TY - JOUR
T1 - Prospective analysis of adoptive TIL therapy in patients with metastatic melanoma
T2 - Response, impact of anti-CTLA4, and biomarkers to predict clinical outcome
AU - Forget, Marie Andree
AU - Haymaker, Cara
AU - Hess, Kenneth R.
AU - Meng, Yuzhong Jeff
AU - Creasy, Caitlin
AU - Karpinets, Tatiana
AU - Fulbright, Orenthial J.
AU - Roszik, Jason
AU - Woodman, Scott E.
AU - Kim, Young Uk
AU - Sakellariou-Thompson, Donastas
AU - Bhatta, Ankit
AU - Wahl, Arely
AU - Flores, Esteban
AU - Thorsen, Shawne T.
AU - Tavera, Rene J.
AU - Ramachandran, Renjith
AU - Gonzalez, Audrey M.
AU - Toth, Christopher L.
AU - Wardell, Seth
AU - Mansaray, Rahmatu
AU - Patel, Vruti
AU - Carpio, Destiny Joy
AU - Vaughn, Carol
AU - Farinas, Chantell M.
AU - Velasquez, Portia G.
AU - Hwu, Wen Jen
AU - Patel, Sapna P.
AU - Davies, Michael A.
AU - Diab, Adi
AU - Glitza, Isabella C.
AU - Tawbi, Hussein
AU - Wong, Michael K.
AU - Cain, Suzanne
AU - Ross, Merrick I.
AU - Lee, Jeffrey E.
AU - Gershenwald, Jeffrey E.
AU - Lucci, Anthony
AU - Royal, Richard
AU - Cormier, Janice N.
AU - Wargo, Jennifer A.
AU - Radvanyi, Laszlo G.
AU - Torres-Cabala, Carlos A.
AU - Beroukhim, Rameen
AU - Hwu, Patrick
AU - Amaria, Rodabe N.
AU - Bernatchez, Chantale
N1 - Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/9/15
Y1 - 2018/9/15
N2 - Purpose: Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has consistently demonstrated clinical efficacy in metastatic melanoma. Recent widespread use of checkpoint blockade has shifted the treatment landscape, raising questions regarding impact of these therapies on response to TIL and appropriate immunotherapy sequence. Patients and Methods: Seventy-four metastatic melanoma patients were treated with autologous TIL and evaluated for clinical response according to irRC, overall survival, and progression-free survival. Immunologic factors associated with response were also evaluated. Results: Best overall response for the entire cohort was 42%; 47% in 43 checkpoint-na€ve patients, 38% when patients were exposed to anti-CTLA4 alone (21 patients) and 33% if also exposed to anti-PD1 (9 patients) prior to TIL ACT. Median overall survival was 17.3 months; 24.6 months in CTLA4-na€ve patients and 8.6 months in patients with prior CTLA4 blockade. The latter patients were infused with fewer TIL and experienced a shorter duration of response. Infusion of higher numbers of TIL with CD8 predominance and expression of BTLA correlated with improved response in anti-CTLA4 na€ve patients, but not in anti-CTLA4 refractory patients. Baseline serum levels of IL9 predicted response to TIL ACT, while TIL persistence, tumor recognition, and mutation burden did not correlate with outcome. Conclusions: This study demonstrates the deleterious effects of prior exposure to anti-CTLA4 on TIL ACT response and shows that baseline IL9 levels can potentially serve as a predictive tool to select the appropriate sequence of immunotherapies.
AB - Purpose: Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has consistently demonstrated clinical efficacy in metastatic melanoma. Recent widespread use of checkpoint blockade has shifted the treatment landscape, raising questions regarding impact of these therapies on response to TIL and appropriate immunotherapy sequence. Patients and Methods: Seventy-four metastatic melanoma patients were treated with autologous TIL and evaluated for clinical response according to irRC, overall survival, and progression-free survival. Immunologic factors associated with response were also evaluated. Results: Best overall response for the entire cohort was 42%; 47% in 43 checkpoint-na€ve patients, 38% when patients were exposed to anti-CTLA4 alone (21 patients) and 33% if also exposed to anti-PD1 (9 patients) prior to TIL ACT. Median overall survival was 17.3 months; 24.6 months in CTLA4-na€ve patients and 8.6 months in patients with prior CTLA4 blockade. The latter patients were infused with fewer TIL and experienced a shorter duration of response. Infusion of higher numbers of TIL with CD8 predominance and expression of BTLA correlated with improved response in anti-CTLA4 na€ve patients, but not in anti-CTLA4 refractory patients. Baseline serum levels of IL9 predicted response to TIL ACT, while TIL persistence, tumor recognition, and mutation burden did not correlate with outcome. Conclusions: This study demonstrates the deleterious effects of prior exposure to anti-CTLA4 on TIL ACT response and shows that baseline IL9 levels can potentially serve as a predictive tool to select the appropriate sequence of immunotherapies.
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U2 - 10.1158/1078-0432.CCR-17-3649
DO - 10.1158/1078-0432.CCR-17-3649
M3 - Article
C2 - 29848573
AN - SCOPUS:85053219246
SN - 1078-0432
VL - 24
SP - 4416
EP - 4428
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 18
ER -