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Front. Oncol. | doi: 10.3389/fonc.2018.00044

Combination of Ipilimumab and Adoptive Cell Therapy with Tumor Infiltrating Lymphocytes for Patients with Metastatic Melanoma

 John E. Mullinax1, 2, Maclean Hall2,  Sangeetha Prabhakaran3, Jeffrey Weber4, Nikhil Khushalani5, Zeynep Eroglu5, Andrew Brohl1, 5, Joseph Markowitz2, 5, Erica Royster5, Allison Richards5, Valerie Stark5, Jonathan S. Zager5, Linda Kelley2, Cheryl Cox6, Vernon K. Sondak5,  James J. Mule'2, 5,  Amod A. Sarnaik2, 5 and  Shari Pilon-Thomas2, 5*
  • 1Sarcoma Department, Moffitt Cancer Center, United States
  • 2Department of Immunology, Moffitt Cancer Center, United States
  • 3Department of Surgery, University of New Mexico, United States
  • 4Department of Medicine, Langone Medical Center,New York University, United States
  • 5Department of Cutaneous Oncology, Moffitt Cancer Center, United States
  • 6Cell Therapy Facility, Moffitt Cancer Center, United States

Purpose: Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) for metastatic melanoma can be highly effective, but attrition due to progression before TIL administration (32% in prior institutional experience) remains a limitation. We hypothesized that combining ACT with CTLA-4 blockade would decrease attrition and allow more patients to receive TIL.
Experimental Design: Thirteen patients with metastatic melanoma were enrolled. Patients received four doses of ipilimumab (3 mg/kg) beginning two weeks prior to tumor resection for TIL generation, then one week after resection, and 2 and 5 weeks after pre-conditioning chemotherapy and TIL infusion followed by IL-2. The primary endpoint was safety and feasibility. Secondary endpoints included of clinical response at 12 weeks and at one year after TIL transfer, disease free survival (DFS) and overall survival (OS).
Results: All patients received at least 2 doses of ipilimumab, and 12 of the 13 (92%) received TIL. A median of 6.5x10^10 (2.3x10^10 - 1.0x10^11) TIL were infused. At 12 weeks following infusion there were 5 patients who experienced objective response (38.5%), 4 of whom continued in objective response at one year and one of which became a complete response at 52 months. Median progression-free survival was 7.3 months (95%CI 6.1-29.9 months). Grade ≥3 immune-related adverse events included hypothyroidism (3), hepatitis (2), uveitis (1) and colitis (1).
Conclusions: Ipilimumab plus ACT for metastatic melanoma is feasible, well tolerated, and associated with a low rate of attrition due to progression during cell expansion. This combination approach serves as a model for future efforts to improve the efficacy of ACT.

Keywords: adoptive cell therapy, Melanoma, ipilimumab, Checkpoint inhibitor, Immunotherapy, TIL

Received: 05 Dec 2017; Accepted: 12 Feb 2018.

Edited by:

Rayne Rouce, Baylor College of Medicine, United States

Reviewed by:

Cara Haymaker, University of Texas MD Anderson Cancer Center, United States
Valentina Hoyos, Baylor College of Medicine, United States  

Copyright: © 2018 Mullinax, Hall, Prabhakaran, Weber, Khushalani, Eroglu, Brohl, Markowitz, Royster, Richards, Stark, Zager, Kelley, Cox, Sondak, Mule', Sarnaik and Pilon-Thomas. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: PhD. Shari Pilon-Thomas, Department of Immunology, Moffitt Cancer Center, Tampa, FL, United States,