A Pilot Study of Preoperative Single-Dose Ipilimumab and/or Cryoablation in Women with Early-Stage Breast Cancer with Comprehensive Immune Profiling

Abstract

Purpose: To assess the safety and tolerability of preoperative cryoablation-mediated tumor antigen presentation and/or ipilimumab-mediated immune modulation in women with operable breast cancer.

Experimental design: In this pilot study, 19 women with breast cancer for whom mastectomy was planned were treated with preoperative tumor cryoablation (n = 7), single-dose ipilimumab at 10 mg/kg (n = 6), or both (n = 6). The primary outcome for this pilot study was safety/tolerability as defined as freedom from delays in pre-planned, curative-intent mastectomy. Exploratory studies of immune activation were performed on peripheral blood and tumor.

Results: Preoperative cryoablation and/or ipilimumab were safe and tolerable, with no delays in pre-planned surgery. Grade III toxicity was seen in 1 of 19 (unrelated rash after ipilimumab). Combination therapy was associated with sustained peripheral elevations in: Th1-type cytokines, activated (ICOS+) and proliferating (Ki67+) CD4+ and CD8+ T cells, and posttreatment proliferative T-effector cells relative to T-regulatory cells within tumor.

Conclusions: Preoperative cryoablation and single-dose ipilimumab are safe alone or in combination with no surgical delays incurred. Potentially favorable intratumoral and systemic immunologic effects were observed with the combination, suggesting the possibility for induced and synergistic antitumor immunity with this strategy. Clin Cancer Res; 22(23); 5729-37. ©2016 AACR.

Conflict of interest statement

Heather L. McArthur has research supported by Bristol-Myers Squibb (BMS); Jianda Yuan has a commercial grant from BMS; Padmanee Sharma has consulted for BMS, has research supported by BMS, and has a spouse with patents licensed to BMS; James P. Allison has intellectual property and royalties from BMS; and Jedd D. Wolchok has grant support from BMS and has consulted for BMS.

©2016 American Association for Cancer Research.

Figures

Figure 1

Study design. The timing of all study interventions (tumor biopsy, cryoablation, ipilimumab administration) was defined by the pre-determined, standard-of-care, non-study mastectomy date.

Figure 2

Changes in peripheral blood mononuclear cells (PBMCs) by flow cytometry. An increased frequency of activated T cells (as indicated by high ICOS expression) and proliferating T cells (as indicated by Ki67-positivity) is observed in peripheral blood mononuclear cells at 30 days post-mastectomy follow-up versus baseline in cryo plus ipi treated groups. Medians with interquartile ranges are depicted. Abbreviations: cryo, cryoablation; ipi, ipilimumab, ICOS, inducible co-stimulator.

Figure 3

Changes in serum cytokines by Meso Scale Discovery serum based multiplex assay. Fold change in cytokines at one month post-mastectomy versus baseline are depicted, with each row representing an individual patient. Blank cells indicate that cytokine concentrations were below the lower limit of detection for both baseline and followup. Yellow indicates a 1 to 2-fold increase from baseline, orange indicates a 2 to 5-fold increase from baseline, and red indicates a greater than 5-fold increase from baseline. Th1-associated cytokines (IFN-γ, IL-2, IL-12) are oriented leftward, and Th2-associated cytokines (IL-5, IL-10, IL-4) are oriented rightward. Abbreviations: IFN, interferon; IL, interleukin; TNF, tumor necrosis factor.

Figure 4

Assessment of tumor infiltrating lymphocytes (TILs) from mastectomy specimens by flow cytometry: The TIL ratio of CD8+ Teff to Tregs appeared greater in mastectomy specimens treated with both cryoablation and ipilimumab when compared with either treatment alone, but only when evaluated by ki67, a marker of proliferation. Medians with interquartile ranges are depicted. Abbreviations: Teff, effector T-cell; Treg, regulatory T-cell; cryo, cryoablation; ipi, ipilimumab.