A phase Ib study of endogenous SLC45A2-specific cytotoxic T cells for the treatment of patients with metastatic uveal melanoma

• Published in: Journal of clinical oncology Vol. 38; no. 15_suppl; p. TPS10086
• Main Authors: Phillips, Suzanne, Lizee, Gregory, Brown, Courtney, Lara, Jacqueline Marie, Bassett, Roland L., Beal, Lisa G, Murthy, Ravi, Talukder, Amjad, Hawke, David H, Lai, Ivy, Hwu, Patrick, Yee, Cassian, Patel, Sapna Pradyuman
• Format: Journal Article
• Language: English
• Published: 20.05.2020
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2020.38.15_suppl.TPS10086

Abstract only TPS10086 Background: Overall survival (OS) for patients (pts) with advanced uveal melanoma (UM) is poor with a median survival of approximately 12 months. Roughly half of all pts with UM will develop distant metastatic disease despite effective treatment of the primary site. Metastatic UM has a 90% prevalence of liver involvement. Currently, there are no specific FDA-approved treatments for metastatic UM and consensus guidelines recommend participation in a clinical trial. Modern treatments such as checkpoint inhibitors and targeted therapy have less impressive outcomes in UM. Our group has identified peptide epitopes of SLC45A2, a melanosomal transport protein, that is highly expressed in UM and present at very low levels in normal melanocytes. We demonstrated that cytotoxic T cells against SLC45A2 were able to kill HLA-matched UM cell lines. Through the use of enabling technologies, SLC45A2-specific cytotoxic T cells can be isolated and expanded ex-vivo from peripheral blood for use in endogenous T cell (ETC) therapy (a form of adoptive cellular therapy). These activated ETCs can then be infused to traffic to tumor sites. CTLA4 is a T-cell surface protein that binds to B7 with a higher affinity than the costimulatory receptor CD28, providing an inhibitory signal to T-cells. Anti-CTLA4 blockade can divert this inhibition and release the brake on antigen-specific T-cell activation of ETC. We hypothesize that antigen-specific ETCs infused via hepatic artery will be safe and tolerable for UM pts with liver metastasis. Methods: We are conducting a first-in-human clinical trial (NCT03068624 ) of ETC therapy targeting SLC45A2 in combination with anti-CTLA4 in pts with metastatic UM. Pts who express HLA-A*02:01 or A*24:02 undergo apheresis to collect T cells. Their cells then undergo ex vivo cloning and interleukin-21 primed expansion. Hepatic arterial infusion of ETCs will ensure direct localization to the target organ of interest. Conditioning with low-dose cyclophosphamide (300 mg/m2) occurs on Day -2. Hepatic arterial infusion of ETCs on Day 0 is followed by low dose subcutaneous interleukin-2 (IL-2) twice daily for 14 days. The initial dose escalation phase is a 3+3 design with a starting dose level of 3.3 x 10 9 cells/m 2 of ETCs alone. Once the maximum tolerated dose of ETCs is established, the dose expansion phase will include ETCs in combination with anti-CTLA4 (Ipilimumab). The primary objective is to evaluate the safety of this first in human T cell regimen. Secondary objectives are to evaluate the in vivo persistence and anti-tumor efficacy. Clinical trial information: NCT03068624.