lymphohistiocytosis (HLH), a hyperinflammatory response marked by significant hyperferritinemia and multiorgan failure.

The examination of efficacy revealed an ORR of 68% and a complete response rate of 53% for all patients treated. A complete response was achieved by fifteen patients (52%) who received the lower dose and five individuals (56%) who received the larger dose.

Researchers found a median PFS of 2.9 months (95% confidence interval [CI], 1.7 to not reached) and a median OS of 22.5 months (95% CI, 8.3 to not reached). In terms of median PFS (3 months vs. 2.6 months) and median OS, the lower and higher doses demonstrated comparable effectiveness (not reached vs. 22.5 months).

As of the study’s end date, only one of twenty patients who had complete remission reported an illness return.

Researchers picked 1 106 cells/kg as the phase 2 dose recommendation because of its superior safety profile and comparable efficacy compared to the larger dose.

As the experiment began in 2018, little was understood about why some CAR-T patients relapse. Frank stated that the fundamental theory, outside of tumor biology, was poor T-cell fitness.

Frank told Healio, “We’ve kind of blown that [thesis] out of the water because we’re taking the same autologous T cells from patients who have had a prior CAR-T and still getting a nearly 70% response rate and a 53% full response rate that appears to be quite durable.” This medication is quite promising, as it has a good response rate and a reasonable safety profile.

A proposed phase 2 multicenter trial using CD22 CAR-T will include patients with large B-cell lymphoma who have relapsed following treatment with CD19-directed CAR-T. The enrollment period will likely begin this summer.

Frank MJ, et al. Abstract 2. Presented at: Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, Feb. 15-19, 2023; Orlando.

Shah NN, et al. J Clin Oncol. 2020;doi:10.1200/JCO.19.03279.