Potent induction of tumor immunity by combining tumor cryoablation with anti-CTLA-4 therapy Journal Article

Authors: Waitz, R.; Solomon, S. B.; Petre, E. N.; Trumble, A. E.; Fassò, M.; Norton, L.; Allison, J. P.
Article Title: Potent induction of tumor immunity by combining tumor cryoablation with anti-CTLA-4 therapy
Abstract: Thermal ablation to destroy tumor tissue may help activate tumor-specific T cells by elevating the presentation of tumor antigens to the immune system. However, the antitumor activity of these T cells may be restrained by their expression of the inhibitory T-cell coreceptor CTLA-4, the target of the recently U.S. Food and Drug Administration-approved antibody drug ipilumimab. By relieving this restraint, CTLA-4-blocking antibodies such as ipilumimab can promote tumor rejection, but the full scope of their most suitable applications has yet to be fully determined. In this study, we offer a preclinical proof-of-concept in the TRAMP C2 mouse model of prostate cancer that CTLA-4 blockade cooperates with cryoablation of a primary tumor to prevent the outgrowth of secondary tumors seeded by challenge at a distant site. Although growth of secondary tumors was unaffected by cryoablation alone, the combination treatment was sufficient to slow growth or trigger rejection. In addition, secondary tumors were highly infiltrated by CD4 + T cells and CD89 + T cells, and there was a significant increase in the ratio of intratumoral T effector cells to CD4 +FoxP3 + T regulatory cells, compared with monotherapy. These findings documented for the first time an effect of this immunotherapeutic intervention on the intratumoral accumulation and systemic expansion of CD8 + T cells specific for the TRAMP C2-specific antigen SPAS-1. Although cryoablation is currently used to treat a targeted tumor nodule, our results suggest that combination therapy with CTLA-4 blockade will augment antitumor immunity and rejection of tumor metastases in this setting. ©2011 AACR.
Keywords: controlled study; disease-free survival; monotherapy; nonhuman; combined modality therapy; cd8+ t lymphocyte; cd8-positive t-lymphocytes; animal cell; mouse; animals; mice; animal tissue; cytotoxic t lymphocyte antigen 4 antibody; metastasis; microscopy, confocal; animal experiment; animal model; cancer cell culture; mice, inbred c57bl; prostate cancer; prostatic neoplasms; regulatory t lymphocyte; antibodies, monoclonal; immune response; t-lymphocytes, regulatory; cd4+ t lymphocyte; cd4-positive t-lymphocytes; neoplasm metastasis; tumor immunity; tumor growth; disease models, animal; cryoablation; tumor rejection; cryosurgery; ctla-4 antigen
Journal Title: Cancer Research
Volume: 72
Issue: 2
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2012-01-15
Start Page: 430
End Page: 439
Language: English
DOI: 10.1158/0008-5472.can-11-1782
PROVIDER: scopus
PUBMED: 22108823
PMCID: PMC4526218
Notes: --- - "Export Date: 1 March 2012" - "CODEN: CNREA" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Larry Norton
    695 Norton
  2. Rebecca Waitz
    13 Waitz
  3. Stephen Solomon
    342 Solomon
  4. James P Allison
    129 Allison
  5. Elena Nadia Petre
    67 Petre