TY - JOUR
T1 - Ipilimumab with stereotactic ablative radiation therapy
T2 - Phase i results and immunologic correlates from peripheral T cells
AU - Tang, Chad
AU - Welsh, James W.
AU - De Groot, Patricia
AU - Massarelli, Erminia
AU - Chang, Joe Y.
AU - Hess, Kenneth R.
AU - Basu, Sreyashi
AU - Curran, Michael A.
AU - Cabanillas, Maria E.
AU - Subbiah, Vivek
AU - Fu, Siqing
AU - Tsimberidou, Apostolia M.
AU - Karp, Daniel
AU - Gomez, Daniel R.
AU - Diab, Adi
AU - Komaki, Ritsuko
AU - Heymach, John V.
AU - Sharma, Padmanee
AU - Naing, Aung
AU - Hong, David S.
N1 - Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2017/3/15
Y1 - 2017/3/15
N2 - Purpose: Little prospective data are available on clinical outcomes and immune correlates from combination radiation and immunotherapy. We conducted a phase I trial (NCT02239900) testing stereotactic ablative radiotherapy (SABR) with ipilimumab. Experimental Design: SABR was given either concurrently (1 day after the first dose) or sequentially (1 week after the second dose) with ipilimumab (3 mg/kg every 3 weeks for 4 doses) to five treatment groups: concurrent 50 Gy (in 4 fractions) to liver; sequential 50 Gy (in 4 fractions) to liver; concurrent 50 Gy (in 4 fractions) to lung; sequential 50 Gy (in 4 fractions) to lung; and sequential 60 Gy (in 10 fractions) to lung or liver. MTD was determined with a 3 + 3 dose deescalation design. Immune marker expression was assessed by flow cytometry. Results: Among 35 patients who initiated ipilimumab, 2 experienced dose-limiting toxicity and 12 (34%) grade 3 toxicity. Response outside the radiation field was assessable in 31 patients. Three patients (10%) exhibited partial response and 7 (23%) experienced clinical benefit (defined as partial response or stable disease lasting ≥6 months). Clinical benefit was associated with increases in peripheral CD8+ T cells, CD8+/CD4+ T-cell ratio, and proportion of CD8+ T cells expressing 4-1BB and PD1. Liver (vs. lung) irradiation produced greater T-cell activation, reflected as increases in the proportions of peripheral T cells expressing ICOS, GITR, and 4-1BB. Conclusions: Combining SABR and ipilimumab was safe with signs of efficacy, peripheral T-cell markers may predict clinical benefit, and systemic immune activation was greater after liver irradiation.
AB - Purpose: Little prospective data are available on clinical outcomes and immune correlates from combination radiation and immunotherapy. We conducted a phase I trial (NCT02239900) testing stereotactic ablative radiotherapy (SABR) with ipilimumab. Experimental Design: SABR was given either concurrently (1 day after the first dose) or sequentially (1 week after the second dose) with ipilimumab (3 mg/kg every 3 weeks for 4 doses) to five treatment groups: concurrent 50 Gy (in 4 fractions) to liver; sequential 50 Gy (in 4 fractions) to liver; concurrent 50 Gy (in 4 fractions) to lung; sequential 50 Gy (in 4 fractions) to lung; and sequential 60 Gy (in 10 fractions) to lung or liver. MTD was determined with a 3 + 3 dose deescalation design. Immune marker expression was assessed by flow cytometry. Results: Among 35 patients who initiated ipilimumab, 2 experienced dose-limiting toxicity and 12 (34%) grade 3 toxicity. Response outside the radiation field was assessable in 31 patients. Three patients (10%) exhibited partial response and 7 (23%) experienced clinical benefit (defined as partial response or stable disease lasting ≥6 months). Clinical benefit was associated with increases in peripheral CD8+ T cells, CD8+/CD4+ T-cell ratio, and proportion of CD8+ T cells expressing 4-1BB and PD1. Liver (vs. lung) irradiation produced greater T-cell activation, reflected as increases in the proportions of peripheral T cells expressing ICOS, GITR, and 4-1BB. Conclusions: Combining SABR and ipilimumab was safe with signs of efficacy, peripheral T-cell markers may predict clinical benefit, and systemic immune activation was greater after liver irradiation.
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U2 - 10.1158/1078-0432.CCR-16-1432
DO - 10.1158/1078-0432.CCR-16-1432
M3 - Article
C2 - 27649551
AN - SCOPUS:85016147574
SN - 1078-0432
VL - 23
SP - 1388
EP - 1396
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 6
ER -