Volume 3 Supplement 1
Pre-operative immunotherapy with tumor cryoablation (cryo) plus ipilimumab (ipi) induces potentially favorable systemic and intratumoral immune effects in early stage breast cancer (ESBC) patients
© Page et al. 2015
Published: 14 August 2015
Women with ESBC were treated 7-10 days preceding mastectomy with either cryo (n=6), single-dose ipi at 10mg/kg (n=6), or cryo+ipi (n=6) . From serial blood (baseline & 1-month post-mastectomy) and tumor (biopsy & mastectomy), fold-changes following cryo+ipi versus monotherapy were compared (Wilcoxon rank-sum) across the following measures: Ki67+ or ICOShi T-cells  and intratumoral T-effector/T-regulatory  cells by flow cytometry, plasma Th1/Th2 cytokines  (Meso Scale Discovery), and intratumoral T-cell expansion by immunohistochemistry  and T-cell receptor (TCR) deep sequencing (ImmunoSEQ) .
Cryo+ipi generated greater increases in peripheral Ki67+CD4+ (p=0.05), Ki67+CD8+ (p=0.05), ICOShiCD4+ (p=0.005), and ICOShiCD8+ (p=0.005) cells. The intratumoral T-effector/regulatory ratio was higher following cryo+ipi, but only when Ki67-gated (p=.01). Cryo+ipi generated greater increases in IL-2 (p=.01), IFNÎ³ (p=.06), and IL-5 (p=.09). Despite negligible intratumoral changes by immunohistochemistry, cryo+ipi generated more high-magnitude (~1000 amplicon) clonal expansions by TCR sequencing (medians: 52 v. 3 clones).
Cryo+ipi is associated with potentially favorable immunologic effects. Ki67-gating and TCR sequencing may identify intratumoral changes otherwise undetectable by flow or IHC.
- Waitz R, Solomon SB, Petre EN, Trumble AE, Fasso M, Norton L, Allison JP: Potent induction of tumor immunity by combining tumor cryoablation with anti-CTLA-4 therapy. Cancer research. 2012, 72: 430-9. 10.1158/0008-5472.CAN-11-1782.PubMed CentralView ArticlePubMedGoogle Scholar
- Di Giacomo AM, Calabro L, Danielli R, Fonsatti E, Bertocci E, Pesce I, Fazio C, Cutaia O, Giannarelli D, Miracco C, Biagioli M, Altomonte M, Maio M: Long-term survival and immunological parameters in metastatic melanoma patients who responded to ipilimumab 10 mg/kg within an expanded access programme. Cancer Immunol Immunother. 2013, 62: 1021-8. 10.1007/s00262-013-1418-6.View ArticlePubMedGoogle Scholar
- Hodi FS, Butler M, Oble DA, Seiden MV, Haluska FG, Kruse A, Macrae S, Nelson M, Canning C, Lowy I, Korman A, Lautz D, Russell S, Jaklitsch MT, Ramaiya N, Chen TC, Neuberg D, Allison JP, Mihm MC, Dranoff G: Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc Natl Acad Sci USA. 2008, 105: 3005-10. 10.1073/pnas.0712237105.PubMed CentralView ArticlePubMedGoogle Scholar
- Yuan JOF, Jefferson M, Li H, Gallardo H, Ku G, Wolchok J, Scher H, Allison J, Slovin S: Cytokine changes in castrate metastatic prostate cancer (CPMC) patients (pts) treated with ipilimumab (Ipi). 2009 ASCO Annual Meeting. 2009, Orlando, FLGoogle Scholar
- Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V, West AN, Carmona M, Kivork C, Seja E, Cherry G, Gutierrez AJ, Grogan TR, Mateus C, Tomasic G, Glaspy JA, Emerson RO, Robins H, Pierce RH, Elashoff DA, Robert C, Ribas A: PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014, 515: 568-71. 10.1038/nature13954.PubMed CentralView ArticlePubMedGoogle Scholar
- Diab A, Solomon SB, Comstock C, Maybody M, Sacchini V, Durack JC, Blum B, Yuan J, Patil S, Neville DA, Sung JS, Kotin A, Morris EA, Brogi E, Morrow M, Wolchok JD, Allison JP, Hudis CA, Norton L, McArthur HL: A pilot study of preoperative (Pre-op), single-dose ipilimumab (Ipi) and/or cryoablation (Cryo) in women (pts) with early-stage/resectable breast cancer (ESBC). 2013 ASCO Breast Cancer Symposium; 2013 September 7-9. 2013, San Francisco, CA.Google Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.