TY - JOUR
T1 - Adoptive transfer of tumor-infiltrating lymphocytes in patients with metastatic melanoma
T2 - Intent-to-treat analysis and efficacy after failure to prior immunotherapies
AU - Besser, Michal J.
AU - Shapira-Frommer, Ronnie
AU - Itzhaki, Orit
AU - Treves, Avraham J.
AU - Zippel, Douglas B.
AU - Levy, Daphna
AU - Kubi, Adva
AU - Shoshani, Noa
AU - Zikich, Dragoslav
AU - Ohayon, Yaara
AU - Ohayon, Daniel
AU - Shalmon, Bruria
AU - Markel, Gal
AU - Yerushalmi, Ronit
AU - Apter, Sara
AU - Ben-Nun, Alon
AU - Ben-Ami, Eytan
AU - Shimoni, Avichai
AU - Nagler, Arnon
AU - Schachter, Jacob
PY - 2013/9/1
Y1 - 2013/9/1
N2 - 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 Altogether 23 patients were withdrawn from the study mainly due to clinical deterioration during TIL preparation.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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84883472041&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-13-0380
DO - 10.1158/1078-0432.CCR-13-0380
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AN - SCOPUS:84883472041
SN - 1078-0432
VL - 19
SP - 4792
EP - 4800
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 17
ER -
