Details

Autor(en) / Beteiligte

• Phillips, Suzanne
• Singh, Shailbala
• Lizee, Gregory
• Solis, Luisa Maren
• Welsh, James William
• Bassett, Roland L.
• Beal, Lisa G
• Kim, Peter Y.
• Murthy, Ravi
• Talukder, Amjad
• Lai, Ivy
• Yee, Cassian
• Patel, Sapna Pradyuman

Titel

A phase Ib study of endogenous T cell therapy using SLC45A2-specific CD8 T cells for patients with metastatic uveal melanoma

Ist Teil von

• Journal of clinical oncology, 2023-06, Vol.41 (16_suppl), p.9588-9588

Erscheinungsjahr

2023

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 9588 Background: Overall survival (OS) for patients (pts) with advanced uveal melanoma (UM) is poor compared with outcomes in cutaneous melanoma. Roughly half of all pts with UM will develop distant metastatic disease despite effective treatment of the primary tumor. Antigen-specific endogenous T cells (ETC) can be expanded and infused successfully in pts with many different types of cancer. Our group has identified epitopes of SLC45A2, a melanosomal transport protein, which are highly expressed in UM and are present at low levels in normal melanocytes. In vitro, we showed that cytotoxic T cells against SLC45A2 were able to kill HLA-matched UM cell lines. In vivo, we hypothesize that infused ETC can traffic to tumor sites. Methods: Between 6/2017 and 12/2022, we conducted a single-center, IRB-approved, first-in-human phase 1b dose escalation study of ETC targeting SLC45A2 in pts with metastatic UM (NCT03068624). Eligible pts with metastatic UM who express HLA-A*02:01 or A*24:02 underwent apheresis to collect peripheral T cells which were then selected and expanded (Turnstile 1). For Turnstile 2, conditioning with low-dose cyclophosphamide (300 mg/m 2 ) occurred on Day -2. For pts in the radiation cohort, radiation occurred between Day -7 and Day -1. Infusion of ETC was done via hepatic arterial or central venous catheter on Day 0 followed by low dose subcutaneous interleukin-2 (IL-2) twice daily for 14 days +/- ipilimumab. The study utilized a 3+3 design with a starting dose level of 3.3 x 10 9 cells/m 2 of ETC alone. The primary objective was to evaluate the safety and tolerability of infusing ETC targeting SLC45A2. Secondary objectives were to evaluate the in vivo persistence and anti-tumor efficacy of this regimen. Results: With a median age of 58 years (30-77), 34 pts were enrolled, 16 (47%) men and 18 (53%) women. 33 (97%) pts underwent apheresis and 11 (32%) received infusion of ETC. One dose limiting toxicity (DLT) thought to be unrelated to treatment or underlying cancer (cardiac disorder Grade 5) occurred at the starting dose level with no additional DLTs. The maximum tolerated dose was established as 1 x 10 10 cells/m 2 . The most common treatment-related grade 3 and 4 toxicities were lymphocyte count decrease 9 (82%), hyponatremia 1 (9%), and hypophosphatemia 1 (9%). Per immune-related response criteria (irRC), 4 (36%) pts had stable disease (SD), 6 (55%) had progression of disease (PD), and 1 (9%) was not evaluable for best response. Median overall survival (OS) was 8.9 weeks (wks). OS was 91% at 4 wks, 55% at 8 wks and 46% at 13 wks. Median progression-free survival was 5.9 wks. In the 4 patients with stable disease, the median duration of SD was 5.7 months. Conclusions: ETC targeting SLC45A2 is safe and well-tolerated in pts with metastatic UM. Further analyses are underway to evaluate T cell trafficking and persistence. Clinical trial information: NCT03068624 .