title: Ipilimumab with Stereotactic Ablative Radiation Therapy: Phase I Results and Immunologic Correlates from Peripheral T Cells.
abstract: 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 de-escalation 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.Clin Cancer Res; 23(6); 1388-96. ©2016 AACR.
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. ctang1@mdanderson.org jwelsh@mdanderson.org dshong@mdanderson.org.
authors.forename: Chad
authors.initials: C
authors.lastname: Tang
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. ctang1@mdanderson.org jwelsh@mdanderson.org dshong@mdanderson.org.
authors.forename: James W
authors.initials: JW
authors.lastname: Welsh
authors.affiliation: Department of Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Patricia
authors.initials: P
authors.lastname: de Groot
authors.affiliation: Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Erminia
authors.initials: E
authors.lastname: Massarelli
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Joe Y
authors.initials: JY
authors.lastname: Chang
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Hess
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Sreyashi
authors.initials: S
authors.lastname: Basu
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Curran
authors.affiliation: Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Cabanillas
authors.affiliation: Department of Investigational Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Vivek
authors.initials: V
authors.lastname: Subbiah
authors.affiliation: Department of Investigational Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Siqing
authors.initials: S
authors.lastname: Fu
authors.affiliation: Department of Investigational Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Apostolia M
authors.initials: AM
authors.lastname: Tsimberidou
authors.affiliation: Department of Investigational Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Daniel
authors.initials: D
authors.lastname: Karp
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Gomez
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Adi
authors.initials: A
authors.lastname: Diab
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Komaki
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: John V
authors.initials: JV
authors.lastname: Heymach
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Padmanee
authors.initials: P
authors.lastname: Sharma
authors.affiliation: Department of Investigational Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.affiliation: Department of Investigational Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas. ctang1@mdanderson.org jwelsh@mdanderson.org dshong@mdanderson.org.
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000528:radiation effects; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D000074324:Ipilimumab / Q000008:administration & dosage* / Q000009:adverse effects; D008099:Liver / Q000473:pathology / Q000528:radiation effects; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D008297:Male; D008875:Middle Aged; D016634:Radiosurgery / Q000009:adverse effects*; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D000074324:Ipilimumab