Abstract OT3-1-01: A pilot study of single-dose ipilimumab and/or cryoablation in women with early-stage breast cancer scheduled for mastectomy
Authors: Diab A , McArthur HL , Solomon S , Comstock C , Maybody M , Sacchini V , Durack J , Gucalp A , Yuan J , Patil S , Thorne A , Sung J , Kotin A , Morris E , Brogi E , Morrow M , Wolchok J , Allison J , Hudis C , Norton L 
Published: August 2014

Abstract
Background: With cryoablation, probes are inserted into tumors to induce crystallization, osmotic changes, vascular stasis, and ultimately tumor necrosis. The resultant release of tumor antigens could activate a tumor-specific immune response through antigen presentation by dendritic cells (DC) to T-cells. Cryoablation is an effective treatment modality in many cancers (Habash 2007), and feasibility studies have shown that thermal ablation can be performed safely and effectively in small breast cancers (Noguchi 2007).
To amplify immune response, we use ipilimumab, a fully human monoclonal antibody that blocks cytotoxic T lymphocyte antigen-4 (CTLA4), a co-inhibitory molecule present on the surface of activated T cells. Durable and clinically significant responses to ipilimumab have been reported in prostate, bladder, and renal cell cancers. Ipilimumab has been most extensively studied in malignant melanoma, with 10–20% response rates and significant survival benefits reported (Wolchok 2010, Hodi 2010).
Cryoablation-mediated tumor destruction exposes DCs to sufficient quantities of tumor antigens and inflammatory cytokines to induce DC maturation and activation. Furthermore, in preclinical murine models, the combination of cryoablation with CTLA4 blockade successfully mediates rejection of metastatic prostate cancer lesions and prevents growth of secondary tumors (Waitz 2012). Combined ablative therapy with CTLA4 blockade is appealing due to the relative safety of percutaneous ablation in early stage breast cancer and the efficacy and tolerability of ipilimumab administration in numerous settings. We therefore hypothesize that this strategy could confer long-term immunity, and ultimately cure, for women with early stage breast cancer.
In this pilot study, the safety and tolerability of pre-operative cryoablation alone, single dose ipilimumab (10mg/kg) alone, or the combination is being evaluated in women with early stage breast cancer.
Design: Three sequential test groups of 6 patients are being enrolled (total N=18). The study groups are: pre-operative cryoablation alone (A), pre-operative single dose ipilimumab alone (B), and pre-operative single-dose ipilimumab followed by cryoablation (C). Groups A and B must meet the safety primary endpoint before enrollment to study arm C is begun. The timing of all study interventions is defined by the pre-determined, non-study surgery date.
Primary aim: To determine the safety and tolerability of pre-operative ipilimumab and/or cryoablation in patients with resectable breast cancer.
Secondary aims: To explore and characterize pre- and post-intervention radiographic and immunological (peripheral blood and tumor tissue) correlates.
Statistics: If at least 5 of the 6 patients in each group proceed with surgery without delay, the regimen will be considered safe/tolerable for further study. Secondary aims are exploratory.
Eligibility: Eligible women are age ≥18y with early-stage, operable, ≥1.5 cm invasive breast cancer, no history of autoimmune disease and planning mastectomy.
Study Status: As of June 12, 2012, Study Arm A is filled: 4 women have undergone cryoablation and mastectomy and 2 have undergone cryoablation and are awaiting surgery.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT3-1-01.