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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. 

Author information

Tang C1, Welsh JW1, de Groot P2, Massarelli E3, Chang JY4, Hess KR5, Basu S6, Curran MA6, Cabanillas ME7, Subbiah V8, Fu S8, Tsimberidou AM8, Karp D8, Gomez DR4, Diab A9, Komaki R4, Heymach JV4, Sharma P6,10, Naing A8, Hong DS11.​

1 Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. ctang1@mdanderson.org jwelsh@mdanderson.org dshong@mdanderson.org.

2 Department of Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

3 Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

4 Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

5 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.

6 Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

7 Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas.

8 Department of Investigational Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.

9 Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

10 Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

11 Department of Investigational Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas. ctang1@mdanderson.org jwelsh@mdanderson.org dshong@mdanderson.org.