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CD22-directed CAR T-cell therapy safe and well-tolerated in R/R LBCL

Expert
Dr Matthew J. Frank, Stanford University School of Medicine, USA
Conference
ASH 2021
med.stanford.edu

In patients with relapsed/refractory large B-cell lymphoma (R/R LBCL), infusion of CD22-directed CAR T-cell therapy (CAR22) was found to be safe and well-tolerated at dose level 1 (DL1, 1×106 CAR+ cells/kg) [1]. The manufacturing of CAR22 was uniformly successful. This was found in an ongoing single-institution phase 1 dose-escalation clinical trial (NCT04088890) from Stanford University School of Medicine, in California, USA.

CD19-directed CAR T-cell therapy (CAR19) has achieved durable complete response (CR) rates of 30-40% in patients with R/R LBCL [2-4]. Unfortunately, after failure of CAR19, these patients have a poor prognosis, with an objective response rate (ORR) of 29% to conventional salvage therapies, a median progression-free survival (PFS) of 1.8 months, and a median overall survival (OS) of 6 months [5].

Approximately 30% of the patients who experienced post-CAR19 relapses had CD19 loss or decreased expression [2,5]. “This suggests that antigen escape represents an important mechanism of relapse in lymphoma,” Dr Matthew J. Frank (Stanford University School of Medicine, USA) argued. “Given the poor prognosis of patients after relapsing to CAR19 therapies, there is an urgent unmet need for this patient population.”

Targeting CD22

CD22 is a sialic acid-binding immunoglobulin-like lectin (Siglec-2) restricted to the B-cell lineage [6]. CD22 is detectable on the surface of malignant B cells in 95% of B-cell acute lymphoblastic leukaemia (B-ALL) and LBCL [6-8], “making it an excellent target for CAR T-cell therapies,” according to Dr Frank.

Treatment with a CD22-directed chimeric antigen receptor (CAR) T-cell therapy resulted in a 70% CR rate in 58 paediatric patients with heavily pre-treated ALL [9]. Based on these encouraging results, Dr Frank and colleagues evaluated CAR22 in adult patients with R/R LBCL (n=21; median age 64), focusing on those with CAR19-refractory disease.

Safety and efficacy findings

CAR22 was successfully manufactured in 100% of the patients using a close CliniMACS Prodigy system. The median vein-to-vein time, defined as the time between apheresis and infusion, was 17 days.

The safety profile of CAR22 appears comparable with CAR19. 1 case of grade 3 cytokine release syndrome (CRS) occurred (none at DL1), and no cases of high-grade immune effector cell-associated neurotoxicity syndrome (ICANS) were reported at any dose level. The 5 cases of macrophage activation syndrome (MAS), an emerging CAR22-related hyperinflammatory toxicity, and grade 3 infections were manageable.

A single infusion of CAR22 produced high response rates in heavily pre-treated patients with LBCL. The best ORR at Day 28 was 79% and the best CR rate was 58%. . Notably, low CD22 expression appears to be a mechanism of resistance to CAR22.

 

    1. Frank MJ, et al. CD22-CAR T-Cell Therapy Mediates High Durable Remission Rates in Adults with Large B-Cell Lymphoma Who Have Relapsed after CD19-CAR T-Cell Therapy. Abstract 741, ASH 2021 Annual Meeting, 11-14 Dec. 
    2. Neelapu SS, et al. Blood 2019;134(suppl_1):203.
    3. Schuster SJ, et al. Blood 2018;132(suppl_1):1684.
    4. Abramson JS, et al. Lancet. 2020;396:839–852.
    5. Spiegel JY, et al. Blood. 2021;137:1832–1835.
    6. Boyd SD, et al. Appl Immunohistochem Mol Morphol. 2013;21:116–31.
    7. Shah NN, et al. Pediatr Blood & Cancer. 2015;62:964–9.
    8. Majzner RG, et al. Cancer Discov. 2020 May;10(5):702–723.
    9. Shah NN, et al. J Clin Oncol. 2020;38:1938–1950.

 

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