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Title

 Next Generation GPC2-CARs for Medulloblastoma

Principal Investigators

Dr. Crystal Mackall

Dr. Steven Feldman

Description

Progress against pediatric solid tumors has stalled. Current standard therapies largely employ dose intensive cytotoxic agents developed in the 1970s and 1980s that incur severe lifelong toxicity and are unable to cure most patients with high-risk, metastatic, recurrent or refractory disease. Medulloblastoma (MB), the most common malignant brain tumor of childhood epitomizes this reality, since standard therapies are exceedingly toxic and outcomes for patients with metastatic, recurrent or refractory disease remain poor. There is an urgent need for novel, effective targeted therapies for MB. Cerebroglycan (GPC-2) is overexpressed on the cell surface of MB and is not expressed on normal postnatal tissues rendering it a compelling target for treatment with chimeric antigen receptor (CAR) based therapies. CAR based therapies have shown impressive activity in B-cell and plasma cell malignancies, and early signals of activity have been observed with GD2-CAR T cells in children with diffuse midline glioma and neuroblastoma respectively, providing evidence that CAR T cells can mediate significant activity in pediatric brain tumors and solid tumors. In stringent preclinical models, we demonstrated that an iteratively optimized GPC2-CAR mediated significant antitumor activity in MB and NB, but also observed late disease recurrence associated with GPC2 downmodulation. Leveraging deep expertise in enhancing the potency of CAR T cells in the Mackall lab, we demonstrated that overexpression of cJUN in GPC2-CAR T cells led to improved long-term disease control against MB and NB without evidence for toxicity. These data align directly with studies from our lab and others demonstrating that cJUN overexpression lowers the antigen density required for CAR T cell activation, diminishes T cell exhaustion and enhances T cell persistence. Aims 1 and 2 of this Project will define the optimal approach to overexpress cJUN in GPC2-CAR T cells at clinical scale testing state-of-the-art approaches to co-transduction, viral free gene integration and cell selection to identify the most efficient and reproductible platform for consistently delivering an optimized clinical GPC2.cJUN-CAR product. In Aim 3 we will apply the optimal process to manufacture clinical grade GPC2.cJUN-CAR T cells in Arm B of a Phase I trial designed to assess the feasibility, safety and efficacy of GPC2.cJUN-CAR T cell therapy against MB. This trial will compare outcomes between patients treated with GPC2-CAR T cells that did not overexpress cJUN who will have previously been enrolled on Arm A. This work will be among the first to test a potency enhanced CAR T cell therapy for pediatric cancer, will provide valuable information about the promise of GPC2 as a target for MB and will provide preliminary evidence regarding whether cJUN OE can enhance CAR T cell potency without incurring significant toxicity in humans.