Abstract CT008: A pilot trial of the combination of transgenic NY-ESO-1-reactive adoptive cellular therapy with dendritic cell vaccination with or without ipilimumab in patients with sarcoma and melanoma
Authors: Nowicki Theodore S. , Berent-Maoz Beata , Huang Rong Rong , Wang Xiaoyan , Cheung-Lau Gardenia , Kaplan-Lefko Paula , Cabrera Paula , Tran Justin , Carretero Ignacio Baselga , Grasso Catherine S. , Hu-Lieskovan Siwen , Chmielowski Bartosz , Comin-Anduix Begoña , Singh Arun , Ribas Antoni 
Published: August 2018

Abstract
Background: Transgenic adoptive cell therapy (ACT) targeting the tumor antigen NY-ESO-1 can be effective for the treatment of sarcoma and melanoma. Preclinical models have shown that this therapy can be improved with the addition of dendritic cell (DC) vaccination and immune checkpoint blockade. In this study, we report the results of the safety, feasibility, and antitumor efficacy of this approach alone and in combination with the CTLA-4 blockade with ipilimumab.
Methods: NY-ESO-1 specific T-cell receptor (TCR) transgenic lymphocytes were adoptively transferred together with NY-ESO-1 peptide-pulsed DC vaccination in HLA-A*0201-positive subjects with (ESO, NCT02070406) or without ipilimumab (INY, NCT01697527) in patients with advanced sarcoma and melanoma under Investigator New Drug IND#15167. Patients received autologous retrovirally TCR-transduced T cells following a lymphodepleting preparative chemotherapy regimen. NY-ESO-1157-165 peptide-pulsed autologous DCs were administered on Days 1, 14 and 30, and low-dose IL-2 was given twice daily for 7-14 days. In the INY cohort, ipilimumab (1mg/kg) was given on day 0 or 1, and every three weeks for a maximum of four doses. Response rates were evaluated by RECIST.
Results: Four patients with synovial sarcoma, two patients with melanoma, one patient with osteosarcoma, one patient with liposarcoma, and one patient with malignant peripheral nerve sheath tumor were enrolled into these cohorts. Two patients (one treated per ESO, and another treated per INY) experienced cytokine release syndrome requiring hospitalization. Patients treated per INY had significantly higher serum levels of the cytokine FLT-3L. Two out of four patients treated per INY, and four out of six patients treated per ESO demonstrated an objective clinical response by day 30. One patient treated per ESO (17%) has had an ongoing complete response for 3 years. One patient was treated per ESO and, following disease progression after an objective clinical response, was subsequently enrolled in INY. TCR sequencing of dextramer-positive cells demonstrated that the NY-ESO TCR integrated across a highly polyclonal population of endogenous TCR clonotypes. Tracking of transgenic T cells to the tumor and acquisition of PD-1 expression was demonstrated by TCR sequencing and immunohistochemistry of on-treatment biospies, respectively.
Conclusions: ACT of fresh NY-ESO-1 transgenic T cells prepared via a short ex vivo protocol and given with DC vaccination and low dose IL-2, with or without ipilimumab, is feasible and results in transient antitumor activity, with no apparent clinical benefit of the addition of ipilimumab. Improvements are needed to maintain tumor responses.
Citation Format: Theodore S. Nowicki, Beata Berent-Maoz, Rong Rong Huang, Xiaoyan Wang, Gardenia Cheung-Lau, Paula Kaplan-Lefko, Paula Cabrera, Justin Tran, Ignacio Baselga Carretero, Catherine S. Grasso, Siwen Hu-Lieskovan, Bartosz Chmielowski, Begoña Comin-Anduix, Arun Singh, Antoni Ribas. A pilot trial of the combination of transgenic NY-ESO-1-reactive adoptive cellular therapy with dendritic cell vaccination with or without ipilimumab in patients with sarcoma and melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT008.