A systematic review and meta-analysis of CD22 CAR T-cells alone or in combination with CD19 CAR T-cells

Abstract

Chimeric antigen receptor (CAR) T-cells are an emerging therapy for the treatment of relapsed/refractory B-cell malignancies. While CD19 CAR-T cells have been FDA-approved, CAR T-cells targeting CD22, as well as dual-targeting CD19/CD22 CAR T-cells, are currently being evaluated in clinical trials. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of CD22-targeting CAR T-cell therapies. We searched MEDLINE, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials from inception to March 3rd 2022 for full-length articles and conference abstracts of clinical trials employing CD22-targeting CAR T-cells in acute lymphocytic leukemia (ALL) and non-Hodgkin's lymphoma (NHL). The primary outcome was best complete response (bCR). A DerSimonian and Laird random-effects model with arcsine transformation was used to pool outcome proportions. From 1068 references screened, 100 were included, representing 30 early phase studies with 637 patients, investigating CD22 or CD19/CD22 CAR T-cells. CD22 CAR T-cells had a bCR of 68% [95% CI, 53-81%] in ALL (n= 116), and 64% [95% CI, 46-81%] in NHL (n= 28) with 74% and 96% of patients having received anti-CD19 CAR T-cells previously in ALL and NHL studies respectively. CD19/CD22 CAR T-cells had a bCR rate of 90% [95% CI, 84-95%] in ALL (n= 297) and 47% [95% CI, 34-61%] in NHL (n= 137). The estimated incidence of total and severe (grade ≥3) CRS were 87% [95% CI, 80-92%] and 6% [95% CI, 3-9%] respectively. ICANS and severe ICANS had an estimated incidence of 16% [95% CI, 9-25%] and 3% [95% CI, 1-5%] respectively. Early phase trials of CD22 and CD19/CD22 CAR T-cells show high remission rates in ALL and NHL. Severe CRS or ICANS were (1)rare and dual-targeting did not increase toxicity. Variability in CAR construct, dose, and patient factors amongst studies limits comparisons, with long-term outcomes yet to be reported.

Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier CRD42020193027.

Keywords: B-cell malignancies; CAR T-cell; CD22; efficacy; safety; systematic review & meta-analysis.

Figure 1

PRISMA flow diagram of references identified, screened, excluded (with reasons) and included.

Figure 2

Forest plot of best complete response rate organized by malignancy type and antigen target. Pooled estimates, represented by the black diamond, were calculated for each subgroup and overall weighted effect.

Figure 3

Forest plot of cytokine release syndrome rate organized by severity. Pooled estimate of effect, black diamond, was calculated for both all grades (1-5) and severe grades (3-5). Pan 2020: cycle 1 (CD19) was excluded from analysis, although rates did not significantly differ from cycle 2 (18/20 all grades, 1/20 severe).

Figure 4

Forest plot of immune effector cell-associated neurotoxicity syndrome rate organized by severity. Pooled estimate of effect, black diamond, was calculated for both all grades (1-5) and severe grades (3-5). Pan 2020: cycle 1 (CD19) was excluded from analysis, although rates did not significantly differ from cycle 2 (3/20 all grades, 1/20 severe).