Adoptive transfer of tumor-infiltrating lymphocytes in patients with metastatic melanoma: intent-to-treat analysis and efficacy after failure to prior immunotherapies.

Abstract

PURPOSE:

Adoptive cell transfer (ACT) using autologous tumor-infiltrating lymphocytes (TIL) was reported to yield objective responses in about 50% of metastatic patients with melanoma. Here, we present the intent-to-treat analysis of TIL ACT and analyze parameters predictive to response as well as the impact of other immunotherapies.

EXPERIMENTAL DESIGN:

Eighty patients with stage IV melanoma were enrolled, of which 57 were treated with unselected/young TIL and high-dose interleukin-2 (IL-2) following nonmyeloablative lymphodepleting conditioning.

RESULTS:

TIL cultures were established from 72 of 80 enrolled patients. Altogether 23 patients were withdrawn from the study mainly due to clinical deterioration during TIL preparation. The overall response rate and median survival was 29% and 9.8 months for enrolled patients and 40% and 15.2 months for treated patients. Five patients achieved complete and 18 partial remission. All complete responders are on unmaintained remission after a median follow-up of 28 months and the 3-year survival of responding patients was 78%. Multivariate analysis revealed blood lactate-dehydrogenase levels, gender, days of TIL in culture, and the total number of infused CD8+ cells as independent predictive markers for clinical outcome. Thirty-two patients received the CTLA-4-blocking antibody ipilimumab prior or post TIL infusion. Retrospective analysis revealed that nonresponders to ipilimumab or IL-2 based therapy had the same overall response rate to ACT as other patients receiving TIL. No additional toxicities to TIL therapy occurred following ipilimumab treatment.

CONCLUSION:

Adoptive transfer of TIL can yield durable and complete responses in patients with refractory melanoma, even when other immunotherapies have failed.

• Authors: Michal J Besser, Ronnie Shapira-Frommer, Orit Itzhaki, Avraham J Treves, Douglas B Zippel, Daphna Levy, Adva Kubi, Noa Shoshani, Dragoslav Zikich, Yaara Ohayon, Daniel Ohayon, Bruria Shalmon, Gal Markel, Ronit Yerushalmi, Sara Apter, Alon Ben-Nun, Eytan Ben-Ami, Avichai Shimoni, Arnon Nagler, Jacob Schachter
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 17 Pg. 4792-800 (Sep 01 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 23690483 (Publication Type: Clinical Trial, Phase II, Journal Article)
• Copyright: ©2013 AACR.

Chemical References

• Antibodies, Monoclonal
• Ipilimumab

Topics

• Adoptive Transfer (methods)
• Adult
• Aged
• Antibodies, Monoclonal (administration & dosage)
• Cell- and Tissue-Based Therapy
• Cytotoxicity, Immunologic
• Female
• Humans
• Immunotherapy
• Ipilimumab
• Kaplan-Meier Estimate
• Lymphocytes, Tumor-Infiltrating
• Male
• Melanoma (drug therapy, immunology, pathology, therapy)
• Middle Aged
• Neoplasm Staging