MART-1 TCR gene-modified peripheral blood T cells for the treatment of metastatic melanoma: a phase I/IIa clinical trial
Maartje W. Rohaan, Raquel Gomez-Eerland, Joost H. van den Berg, Marnix H. Geukes Foppen, Maaike van Zon, Brenda Raud, I. Jedema, Saskia Scheij, Renate de Boer, Noor A. M. Bakker, Daan van den Broek, Loes M. Pronk, Lindsay G. Grijpink-Ongering, Ayşegül Sarı, R. Kessels, Markus Haak, Henk Mallo, Matthias Karger, Bart A. van de Wiel, Charlotte L. Zuur, Charlotte W. Duinkerken, Ferry Lalezari, Johannes V. van Thienen, Sofie Wilgenhof, Christian U. Blank, Jos H. Beijnen, Bastiaan Nuijen, Ton N. Schumacher, John B.A.G. Haanen
Abstract
Background: Adoptive cell therapy with peripheral blood T cells expressing transgenic T-cell receptors (TCRs) is an innovative therapeutic approach for solid malignancies. We investigated the safety and feasibility of adoptive transfer of autologous T cells expressing melanoma antigen recognized by T cells 1 (MART-1)-specific TCR, cultured to have less differentiated phenotypes, in patients with metastatic melanoma. Materials and methods: In this phase I/IIa trial, peripheral blood T cells from HLA-A2*02:01-positive patients with unresectable stage IIIC/IV melanoma expressing MART-1 were selected and stimulated with anti-CD3/CD28 beads, transduced with a modified MART-1 (26-35) -specific 1D3 TCR (1D3HMCys) and expanded in interleukin (IL)-7 and IL-15. Patients received a single infusion of transgenic T cells in a dose-escalating manner. Feasibility, safety and objective response rate were assessed. Results: Twelve pretreated metastatic cutaneous (n 7) and uveal (n 5) melanoma patients were included. Patient 1 received 4.6 10 9 1D3HMCys T cells and experienced grade 5 toxicity after 9 days. Subsequent patients received 5.0 10 7 [n 3; cohort (c) 2], 2.5 10 8 (n 2; c3) and 1.0 10 8 (n 6; c4) 1D3HMCys T cells. The study was prematurely terminated because of dose-dependent toxicity, concerning skin (10/12), eyes (3/12), ears (4/12) and cytokine release syndrome (5/12), with 7 patients experiencing grade 3-5 toxicity. Partial responses were seen in 2/11 (18%) assessable patients and persistence of 1D3HMCys T cells corresponded to infused cell dose. Conclusions: Production of TCR-modified cells as described leads to highly potent T cells. Partial responses were seen in 18% of patients with dose-dependent 'on-target, off-tumor' toxicity and a maximum tolerated dose of 1.0 10 8 cells.