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.

©2016 American Association for Cancer Research.

Figures

Figure 1

Disease response on protocol. Disease response over time (spider plots) and best achieved disease response (waterfall plots) for irradiated lesions (A) and for lesions outside the radiation field (B). For reference, the immune-related response criteria (ir-RC) cutpoints for partial response (irPR) are shown in green and for progressive disease (irPD) are shown in red.

Figure 2

(A) Disease response over time for a patient with neuroendocrine tumor who received sequential radiation and ipilimumab to a liver lesion; solid green line indicates the irradiated lesion, solid orange line, non-irradiated (out-of-field) disease; and solid red line, all disease. Dotted lines indicate immune-related response criteria cutpoints for partial response (irPR) (red) and progressive disease (irPD) (green). (B) Representative CT scans with contrast show hepatic lesions outside the radiation field at first and the third restaging assessment. Abbreviations: C1D1, cycle 1 day 1, C4D1, cycle 4 day 1, and IPI, ipilimumab.

Figure 3

Association of peripheral blood mononuclear populations with clinical benefit. (A) Representative flow cytometry plots showing cell gating for immune correlate analysis of lymphocyte subpopulations. A schematic is shown of blood draw timing in relationship to ipilimumab and radiation administration. (B) Changes in peripheral blood mononuclear cell populations from baseline to after the first 1–2 cycles of ipilimumab and radiation therapy (mid IPI) and after the last dose of ipilimumab (post IPI), stratified by clinical benefit (defined as immune-related Response Criteria rating of stable disease [irSD] lasting ≥6 months, complete response [irCR], or partial response [irPR] of out-of-field lesions). Significant differences were seen between patients with or without clinical benefit in CD8+ T-cells after ipilumumab (post-IPI; P=0.004) and in CD8+/CD4+ ratio after radiation (post-RT; P=0.02) and after ipilimumab (post-IPI; P=0.009). Abbreviations: C1D1, cycle 1 day 1, C2D1, cycle 2 day 1, C3D1, cycle 3 day 1, C4D1, cycle 4 day 1, RT, radiation, and IPI, ipilimumab.

Figure 4

Peripheral blood mononuclear cell surface marker expression and association with radiation target and clinical benefit. Changes in expression of immune-activating and -inhibitory markers from baseline until after the first 1–2 cycles of ipilimumab and radiation therapy (mid IPI) and from after the last dose of ipilimumab (post IPI) in peripheral CD8+ T-cells stratified by clinical benefit (A), in peripheral CD8+ T-cells stratified by radiation target (B), and in CD4+ Treg cells stratified by radiation target (C). Values are expressed as percentage of peripheral CD4+ Treg or CD8+ T-cells with marker expression. Abbreviations: N.S., not significant.