Molecular Pharmacology Program, Sloan Kettering Institute, New York, NY.
Pharmacology Program, Weill Cornell Medicine, New York, NY.
Blood. 2023 Apr 20;141(16):2003-2015. doi: 10.1182/blood.2022016101.
Chimeric antigen receptor (CAR) T-cell therapy has shown success in the treatment of hematopoietic malignancies; however, relapse remains a significant issue. To overcome this, we engineered "Orexi" CAR T cells to locally secrete a high-affinity CD47 blocker, CV1, at the tumor and treated tumors in combination with an orthogonally targeted monoclonal antibody. Traditional CAR T cells plus the antibody had an additive effect in xenograft models, and this effect was potentiated by CAR T-cell local CV1 secretion. Furthermore, OrexiCAR-secreted CV1 reversed the immunosuppression of myelomonocytoid cells both in vitro and within the tumor microenvironment. Local secretion of the CD47 inhibitor bypasses the CD47 sink found on all cells in the body and may prevent systemic toxicities. This combination of CAR T-cell therapy, local CD47 blockade, and orthogonal antibody may be a combinatorial strategy to overcome the limitations of each monotherapy.
嵌合抗原受体 (CAR) T 细胞疗法已在治疗血液系统恶性肿瘤方面取得成功；然而，复发仍是一个重大问题。为了克服这一问题，我们设计了“Orexi”CAR T 细胞，使其在肿瘤部位局部分泌高亲和力的 CD47 阻断剂 CV1，并与正交靶向单克隆抗体联合治疗肿瘤。在异种移植模型中，传统的 CAR T 细胞加抗体具有相加作用，而 CAR T 细胞局部 CV1 分泌增强了这种作用。此外，OrexiCAR 分泌的 CV1 在体外和肿瘤微环境中逆转了髓样细胞的免疫抑制作用。CD47 抑制剂的局部分泌绕过了体内所有细胞上发现的 CD47 吸收剂，可能防止全身毒性。这种 CAR T 细胞疗法、局部 CD47 阻断和正交抗体的组合可能是克服每种单药治疗局限性的联合策略。
