Phase I Trial of GD2.CART Cells Augmented With Constitutive Interleukin-7 Receptor for Treatment of High-Grade Pediatric CNS Tumors
Frank Y. Lin, Austin J. Stuckert, Candise Tat, Mark D. White, Lucia Ruggieri, Huimin Zhang, Birju Mehta, Natalia Lapteva, Zhuyong Mei, Angela M. Major, Sachin G. Thakkar, Thomas Shum, Kathan Parikh, Meng-Fen Wu, Holly Lindsay, Lauren Scherer, Meghan Shekar, Darryl Kinnear, Melissa M. Blessing, Patricia Baxter, Tao Wang, Bambi Grilley, Karen Moeller, John Hicks, Angshumoy Roy, Jamie Anastas, Fatema Malbari, Guillermo Aldave, Murali Chintagumpala, Susan Blaney, D. Williams Parsons, Malcolm K. Brenner, Helen E. Heslop, Cliona M. Rooney, Bilal Omer
Abstract
PURPOSE T cells modified with chimeric antigen receptors (CARTs) have demonstrated efficacy for hematologic malignancies; however, benefit for patients with CNS tumors has been limited. To enhance T cell activity against GD2+ CNS malignancies, we modified GD2-directed CART cells (GD2.CARTs) with a constitutively active interleukin (IL)-7 receptor (C7R-GD2.CARTs). METHODS Patients age 1-21 years with H3K27-altered diffuse midline glioma (DMG) or other recurrent GD2-expressing CNS tumors were eligible for this phase I trial (ClinicalTrials.gov identifier: NCT04099797 ). All subjects received standard-of-care adjuvant radiation therapy or chemotherapy before study enrollment. The first treatment cohort received GD2.CARTs alone (1 × 10 7 cells/m 2 ), and subsequent cohorts received C7R-GD2.CARTs at two dose levels (1 × 10 7 cells/m 2 ; 3 × 10 7 cells/m 2 ). Standard lymphodepletion with cyclophosphamide and fludarabine was included at all dose levels. RESULTS Eleven patients (age 4-18 years) received therapy without dose-limiting toxicity. The GD2.CART cohort did not experience toxicity, but had disease progression after brief improvement of residual neurologic deficits (≤3 weeks). The C7R-GD2.CART cohort developed grade 1 tumor inflammation–associated neurotoxicity in seven of eight (88%) cases, controllable with anakinra. Cytokine release syndrome was observed in six of eight (75%, grade 1 in all but one patient) and associated with increased circulating IL-6 and IP-10 ( P < .05). Patients receiving C7R-GD2.CARTs experienced temporary improvement from baseline neurologic deficits (range, 2 to >12 months), and seven of eight (88%) remained eligible for additional treatment cycles (range 2-4 cycles). Partial responses by iRANO criteria were observed in two of seven (29%) patients with DMG treated by C7R-GD2.CARTs. CONCLUSION Intravenous GD2.CARTs with and without C7R were well tolerated. Patients treated with C7R-GD2.CARTs exhibited transient improvement of neurologic deficits and increased circulating cytokines/chemokines. Treatment with C7R-GD2.CARTs represents a novel approach warranting further investigation for children with these incurable CNS cancers.