Potent ex vivo armed T cells using recombinant bispecific antibodies for adoptive immunotherapy with reduced cytokine release
Jeong A Park, Brian H Santich, Hong Xu, Lawrence G Lum, Nai-Kong V Cheung, Jeong A Park, Brian H Santich, Hong Xu, Lawrence G Lum, Nai-Kong V Cheung
Abstract
Background: T cell-based immunotherapies using chimeric antigen receptors (CAR) or bispecific antibodies (BsAb) have produced impressive responses in hematological malignancies. However, major hurdles remained, including cytokine release syndrome, neurotoxicity, on-target off-tumor effects, reliance on autologous T cells, and failure in most solid tumors. BsAb armed T cells offer a safe alternative.
Methods: We generated ex vivo armed T cells (EATs) using IgG-[L]-scFv-platformed BsAb, where the anti-CD3 (huOKT3) scFv was attached to the light chain of a tumor-binding IgG. BsAb density on EAT, in vitro cytotoxicity, cytokine release, in vivo trafficking into tumors, and their antitumor activities were evaluated in multiple cancer cell lines and patient-derived xenograft mouse models. The efficacy of EATs after cryopreservation was studied, and gamma delta (γδ) T cells were investigated as unrelated alternative effector T cells.
Results: The antitumor potency of BsAb armed T cells was substantially improved using the IgG-[L]-scFv BsAb platform. When compared with separate BsAb and T cell injection, EATs released less TNF-α, and infiltrated tumors faster, while achieving robust antitumor responses. The in vivo potency of EAT therapy depended on BsAb dose for arming, EAT cell number per injection, total number of EAT doses, and treatment schedule intensity. The antitumor efficacy of EATs was preserved following cryopreservation, and EATs using γδ T cells were safe and as effective as αβ T cell-EATs.
Conclusions: EATs exerted potent antitumor activities against a broad spectrum of human cancer targets with remarkable safety. The antitumor potency of EATs depended on BsAb dose, cell number and total dose, and schedule. EATs were equally effective after cryopreservation, and the feasibility of third-party γδ-EATs offered an alternative for autologous T cell sources.
Trial registration: ClinicalTrials.gov NCT02173093 NCT00027807 NCT04137536.
Keywords: adoptive; immunotherapy; investigational; neuroblastoma; sarcoma; therapies; translational medical research.
Conflict of interest statement
Competing interests: Both MSK and N-KVC have financial interest in Y-mAbs, Abpro-Labs and Eureka Therapeutics. N-KVC reports receiving commercial research grants from Y-mAbs Therapeutics and Abpro-Labs. N-KVC was named as inventor on multiple patents filed by MSK, including those licensed to Y-mAbs Therapeutics, Biotec Pharmacon, and Abpro-Labs. N-KVC is a SAB member for Abpro-Labs and Eureka Therapeutics. LL is cofounder of Transtarget and is a SAB member for Rapa Therapeutics. JAP has no disclosures to report.
© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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