(P 110) GCAR1: GPNMB CAR T THERAPY FOR MIT FAMILY TRANSLOCATION POSITIVE CANCERS

Objective: Motivated by a local AYA patient with recurrent, metastatic alveolar soft part sarcoma (ASPS), we have designed a novel Chimeric Antigen Receptor (CAR) T therapy targeting Glycoprotein NMB (GPNMB). GPNMB expression is regulated by members of the microphthalmia-associated transcription factor (MiT) family which includes TFE3, TFEB and MITF. In ASPS, translocation-positive renal cell carcinoma (tRCC), and some cases of epithelioid hemangiosarcoma (EHE), GPNMB is driven to high and homogenous levels by pathognomonic fusion proteins containing MiTF family members. Encouraged by GPNMB’s low expression in normal tissue and ubiquitous expression in these cancers, we are proceeding into a first-in-person single patient study (SPS) that will expand to a pan-Canadian, multicenter Phase I.

Methods: GCAR1 is a novel, 2nd generation CAR T therapy containing a scFV targeting GPNMB and 41bb and CD3ζ T cell signalling domains. Preclinical testing utilized an ASPS patient-derived xenograft (PDX) and preclinically manufactured healthy donor or patient-matched CAR T cells. Clinical development of GCAR1 included producing a lentiviral product under principles of GMP in collaboration with the BC Cancer Agency and Biotherapeutics Manufacturing Centre at the Ottawa Hospital Research Institute. In-house manufacturing validation runs were performed by Alberta Precision Laboratory Cell Therapy Labs on the CliniMACS Prodigy® using healthy or patient-derived apheresis material. Phase I clinical trial design is currently being developed in collaboration with the Canadian Clinical Trials Group (CCTG).

Results: In preclinical testing, we found GCAR1 efficiently kills GPNMB-expressing ASPS and tRCC cells lines in culture, while resulting in complete and durable remissions when systemically delivered to orthotopic PDX mouse models of ASPS primary tumours and brain metastasis. In primary tumour models, GCAR1 expanded within the tumour microenvironment resulting in a >500-fold expansion in the blood without detectable toxicities. GCAR1 clinical development included three validation runs on the CliniMACS Prodigy®, all of which expanded functional GCAR1 CAR T cells that met standard release criteria. A first-in-person SPS of GCAR1 in a AYA ASPS patient with multiple, progressing pulmonary metastasis is nearing initiation. The SPS protocol will administer 1e6 GCAR1/kg with primary endpoints measuring CAR-related toxicity and efficacy. If available, preliminary results of the SPS to be presented at the meeting.

Conclusion: Preclinical evaluation of GCAR1 demonstrated robust anti-tumour activity against GPNMB-expressing cells in vitro and in vivo, which has led to the rapid translation of this therapeutic for an ASPS patient without further treatment options. These studies are informing the design of a CCTG-sponsored Phase I clinical trial indicated for all MiT-translation cancers.