If CD19 CAR T-Cell Therapy Fails in Lymphoma, Try a CD22 Version

Most though not all patients with large B-cell lymphoma who progressed after CD19-directed chimeric antigen receptor (CAR) T-cell therapy (CAR19) achieved durable responses with a different CAR T-cell treatment, according to results from a dose-finding phase I study.

Autologous CD22-directed CAR T-cell therapy (CAR22) in 38 patients failing CAR19 therapy resulted in an overall response rate of 68%, and a complete response rate of 53%, with a median duration of response of 27.8 months, reported Matthew J. Frank, MD, of Stanford University in Stanford, California, and colleagues.

“Although these findings are promising, it is essential to recognise that this is a phase 1 dose-finding study,” the authors cautioned in The Lancet. They added, however, that the results suggest that even in cases of early relapse after initial CAR T therapy, positive outcomes are possible after subsequent autologous CAR T-cell therapy, and that the study “provides compelling initial evidence to indicate CAR22 might become a new standard of care for patients who relapse after CAR19 therapy.”

In a commentary accompanying the study, Maria-Luisa Schubert, MSc, and Peter Dreger, MD, both of the University of Heidelberg in Germany, agreed the results “could be practice changing,” but added that is it “mandatory that this promise is substantiated by validating CAR22 safety and efficacy in larger samples and outside Stanford University.”

A multicenter study investigating CAR22 for patients with large B-cell lymphoma who have relapsed after CAR19 is actively enrolling.

While CAR T-cell therapies targeting CAR19 — such as the commercially available therapies axicabtagene ciloleucel (Yescarta), lisocabtagene maraleucel (Breyanzi), and tisagenlecleucel (Kymriah) — have shown durable responses in 30%-50% of patients with relapsed or refractory large B-cell lymphoma, the outcomes of those who relapse after CAR19 therapy are poor, Frank and colleagues pointed out, with median overall survival of approximately 6 months at the time this trial took place.

Thus there is a substantial unmet need for large B-cell lymphoma patients after CAR T-cell therapy.

In this open-label study conducted at Stanford, the investigators intravenously administered CAR22 at two dose levels — 1 million and 3 million CAR22-positive T cells per kg of body weight — to adult patients aged ≥18 years who relapsed after CAR19 or had CD19-negative large B-cell lymphoma.

Of the 40 patients who underwent leukapheresis, 38 had CAR T-cell products successfully manufactured. These patients had a median age of 65 years; 17 (45%) were women, 32 (84%) had elevated pretreatment lactate dehydrogenase, 37 (97%) had relapsed after previous CAR19, and 11 (29%) had refractory disease to all previous therapies. Patients had received a median of four lines of previous therapy.

The maximum tolerated dose was identified as 1 million CAR T cells per kg. Of the 29 patients who received the maximum tolerated dose, none developed a dose-limiting toxicity, or grade 3 or higher cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), or immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS).

Regarding other efficacy outcomes, median progression-free survival for all patients was 3.0 months (95% CI 1.8-not evaluable) and the median overall survival (OS) for all patients was 14.1 months (95% CI 9.1-not evaluable).

The estimated 1-year OS at the maximum tolerated dose was 57%, and 2-year survival was 52%, a figure “in stark contrast to the median overall survival of 6 months observed in patients who relapsed after CAR19,” Frank and colleagues observed. “However, those who did not have a complete response after CAR22 had poor overall survival rates, echoing outcomes seen after CAR19 relapse.”

The most common grade ≥3 adverse events were hematological events and included neutropenia (38/38 [100%]), anemia (23/38 [61%]), and thrombocytopenia (24/38 [63%]). Recovery to grade ≤2 cytopenias occurred within the first 60 days after infusion in most patients.

After CAR22 infusion, infections occurred in 16 (42%) patients, of which only two were grade ≥3.

“Notably, at the maximum tolerated dose, no patient had grade 3 or higher CRS, ICANS, or IEC-HS,” the authors reported. “Moreover, ICANS incidence was rare, a stark contrast from the outcomes of those with CAR19, with most cases resolving typically within a day.”

Schubert and Dreger suggested the study raises several questions regarding CAR22 beyond the setting of CAR19 failure.

These include the prospect of using CAR22 earlier in the disease course, and in patients who are CAR T-cell therapy naive, as well as “its synergies with other immune therapeutics, the potential for a possible combination with CD19 CAR T-cell therapy, and, last but not least, uncovering the cause that makes CAR22 apparently much more effective than other CD22-based CAR T-cell therapy products,” the editorialists said.

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