CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial

Abstract

Despite impressive progress, more than 50% of patients treated with CD19-targeting chimeric antigen receptor T cells (CAR19) experience progressive disease. Ten of 16 patients with large B cell lymphoma (LBCL) with progressive disease after CAR19 treatment had absent or low CD19. Lower surface CD19 density pretreatment was associated with progressive disease. To prevent relapse with CD19− or CD19lo disease, we tested a bispecific CAR targeting CD19 and/or CD22 (CD19-22.BB.z-CAR) in a phase I clinical trial (NCT03233854) of adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) and LBCL. The primary end points were manufacturing feasibility and safety with a secondary efficacy end point. Primary end points were met; 97% of products met protocol-specified dose and no dose-limiting toxicities occurred during dose escalation. In B-ALL (n = 17), 100% of patients responded with 88% minimal residual disease-negative complete remission (CR); in LBCL (n = 21), 62% of patients responded with 29% CR. Relapses were CD19−/lo in 50% (5 out of 10) of patients with B-ALL and 29% (4 out of 14) of patients with LBCL but were not associated with CD22−/lo disease. CD19/22-CAR products demonstrated reduced cytokine production when stimulated with CD22 versus CD19. Our results further implicate antigen loss as a major cause of CAR T cell resistance, highlight the challenge of engineering multi-specific CAR T cells with equivalent potency across targets and identify cytokine production as an important quality indicator for CAR T cell potency.

Engineering the next generation of CAR-NK immunotherapies

“…Besides the cumbersome logistics associated with autologous cell manufacturing and high rates of cell therapy-related toxicities, the most pressing concern remains suboptimal long-term disease control. As the most recent results from the initial pivotal trials show, current generation CAR-T products still fail to deliver long-term responses for many patients, with a significant proportion of treated patients eventually relapsing and succumbing to their disease [ 9 – 11 ].…”

Genomic drivers of large B-cell lymphoma resistance to CD19 CAR-T therapy

“…Efforts to improve efficacy such as dual-targeting strategies [14][15][16] remain uninformed by an understanding of the lymphoma cell-intrinsic factors that drive CAR-19 failures. In particular, there is a lack of knowledge on tumor cell genomic drivers involved in relapse.…”

Siglecs as Therapeutic Targets in Cancer

“…Unlike CD19-targeting chimeric antigen receptors (CAR) T cell therapy with acquired resistance due to surface CD19 antigen loss [39,40], CD22 usually retains expression in CD19 neg tumors [41,42]. As such, CD22 or tandem CD19 and CD22 targeting CAR-T cells are being pursued in treating B cell malignancies such as non-Hodgkin lymphomas and acute lymphoblastic leukemia [43][44][45]. However, even CD22 expression can be low or even null in several human lung cancer cells, including pancreatic, prostate, breast, and liver cancers to be considered targetable (https://www.proteinatlas.org/ENSG000000121 24-CD22/pathology, accessed on 3 November 2021) [46].…”