CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial.
Jay Y SpiegelShabnum PatelLori S MufflyNasheed M HossainJean OakJohn H BairdMatthew J FrankParveen ShirazBita SahafJuliana K CraigMaria IglesiasSheren YounesYasodha NatkunamMichael G OzawaEric YangJohn TamaresisHarshini ChinnasamyZach EhlingerWarren ReynoldsRachel LynnMaria Caterina RotirotiNikolaos GkitsasSally AraiLaura JohnstonRobert LowskyRobbie G MajznerEverett MeyerRobert S NegrinAndrew R RezvaniSurbhi SidanaJudith A ShizuruWen-Kai WengChelsea MullinsAllison JacobIlan KirschMagali BazzanoJing ZhouSean MackayScott J BornheimerLiora SchultzSneha RamakrishnaKara L DavisKatherine A KongNirali N ShahHaiying QinTerry J FrySteven FeldmanCrystal L MackallDavid Bernard MiklosPublished in: Nature medicine (2021)
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.
Keyphrases
- acute lymphoblastic leukemia
- clinical trial
- nk cells
- end stage renal disease
- multiple sclerosis
- chronic kidney disease
- randomized controlled trial
- newly diagnosed
- cell death
- peritoneal dialysis
- oxidative stress
- signaling pathway
- open label
- study protocol
- cell cycle arrest
- induced apoptosis
- multiple myeloma
- phase ii
- ulcerative colitis