Pinto Navin, Albert Catherine M, Taylor Mallory R, Ullom Heidi B, Wilson Ashley L, Huang Wenjun, Wendler Jason, Pattabhi Sowmya, Seidel Kristy, Brown Christopher, Gustafson Joshua A, Rawlings-Rhea Stephanie D, Cheeney Safia H E, Burleigh Katelyn, Gustafson Heather H, Orentas Rimas J, Vitanza Nicholas A, Gardner Rebecca A, Jensen Michael C, Park Julie R
Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA.
Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA.
J Clin Oncol. 2024 Dec 10;42(35):4163-4172. doi: 10.1200/JCO.23.02229. Epub 2024 Sep 10.
B7-H3 is an immunoregulatory protein overexpressed by many pediatric solid tumors with limited expression on critical organs, making it an attractive immunotherapy target. We present a first-in-human phase I clinical trial systemically administered B7-H3 chimeric antigen receptor (CAR) T cells for young patients with relapsed or refractory solid tumors.
Patients were enrolled onto a phase I trial to examine the safety of B7-H3-specific CARs at various dose levels (DLs) using a standard 3 + 3 dose escalation design.
Sixteen patients (range, 11-24 years; median, 18.5 years) were enrolled, and nine were treated at DL1 (0.5 × 10 CAR T cells/kg; n = 3) or DL2 (1 × 10 CAR T cells/kg; n = 6). There were no first infusion dose-limiting toxicities. Maximum first-infusion circulating CAR T cells detected in the peripheral blood were 4.98 cells/μL (range, 0-4.98 cells/μL) with detection of CAR T cells colocalizing with tumor cells at the site of metastatic disease in one patient. Patients were eligible for subsequent infusions. An objective partial response by PERCIST criteria was observed 28 days after a second CAR T cell infusion in a patient who did not have an objective response after the first infusion. The second infusion demonstrated marked enhancement of CAR T cell expansion to 1,590 cells/μL and was accompanied by cytokine release syndrome and dose-limiting transaminitis. Detailed peripheral blood cytokine profiling revealed elevated IL-21 levels preinfusion 2 compared with infusion 1.
B7-H3 CAR T cells are tolerable and demonstrate limited antitumor activity without acute on-target, off-tumor toxicity. High levels of CAR T cell expansion may be necessary to achieve objective responses, but undefined host and tumor microenvironment factors appear to be critical (ClinicalTrials.gov identifier: NCT04483778).
B7-H3是一种免疫调节蛋白，在许多儿科实体瘤中过表达，而在关键器官中表达有限，这使其成为一个有吸引力的免疫治疗靶点。我们开展了一项针对复发或难治性实体瘤年轻患者的I期人体临床试验，系统性地给予B7-H3嵌合抗原受体（CAR）T细胞。
患者入组一项I期试验，采用标准的3+3剂量递增设计，在不同剂量水平（DLs）检测B7-H3特异性CAR的安全性。
共入组16例患者（年龄范围11-24岁；中位年龄18.5岁），9例在DL1（0.5×10 CAR T细胞/kg；n=3）或DL2（1×10 CAR T细胞/kg；n=6）接受治疗。未出现首次输注剂量限制性毒性。外周血中检测到的首次输注后循环CAR T细胞的最高值为4.98个细胞/μL（范围0-4.98个细胞/μL），在1例患者的转移病灶部位检测到CAR T细胞与肿瘤细胞共定位。患者有资格接受后续输注。1例首次输注后未出现客观缓解的患者在第二次CAR T细胞输注28天后，根据PERCIST标准观察到客观部分缓解。第二次输注显示CAR T细胞显著扩增至1590个细胞/μL，并伴有细胞因子释放综合征和剂量限制性转氨酶升高。详细的外周血细胞因子谱分析显示，与输注1相比，输注2前IL-21水平升高。
B7-H3 CAR T细胞耐受性良好，显示出有限的抗肿瘤活性，无急性靶向脱瘤毒性。可能需要高水平的CAR T细胞扩增才能实现客观缓解，但未明确的宿主和肿瘤微环境因素似乎至关重要（ClinicalTrials.gov标识符：NCT04483778）。
