Journal Article
. 2014 Sep; 12:245.
doi: 10.1186/s12967-014-0245-7.

Neoadjuvant anti-tumor vaccination prior to surgery enhances survival

Scott A Fisher 1 Amanda Cleaver  Devina D Lakhiani  Andrea Khong  Theresa Connor  Ben Wylie  W Joost Lesterhuis  Bruce W S Robinson  Richard A Lake  
Affiliations
  • PMID: 25186961
  •     46 References
  •     8 citations

Abstract

Background: This study was conducted to determine if anti-tumor vaccination administered prior to partial debulking surgery could improve survival using a murine solid tumour model.

Methods: Tumor incidence and survival rates were compared in mice bearing subcutaneous AB1-HA mesothelioma tumors that received either sham surgery, debulking surgery or vaccination prior to debulking surgery. Additionally, mice were depleted of CD4 and/or CD8 T lymphocytes during vaccination to assess their involvement in vaccine induced anti-tumor immunity. Flow cytometry was performed to characterise changes in the proportion and activation status of immune cells associated with anti-tumor immunity.

Results: Neoadjuvant vaccination combined with debulking surgery resulted in decreased tumor burden, increased survival and generation of tumor-specific immunity compared to surgery alone. Depletion of CD8 T cells completely abrogated any vaccine induced anti-tumor immune response. Conversely, CD4 depletion enhanced CD8 T cell activation resulting in complete tumor regression in 70% of mice treated with combined surgery and vaccination therapy. Tumor free survival was associated with established immunological memory as defined by the induction of effector memory T cells and resistance to rechallenge with parental AB1 mesothelioma cells.

Conclusions: Neoadjuvant anti-cancer vaccination combined with partial debulking surgery induced CD8-dependent anti-tumor immunity that significantly delayed tumor outgrowth relative to surgery alone. Complete tumor eradication was observed when vaccination and surgery were performed in CD4 T cell depleted animals. This demonstrates that adjuvant immunotherapy can improve post-surgical survival following cancer debulking surgery and provides a scientific rational for clinical trials of such an approach.

Partial, but not complete, tumor-debulking surgery promotes protective antitumor memory when combined with chemotherapy and adjuvant immunotherapy.
Steve Broomfield, Andrew Currie, +4 authors, Richard A Lake.
Cancer Res, 2005 Sep 06; 65(17). PMID: 16140921
Programmed death ligand 2 in cancer-induced immune suppression.
Esdy N Rozali, Stanleyson V Hato, +2 authors, W Joost Lesterhuis.
Clin Dev Immunol, 2012 May 23; 2012. PMID: 22611421    Free PMC article.
Highly Cited. Review.
Vaccines against advanced melanoma.
Tatiana Blanchard, Pramod K Srivastava, Fei Duan.
Clin Dermatol, 2013 Feb 27; 31(2). PMID: 23438381
Review.
Simultaneous immunisation with a Wilms' tumour 1 epitope and its ubiquitin fusions results in enhanced cell mediated immunity and tumour rejection in C57BL/6 mice.
Nasir Saeedi Eslami, Mohammad Ali Shokrgozar, +6 authors, Mohammad Hossein Alimohammadian.
Mol Immunol, 2012 Apr 25; 51(3-4). PMID: 22525006
Randomized selection design trial evaluating CD8+-enriched versus unselected tumor-infiltrating lymphocytes for adoptive cell therapy for patients with melanoma.
Mark E Dudley, Colin A Gross, +15 authors, Steven A Rosenberg.
J Clin Oncol, 2013 May 08; 31(17). PMID: 23650429    Free PMC article.
Highly Cited.
Hemithoracic radiation therapy after pleurectomy/decortication for malignant pleural mesothelioma.
Vishal Gupta, Borys Mychalczak, +4 authors, Kenneth E Rosenzweig.
Int J Radiat Oncol Biol Phys, 2005 Aug 02; 63(4). PMID: 16054774
Intergenic region 3 of modified vaccinia ankara is a functional site for insert gene expression and allows for potent antigen-specific immune responses.
Edwin R Manuel, Zhongde Wang, +3 authors, Don J Diamond.
Virology, 2010 May 18; 403(2). PMID: 20471051    Free PMC article.
Attenuated recombinant vaccinia virus expressing oncofetal antigen (tumor-associated antigen) 5T4 induces active therapy of established tumors.
Kate Mulryan, Matthew G Ryan, +5 authors, Miles W Carroll.
Mol Cancer Ther, 2002 Dec 17; 1(12). PMID: 12481437
Inhibitory influence of the hexapeptidic sequence SLIGRL on influenza A virus infection in mice.
Richard J Betts, Tracy S Mann, Peter J Henry.
J Pharmacol Exp Ther, 2012 Sep 19; 343(3). PMID: 22988062
Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients.
François Ghiringhelli, Cedric Menard, +7 authors, Bruno Chauffert.
Cancer Immunol Immunother, 2006 Sep 09; 56(5). PMID: 16960692
Highly Cited.
Immunotherapies for non-small-cell lung cancer and mesothelioma.
Anish Thomas, Raffit Hassan.
Lancet Oncol, 2012 Jul 04; 13(7). PMID: 22748269    Free PMC article.
Review.
The immune anti-tumor effects of GM-CSF and B7-1 gene transfection are enhanced by surgical debulking of tumor.
S Mukherjee, D Nelson, +5 authors, B W Robinson.
Cancer Gene Ther, 2001 Sep 26; 8(8). PMID: 11571536
Deliberately provoking local inflammation drives tumors to become their own protective vaccine site.
Connie Jackaman, Andrew M Lew, +5 authors, Delia J Nelson.
Int Immunol, 2008 Oct 01; 20(11). PMID: 18824504
A phase II trial of surgical resection and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma.
V W Rusch, K Rosenzweig, +6 authors, R J Ginsberg.
J Thorac Cardiovasc Surg, 2001 Oct 03; 122(4). PMID: 11581615
Neoadjuvant vaccination provides superior protection against tumor relapse following surgery compared with adjuvant vaccination.
Natalie Grinshtein, Byram Bridle, Yonghong Wan, Jonathan L Bramson.
Cancer Res, 2009 Apr 23; 69(9). PMID: 19383917
Immunosuppressive networks and checkpoints controlling antitumor immunity and their blockade in the development of cancer immunotherapeutics and vaccines.
A Q Butt, K H G Mills.
Oncogene, 2013 Oct 22; 33(38). PMID: 24141774
Review.
Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival.
Steffen Walter, Toni Weinschenk, +36 authors, Harpreet Singh-Jasuja.
Nat Med, 2012 Jul 31; 18(8). PMID: 22842478
Highly Cited.
Preclinical qualification of a new multi-antigen candidate vaccine for metastatic melanoma.
Thorsten U Vogel, Lucian Visan, +18 authors, Neil L Berinstein.
J Immunother, 2010 Sep 16; 33(8). PMID: 20842062
Suppression of antitumor immunity by IL-10 and TGF-beta-producing T cells infiltrating the growing tumor: influence of tumor environment on the induction of CD4+ and CD8+ regulatory T cells.
Andrew G Jarnicki, Joanne Lysaght, Stephen Todryk, Kingston H G Mills.
J Immunol, 2006 Jul 05; 177(2). PMID: 16818744
Improved survival with ipilimumab in patients with metastatic melanoma.
F Stephen Hodi, Steven J O'Day, +26 authors, Walter J Urba.
N Engl J Med, 2010 Jun 08; 363(8). PMID: 20525992    Free PMC article.
Highly Cited.
Advances in malignant mesothelioma.
Bruce W S Robinson, Richard A Lake.
N Engl J Med, 2005 Oct 14; 353(15). PMID: 16221782
Highly Cited. Review.
Cancer immunotherapy--revisited.
W Joost Lesterhuis, John B A G Haanen, Cornelis J A Punt.
Nat Rev Drug Discov, 2011 Aug 02; 10(8). PMID: 21804596
Highly Cited. Review.
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.
Suzanne L Topalian, F Stephen Hodi, +27 authors, Mario Sznol.
N Engl J Med, 2012 Jun 05; 366(26). PMID: 22658127    Free PMC article.
Highly Cited.
Tumor eradication after cyclophosphamide depends on concurrent depletion of regulatory T cells: a role for cycling TNFR2-expressing effector-suppressor T cells in limiting effective chemotherapy.
Robbert G van der Most, Andrew J Currie, +5 authors, Richard A Lake.
Cancer Immunol Immunother, 2008 Dec 05; 58(8). PMID: 19052741
Diffuse malignant mesothelioma of the pleural space and its management.
Lambros S Zellos, David J Sugarbaker.
Oncology (Williston Park), 2002 Aug 08; 16(7). PMID: 12164558
Review.
Establishment of a murine model of malignant mesothelioma.
M R Davis, L S Manning, +2 authors, B W Robinson.
Int J Cancer, 1992 Dec 02; 52(6). PMID: 1459729
Cyclophosphamide chemotherapy sensitizes tumor cells to TRAIL-dependent CD8 T cell-mediated immune attack resulting in suppression of tumor growth.
Robbert G van der Most, Andrew J Currie, +10 authors, Richard A Lake.
PLoS One, 2009 Sep 12; 4(9). PMID: 19746156    Free PMC article.
Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide.
M E Christine Lutsiak, Roshanak T Semnani, +3 authors, Helen Sabzevari.
Blood, 2004 Dec 14; 105(7). PMID: 15591121
Highly Cited.
Recruitment of latent pools of high-avidity CD8(+) T cells to the antitumor immune response.
Anne M Ercolini, Brian H Ladle, +7 authors, Elizabeth M Jaffee.
J Exp Med, 2005 May 11; 201(10). PMID: 15883172    Free PMC article.
Highly Cited.
Radiotherapy for mesothelioma.
Craig W Stevens, Kenneth M Forster, W Roy Smythe, David Rice.
Hematol Oncol Clin North Am, 2005 Dec 06; 19(6). PMID: 16325126
Review.
Non-small-cell lung cancer.
Peter Goldstraw, David Ball, +4 authors, Frances A Shepherd.
Lancet, 2011 May 14; 378(9804). PMID: 21565398
Highly Cited. Review.
Agonistic anti-CD40 antibody therapy is effective against postoperative cancer recurrence and metastasis in a murine tumor model.
Andrea Khong, Matthew D Brown, +2 authors, Andrew J Currie.
J Immunother, 2013 Aug 09; 36(7). PMID: 23924788
Immunotherapy and chemotherapy--a practical partnership.
Richard A Lake, Bruce W S Robinson.
Nat Rev Cancer, 2005 May 03; 5(5). PMID: 15864281
Highly Cited. Review.
How numbers, nature, and immune status of foxp3(+) regulatory T-cells shape the early immunological events in tumor development.
Guillaume Darrasse-Jèze, Katrina Podsypanina.
Front Immunol, 2013 Oct 18; 4. PMID: 24133490    Free PMC article.
Review.
Immunotherapy for colorectal cancer.
Shigeo Koido, Toshifumi Ohkusa, +12 authors, Hisao Tajiri.
World J Gastroenterol, 2014 Jan 01; 19(46). PMID: 24379570    Free PMC article.
Review.
Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy.
Steven A Rosenberg, James C Yang, +12 authors, Mark E Dudley.
Clin Cancer Res, 2011 Apr 19; 17(13). PMID: 21498393    Free PMC article.
Highly Cited.
Ipilimumab: controversies in its development, utility and autoimmune adverse events.
Jeffrey Weber.
Cancer Immunol Immunother, 2009 Feb 10; 58(5). PMID: 19198837
Review.
Regulatory T cells in cancer immunotherapy.
Hiroyoshi Nishikawa, Shimon Sakaguchi.
Curr Opin Immunol, 2014 Jan 15; 27. PMID: 24413387
Highly Cited. Review.
Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.
Caroline Robert, Luc Thomas, +21 authors, Jedd D Wolchok.
N Engl J Med, 2011 Jun 07; 364(26). PMID: 21639810
Highly Cited.
Synergistic effect of CTLA-4 blockade and cancer chemotherapy in the induction of anti-tumor immunity.
W Joost Lesterhuis, Joanne Salmons, +6 authors, Richard A Lake.
PLoS One, 2013 Apr 30; 8(4). PMID: 23626745    Free PMC article.
Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma.
Tyler R Simpson, Fubin Li, +11 authors, Sergio A Quezada.
J Exp Med, 2013 Jul 31; 210(9). PMID: 23897981    Free PMC article.
Highly Cited.
T-cell receptor transgenic analysis of tumor-specific CD8 and CD4 responses in the eradication of solid tumors.
A L Marzo, R A Lake, B W Robinson, B Scott.
Cancer Res, 1999 Mar 10; 59(5). PMID: 10070965
Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies.
Karl S Peggs, Sergio A Quezada, +2 authors, James P Allison.
J Exp Med, 2009 Jul 08; 206(8). PMID: 19581407    Free PMC article.
Highly Cited.
CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative.
François Ghiringhelli, Nicolas Larmonier, +7 authors, François Martin.
Eur J Immunol, 2004 Feb 10; 34(2). PMID: 14768038
Highly Cited.
Loss of antigen cross-presentation after complete tumor resection is associated with the generation of protective tumor-specific CD8(+) T-cell immunity.
Matthew D Brown, Robbert van der Most, +4 authors, Andrew J Currie.
Oncoimmunology, 2012 Nov 22; 1(7). PMID: 23170256    Free PMC article.
Cell transfer immunotherapy for metastatic solid cancer--what clinicians need to know.
Steven A Rosenberg.
Nat Rev Clin Oncol, 2011 Aug 03; 8(10). PMID: 21808266    Free PMC article.
Highly Cited. Review.
Biologic therapy and gene therapy in the multimodality treatment of malignant pleural mesothelioma.
Andrea Viti, Luca Bertolaccini, Alberto Terzi.
Ann Transl Med, 2015 Nov 26; 3(17). PMID: 26605294    Free PMC article.
Review.
Human malignant mesothelioma is recapitulated in immunocompetent BALB/c mice injected with murine AB cells.
Rosanna Mezzapelle, Eltjona Rrapaj, +21 authors, Massimo P Crippa.
Sci Rep, 2016 Mar 11; 6. PMID: 26961782    Free PMC article.
Transient Treg depletion enhances therapeutic anti-cancer vaccination.
Scott A Fisher, Wayne J Aston, +11 authors, Richard A Lake.
Immun Inflamm Dis, 2017 Mar 03; 5(1). PMID: 28250921    Free PMC article.
Tumor reductive therapies and antitumor immunity.
Huiqin Guo, Kangla Tsung.
Oncotarget, 2017 Sep 15; 8(33). PMID: 28903456    Free PMC article.
Review.
Chemo-immunotherapy improves long-term survival in a preclinical model of MMR-D-related cancer.
Claudia Maletzki, Leonie Wiegele, +2 authors, Christian Junghanss.
J Immunother Cancer, 2019 Jan 12; 7(1). PMID: 30630527    Free PMC article.
Enhanced immunogenicity of leukemia-derived exosomes via transfection with lentiviral vectors encoding costimulatory molecules.
Weiwei Hu, Fang Huang, +3 authors, Siguo Hao.
Cell Oncol (Dordr), 2020 Jun 25; 43(5). PMID: 32578140    Free PMC article.
Vaccine-Based Immunotherapy for Head and Neck Cancers.
Simon Beyaert, Jean-Pascal Machiels, Sandra Schmitz.
Cancers (Basel), 2021 Dec 11; 13(23). PMID: 34885150    Free PMC article.
Review.
How Our Continuing Studies of the Pre-clinical Inbred Mouse Models of Mesothelioma Have Influenced the Development of New Therapies.
Bruce W S Robinson, Alec J Redwood, Jenette Creaney.
Front Pharmacol, 2022 Apr 19; 13. PMID: 35431929    Free PMC article.
Review.