. 2014 Jun; 2014:789069.
doi: 10.1155/2014/789069.

The "Trojan Horse" approach to tumor immunotherapy: targeting the tumor microenvironment

Delia Nelson 1 Scott Fisher 2 Bruce Robinson 2 
  • PMID: 24955376
  •     127 References
  •     20 citations


Most anticancer therapies including immunotherapies are given systemically; yet therapies given directly into tumors may be more effective, particularly those that overcome natural suppressive factors in the tumor microenvironment. The "Trojan Horse" approach of intratumoural delivery aims to promote immune-mediated destruction by inducing microenvironmental changes within the tumour at the same time as avoiding the systemic toxicity that is often associated with more "full frontal" treatments such as transfer of large numbers of laboratory-expanded tumor-specific cytotoxic T lymphocytes or large intravenous doses of cytokine. Numerous studies have demonstrated that intratumoural therapy has the capacity to minimizing local suppression, inducing sufficient "dangerous" tumor cell death to cross-prime strong immune responses, and rending tumor blood vessels amenable to immune cell traffic to induce effector cell changes in secondary lymphoid organs. However, the key to its success is the design of a sound rational approach based on evidence. There is compelling preclinical data for local immunotherapy approaches in tumor immunology. This review summarises how immune events within a tumour can be modified by local approaches, how this can affect systemic antitumor immunity such that distal sites are attacked, and what approaches have been proven most successful so far in animals and patients.

Clinical development of immunostimulatory monoclonal antibodies and opportunities for combination.
Ignacio Melero, Antonio M Grimaldi, Jose L Perez-Gracia, Paolo A Ascierto.
Clin Cancer Res, 2013 Mar 06; 19(5). PMID: 23460531
Highly Cited.
Targeted therapeutic remodeling of the tumor microenvironment improves an HER-2 DNA vaccine and prevents recurrence in a murine breast cancer model.
Debbie Liao, Ze Liu, +5 authors, Ralph A Reisfeld.
Cancer Res, 2011 Jul 26; 71(17). PMID: 21784871
Locally administered TLR7 agonists drive systemic antitumor immune responses that are enhanced by anti-CD40 immunotherapy.
Steve A Broomfield, Robbert G van der Most, +5 authors, Andrew J Currie.
J Immunol, 2009 Apr 22; 182(9). PMID: 19380767
Cross-priming in health and disease.
Christian Kurts, Bruce W S Robinson, Percy A Knolle.
Nat Rev Immunol, 2010 May 26; 10(6). PMID: 20498667
Highly Cited. Review.
Cross-talk between myeloid-derived suppressor cells (MDSC), macrophages, and dendritic cells enhances tumor-induced immune suppression.
Suzanne Ostrand-Rosenberg, Pratima Sinha, Daniel W Beury, Virginia K Clements.
Semin Cancer Biol, 2012 Feb 09; 22(4). PMID: 22313874    Free PMC article.
Highly Cited. Review.
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
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
The OX40 costimulatory receptor determines the development of CD4 memory by regulating primary clonal expansion.
I Gramaglia, A Jember, +3 authors, M Croft.
J Immunol, 2000 Sep 07; 165(6). PMID: 10975814
Intratumoral interleukin-2/agonist CD40 antibody drives CD4+ -independent resolution of treated-tumors and CD4+ -dependent systemic and memory responses.
Connie Jackaman, Delia J Nelson.
Cancer Immunol Immunother, 2011 Oct 18; 61(4). PMID: 22002241
Activation of NF-kappaB1 by OX40 contributes to antigen-driven T cell expansion and survival.
Jianxun Song, Takanori So, Michael Croft.
J Immunol, 2008 May 21; 180(11). PMID: 18490723    Free PMC article.
CD40-activated B cells contribute to mesothelioma tumor regression.
Connie Jackaman, Scott Cornwall, Peter Thomas Graham, Delia Jane Nelson.
Immunol Cell Biol, 2010 Jul 16; 89(2). PMID: 20628372
Endobronchial intratumoral chemotherapy (EITC) followed by surgery in early non-small cell lung cancer with polypoid growth causing erroneous impression of advanced disease.
Seyhan I Celikoglu, Firuz Celikoglu, Eugene P Goldberg.
Lung Cancer, 2006 Oct 19; 54(3). PMID: 17045361
Enhanced apoptotic cell clearance capacity and B cell survival factor production by IL-10-activated macrophages: implications for Burkitt's lymphoma.
Carol Anne Ogden, John D Pound, +4 authors, Christopher D Gregory.
J Immunol, 2005 Feb 25; 174(5). PMID: 15728515
Cancer immunotherapy by dendritic cells.
Cornelis J M Melief.
Immunity, 2008 Sep 19; 29(3). PMID: 18799145
Highly Cited. Review.
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.
IFN-gamma mediates CD4+ T-cell loss and impairs secondary antitumor responses after successful initial immunotherapy.
Vanessa Berner, Haiyan Liu, +10 authors, William J Murphy.
Nat Med, 2007 Mar 06; 13(3). PMID: 17334371
Targeted drug delivery to tumors: myths, reality and possibility.
You Han Bae, Kinam Park.
J Control Release, 2011 Jun 15; 153(3). PMID: 21663778    Free PMC article.
Highly Cited.
A cytokine-mediated link between innate immunity, inflammation, and cancer.
Wan-Wan Lin, Michael Karin.
J Clin Invest, 2007 May 04; 117(5). PMID: 17476347    Free PMC article.
Highly Cited. Review.
Local administration of TLR ligands rescues the function of tumor-infiltrating CD8 T cells and enhances the antitumor effect of lentivector immunization.
Haiyan Xiao, Yibing Peng, +7 authors, Yukai He.
J Immunol, 2013 Apr 24; 190(11). PMID: 23610140    Free PMC article.
Natural killer cells are present in the normal human lung but are functionally impotent.
B W Robinson, P Pinkston, R G Crystal.
J Clin Invest, 1984 Sep 01; 74(3). PMID: 6590570    Free PMC article.
Selective depletion of Foxp3+ regulatory T cells improves effective therapeutic vaccination against established melanoma.
Katjana Klages, Christian T Mayer, +7 authors, Tim Sparwasser.
Cancer Res, 2010 Oct 07; 70(20). PMID: 20924102
Highly Cited.
Molecular mechanisms of T cell co-stimulation and co-inhibition.
Lieping Chen, Dallas B Flies.
Nat Rev Immunol, 2013 Mar 09; 13(4). PMID: 23470321    Free PMC article.
Highly Cited. Review.
Results of a phase II study of sirolimus and cyclophosphamide in patients with advanced sarcoma.
Scott M Schuetze, Lili Zhao, +5 authors, Laurence H Baker.
Eur J Cancer, 2012 Apr 25; 48(9). PMID: 22525224
Local effector failure in mesothelioma is not mediated by CD4+ CD25+ T-regulator cells.
C Jackaman, S Cornwall, +3 authors, D J Nelson.
Eur Respir J, 2009 Mar 03; 34(1). PMID: 19251786
Interleukin-12 induces an effective antitumor response in malignant mesothelioma.
I Caminschi, E Venetsanakos, +3 authors, B W Robinson.
Am J Respir Cell Mol Biol, 1998 Nov 07; 19(5). PMID: 9806738
Vascular targeting of anti-CD40 antibodies and IL-2 into autochthonous tumors enhances immunotherapy in mice.
Juliana Hamzah, Delia Nelson, +3 authors, Ruth Ganss.
J Clin Invest, 2008 Apr 10; 118(5). PMID: 18398504    Free PMC article.
IL-2/CD40-driven NK cells install and maintain potency in the anti-mesothelioma effector/memory phase.
Connie Jackaman, Sally Lansley, +2 authors, Delia J Nelson.
Int Immunol, 2012 Feb 23; 24(6). PMID: 22354912
Synergy between chemotherapy and immunotherapy in the treatment of established murine solid tumors.
Anna K Nowak, Bruce W S Robinson, Richard A Lake.
Cancer Res, 2003 Aug 09; 63(15). PMID: 12907622
Highly Cited.
Regulating the suppressors: apoptosis and inflammation govern the survival of tumor-induced myeloid-derived suppressor cells (MDSC).
Suzanne Ostrand-Rosenberg, Pratima Sinha, Olesya Chornoguz, Christopher Ecker.
Cancer Immunol Immunother, 2012 May 02; 61(8). PMID: 22546994
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.
Correlation of CXCL12 expression and FoxP3+ cell infiltration with human papillomavirus infection and clinicopathological progression of cervical cancer.
Fatimah Jaafar, Elda Righi, +9 authors, Mark C Poznansky.
Am J Pathol, 2009 Oct 08; 175(4). PMID: 19808652    Free PMC article.
4-1BB costimulation of effector T cells for adoptive immunotherapy of cancer: involvement of Bcl gene family members.
Hidde M Kroon, Qiao Li, +3 authors, Alfred E Chang.
J Immunother, 2007 Apr 26; 30(4). PMID: 17457215
Elevated frequencies of CD4⁺ CD25⁺ CD127lo regulatory T cells is associated to poor prognosis in patients with acute myeloid leukemia.
Zhang Shenghui, Han Yixiang, +4 authors, Xu Xi.
Int J Cancer, 2010 Nov 26; 129(6). PMID: 21105040
Negative regulation of T-cell function by PD-1.
Yuan yuan Zha, Christian Blank, Thomas F Gajewski.
Crit Rev Immunol, 2004 Dec 14; 24(4). PMID: 15588223
Augmented macrophage differentiation and polarization of tumor-associated macrophages towards M1 subtype in listeria-administered tumor-bearing host.
Rakesh K Rai, Naveen K Vishvakarma, Tribhuban M Mohapatra, Sukh Mahendra Singh.
J Immunother, 2012 Aug 16; 35(7). PMID: 22892451
Effective migration of antigen-pulsed dendritic cells to lymph nodes in melanoma patients is determined by their maturation state.
I Jolanda M De Vries, Daniëlle J E B Krooshoop, +10 authors, Carl G Figdor.
Cancer Res, 2003 Jan 09; 63(1). PMID: 12517769
Highly Cited.
A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell.
J P Ridge, F Di Rosa, P Matzinger.
Nature, 1998 Jun 12; 393(6684). PMID: 9624003
Highly Cited.
CD4+CD25high T cells are enriched in the tumor and peripheral blood of prostate cancer patients.
Ashley M Miller, Kajsa Lundberg, +4 authors, Pavel Pisa.
J Immunol, 2006 Nov 04; 177(10). PMID: 17082659
Highly Cited.
Targeting the effector site with IFN-alphabeta-inducing TLR ligands reactivates tumor-resident CD8 T cell responses to eradicate established solid tumors.
Andrew J Currie, Robbert G van der Most, +3 authors, Bruce W S Robinson.
J Immunol, 2008 Jan 23; 180(3). PMID: 18209049
Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy.
Rakesh K Jain.
Science, 2005 Jan 08; 307(5706). PMID: 15637262
Highly Cited. Review.
Turning the tumor microenvironment into a self vaccine site.
Delia J Nelson.
Oncoimmunology, 2012 Nov 20; 1(6). PMID: 23162782    Free PMC article.
Intralesional cytokine therapy in cancer: a pilot study of GM-CSF infusion in mesothelioma.
J A Davidson, A W Musk, +6 authors, B W Robinson.
J Immunother, 1998 Oct 28; 21(5). PMID: 9789201
Depleting tumor-specific Tregs at a single site eradicates disseminated tumors.
Aurélien Marabelle, Holbrook Kohrt, +13 authors, Ronald Levy.
J Clin Invest, 2013 Jun 04; 123(6). PMID: 23728179    Free PMC article.
Highly Cited.
Tumor cells convert immature myeloid dendritic cells into TGF-beta-secreting cells inducing CD4+CD25+ regulatory T cell proliferation.
François Ghiringhelli, Pierre E Puig, +7 authors, Laurence Zitvogel.
J Exp Med, 2005 Sep 28; 202(7). PMID: 16186184    Free PMC article.
Highly Cited.
Myeloid-derived suppressor cells as a vehicle for tumor-specific oncolytic viral therapy.
Samuel Eisenstein, Brian A Coakley, +8 authors, Ping-Ying Pan.
Cancer Res, 2013 Mar 29; 73(16). PMID: 23536556    Free PMC article.
OX40 costimulation can abrogate Foxp3+ regulatory T cell-mediated suppression of antitumor immunity.
Naomi Kitamura, Satoshi Murata, +4 authors, Tohru Tani.
Int J Cancer, 2009 May 21; 125(3). PMID: 19455675    Free PMC article.
The emerging toxicity profiles of anti-CTLA-4 antibodies across clinical indications.
Anna Maria Di Giacomo, Maurizio Biagioli, Michele Maio.
Semin Oncol, 2010 Nov 16; 37(5). PMID: 21074065
Intratumoral administration of cisplatin through a bronchoscope followed by irradiation for treatment of inoperable non-small cell obstructive lung cancer.
Firuz Celikoglu, Seyhan I Celikoglu, Amanda M York, Eugene P Goldberg.
Lung Cancer, 2005 Dec 20; 51(2). PMID: 16359751
CTLA-4 overexpression inhibits T cell responses through a CD28-B7-dependent mechanism.
John J Engelhardt, Timothy J Sullivan, James P Allison.
J Immunol, 2006 Jul 05; 177(2). PMID: 16818761
Coley's toxin: historical perspective.
Jacob Bickels, Yehuda Kollender, Ofer Merinsky, Isaac Meller.
Isr Med Assoc J, 2002 Jun 21; 4(6). PMID: 12073431
Mechanisms and functional significance of tumour-induced dendritic-cell defects.
Dmitry Gabrilovich.
Nat Rev Immunol, 2004 Dec 02; 4(12). PMID: 15573129
Highly Cited. Review.
IL-2 intratumoral immunotherapy enhances CD8+ T cells that mediate destruction of tumor cells and tumor-associated vasculature: a novel mechanism for IL-2.
Connie Jackaman, Christine S Bundell, +5 authors, Delia J Nelson.
J Immunol, 2003 Nov 11; 171(10). PMID: 14607902
MSCs, macrophages, and cancer: a dangerous ménage-à-trois.
Alberto Mantovani.
Cell Stem Cell, 2012 Dec 12; 11(6). PMID: 23217416
Malignant mesothelioma: new insights into tumour biology and immunology as a basis for new treatment approaches.
J W Upham, M J Garlepp, A W Musk, B W Robinson.
Thorax, 1995 Aug 01; 50(8). PMID: 7570443    Free PMC article.
Activated but not resting regulatory T cells accumulated in tumor microenvironment and correlated with tumor progression in patients with colorectal cancer.
Yung-Chang Lin, Jayashri Mahalingam, +7 authors, Chun-Yen Lin.
Int J Cancer, 2012 Aug 22; 132(6). PMID: 22907255
Cytokine-armed vaccinia virus infects the mesothelioma tumor microenvironment to overcome immune tolerance and mediate tumor resolution.
C Jackaman, D J Nelson.
Cancer Gene Ther, 2010 Feb 13; 17(6). PMID: 20150930
Re-polarization of tumor-associated macrophages to pro-inflammatory M1 macrophages by microRNA-155.
Xing Cai, Yuan Yin, +4 authors, Ke Zen.
J Mol Cell Biol, 2012 Jul 27; 4(5). PMID: 22831835
Tumor targeting in vivo and metabolic fate of 5-[iodine-125]iodo-2'-deoxyuridine following intratumoral injection in patients with colorectal cancer.
G Mariani, A Cei, +7 authors, S Di Sacco.
J Nucl Med, 1993 Jul 01; 34(7). PMID: 8315499
Dual anti-OX40/IL-2 therapy augments tumor immunotherapy via IL-2R-mediated regulation of OX40 expression.
William L Redmond, Todd Triplett, Kevin Floyd, Andrew D Weinberg.
PLoS One, 2012 Apr 13; 7(4). PMID: 22496812    Free PMC article.
The immunobiology of cancer immunosurveillance and immunoediting.
Gavin P Dunn, Lloyd J Old, Robert D Schreiber.
Immunity, 2004 Aug 17; 21(2). PMID: 15308095
Highly Cited. Review.
Triggering CD40 on endothelial cells contributes to tumor growth.
Claudia Chiodoni, Manuela Iezzi, +7 authors, Mario P Colombo.
J Exp Med, 2006 Oct 18; 203(11). PMID: 17043144    Free PMC article.
Tumor cells, rather than dendritic cells, deliver antigen to the lymph node for cross-presentation.
Alison M McDonnell, Andrew J Currie, +5 authors, Bruce W S Robinson.
Oncoimmunology, 2012 Nov 20; 1(6). PMID: 23162751    Free PMC article.
Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival.
Tyler J Curiel, George Coukos, +18 authors, Weiping Zou.
Nat Med, 2004 Aug 24; 10(9). PMID: 15322536
Highly Cited.
Cytokine gene therapy or infusion as treatment for solid human cancer.
B W Robinson, S A Mukherjee, +11 authors, B Scott.
J Immunother, 1998 Jun 04; 21(3). PMID: 9610913
Replication-restricted vaccinia as a cytokine gene therapy vector in cancer: persistent transgene expression despite antibody generation.
S Mukherjee, T Haenel, +10 authors, B Robinson.
Cancer Gene Ther, 2000 Jun 01; 7(5). PMID: 10830713
CD4+CXCR4highCD69+ T cells accumulate in lung adenocarcinoma.
Ori Wald, Uzi Izhar, +6 authors, Amnon Peled.
J Immunol, 2006 Nov 04; 177(10). PMID: 17082613
Adjuvant therapy with agonistic antibodies to CD134 (OX40) increases local control after surgical or radiation therapy of cancer in mice.
Michael J Gough, Marka R Crittenden, +7 authors, Andrew D Weinberg.
J Immunother, 2010 Sep 16; 33(8). PMID: 20842057    Free PMC article.
Angiogenesis in cancer, vascular, rheumatoid and other disease.
J Folkman.
Nat Med, 1995 Jan 01; 1(1). PMID: 7584949
Highly Cited. Review.
Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation.
M Cella, D Scheidegger, +3 authors, G Alber.
J Exp Med, 1996 Aug 01; 184(2). PMID: 8760829    Free PMC article.
Highly Cited.
The inflammatory microenvironment in hepatocellular carcinoma: a pivotal role for tumor-associated macrophages.
Daria Capece, Mariafausta Fischietti, +5 authors, Edoardo Alesse.
Biomed Res Int, 2013 Mar 28; 2013. PMID: 23533994    Free PMC article.
Highly Cited. Review.
CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation.
M F Krummel, J P Allison.
J Exp Med, 1995 Aug 01; 182(2). PMID: 7543139    Free PMC article.
Highly Cited.
The induction of immune responses to murine malignant mesothelioma by IL-2 gene transfer.
C C Leong, J V Marley, +2 authors, M J Garlepp.
Immunol Cell Biol, 1997 Aug 01; 75(4). PMID: 9315477
Nanoparticles for tumor targeted therapies and their pharmacokinetics.
Jianqiu Wang, Meihua Sui, Weimin Fan.
Curr Drug Metab, 2010 Apr 03; 11(2). PMID: 20359289
OX40 engagement and chemotherapy combination provides potent antitumor immunity with concomitant regulatory T cell apoptosis.
Daniel Hirschhorn-Cymerman, Gabrielle A Rizzuto, +6 authors, Alan N Houghton.
J Exp Med, 2009 May 06; 206(5). PMID: 19414558    Free PMC article.
Skin-test infiltrating lymphocytes early predict clinical outcome of dendritic cell-based vaccination in metastatic melanoma.
Erik H J G Aarntzen, Kalijn Bol, +7 authors, I Jolanda M De Vries.
Cancer Res, 2012 Sep 27; 72(23). PMID: 23010076
Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors.
Jaikumar Duraiswamy, Karen M Kaluza, Gordon J Freeman, George Coukos.
Cancer Res, 2013 May 02; 73(12). PMID: 23633484    Free PMC article.
Highly Cited.
Hypoxia enhances tumor stemness by increasing the invasive and tumorigenic side population fraction.
Bikul Das, Rika Tsuchida, +3 authors, Herman Yeger.
Stem Cells, 2008 May 10; 26(7). PMID: 18467664
Highly Cited.
Glucocorticoid-induced TNF receptor family related gene activation overcomes tolerance/ignorance to melanoma differentiation antigens and enhances antitumor immunity.
Teresa Ramirez-Montagut, Andrew Chow, +7 authors, Marcel R M van den Brink.
J Immunol, 2006 May 20; 176(11). PMID: 16709800
Intratumoral chemotherapy for lung cancer: re-challenge current targeted therapies.
Wolfgang Hohenforst-Schmidt, Paul Zarogoulidis, +13 authors, Johannes Brachmann.
Drug Des Devel Ther, 2013 Jul 31; 7. PMID: 23898222    Free PMC article.
Soluble and membrane-bound TGF-β-mediated regulation of intratumoral T cell differentiation and function in B-cell non-Hodgkin lymphoma.
Zhi-Zhang Yang, Deanna M Grote, +7 authors, Stephen M Ansell.
PLoS One, 2013 Apr 05; 8(3). PMID: 23555036    Free PMC article.
Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo.
D Gabrilovich, T Ishida, +4 authors, D P Carbone.
Blood, 1998 Dec 03; 92(11). PMID: 9834220
Highly Cited.
Continuous intratumoral infusion of methotrexate for recurrent glioblastoma: a pilot study.
D Nierenberg, R Harbaugh, +4 authors, E Newman.
Neurosurgery, 1991 May 01; 28(5). PMID: 1652112
Early detection of tumor cells by innate immune cells leads to T(reg) recruitment through CCL22 production by tumor cells.
Julien Faget, Cathy Biota, +8 authors, Christine Ménétrier-Caux.
Cancer Res, 2011 Aug 20; 71(19). PMID: 21852386
Inhibition of p300 impairs Foxp3⁺ T regulatory cell function and promotes antitumor immunity.
Yujie Liu, Liqing Wang, +11 authors, Wayne W Hancock.
Nat Med, 2013 Aug 21; 19(9). PMID: 23955711    Free PMC article.
A phase I/II trial of intratumoral endoscopic ultrasound injection of ONYX-015 with intravenous gemcitabine in unresectable pancreatic carcinoma.
J Randolph Hecht, Rudolph Bedford, +5 authors, Scott M Freeman.
Clin Cancer Res, 2003 Feb 11; 9(2). PMID: 12576418
Highly Cited.
Cutting edge: tumor-specific CTL are constitutively cross-armed in draining lymph nodes and transiently disseminate to mediate tumor regression following systemic CD40 activation.
Philip A Stumbles, Robyn Himbeck, +3 authors, Bruce W S Robinson.
J Immunol, 2004 Nov 06; 173(10). PMID: 15528325
Potentiation of a p53-SLP vaccine by cyclophosphamide in ovarian cancer: a single-arm phase II study.
Renee Vermeij, Ninke Leffers, +13 authors, Hans W Nijman.
Int J Cancer, 2011 Dec 06; 131(5). PMID: 22139992
A comparative study of intratumoral chemotherapy in advanced childhood common solid tumors.
Rajeev Rahi, K Vijyendra, +5 authors, A N Gangopadhyay.
Indian J Urol, 2007 Oct 01; 23(4). PMID: 19718288    Free PMC article.
Synergistic anti-tumor responses after administration of agonistic antibodies to CD40 and IL-2: coordination of dendritic and CD8+ cell responses.
William J Murphy, Lisbeth Welniak, +9 authors, Robert H Wiltrout.
J Immunol, 2003 Feb 21; 170(5). PMID: 12594303
The treatment of malignant tumors by bacterial toxins as developed by the late William B. Coley, M.D., reviewed in the light of modern research.
Cancer Res, 1946 Apr 01; 6. PMID: 21018724
Highly Cited.
Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection.
Cristiana Guiducci, Alain P Vicari, +2 authors, Mario P Colombo.
Cancer Res, 2005 Apr 19; 65(8). PMID: 15833879
Highly Cited.
Nivolumab plus ipilimumab in advanced melanoma.
Jedd D Wolchok, Harriet Kluger, +21 authors, Mario Sznol.
N Engl J Med, 2013 Jun 04; 369(2). PMID: 23724867    Free PMC article.
Highly Cited.
Home sweet home: the tumor microenvironment as a haven for regulatory T cells.
Beatrice Ondondo, Emma Jones, Andrew Godkin, Awen Gallimore.
Front Immunol, 2013 Jul 23; 4. PMID: 23874342    Free PMC article.
Contribution of Fibroblast and Mast Cell (Afferent) and Tumor (Efferent) IL-6 Effects within the Tumor Microenvironment.
Honor J Hugo, Stephanie Lebret, +5 authors, M Leigh Ackland.
Cancer Microenviron, 2012 Feb 09; 5(1). PMID: 22314376    Free PMC article.
Interleukin-6 involvement in mesothelioma pathobiology: inhibition by interferon alpha immunotherapy.
H Bielefeldt-Ohmann, A L Marzo, +3 authors, D R Fitzpatrick.
Cancer Immunol Immunother, 1995 Apr 01; 40(4). PMID: 7750122
Transfection of the gene for B7-1 but not B7-2 can induce immunity to murine malignant mesothelioma.
C C Leong, J V Marley, +3 authors, M J Garlepp.
Int J Cancer, 1997 May 02; 71(3). PMID: 9139887
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.
Generation of an antitumour immune response to a murine mesothelioma cell line by the transfection of allogeneic MHC genes.
C C Leong, B W Robinson, M J Garlepp.
Int J Cancer, 1994 Oct 15; 59(2). PMID: 7927922
Gene therapy for malignant mesothelioma: beyond the infant years.
R G van der Most, B W S Robinson, D J Nelson.
Cancer Gene Ther, 2006 Jan 28; 13(10). PMID: 16439992
Intratumoral cisplatin/adrenaline injectable gel for the treatment of patients with cutaneous and soft tissue metastases of malignant melanoma.
Ruth Oratz, Axel Hauschild, +4 authors, Elaine K Orenberg.
Melanoma Res, 2003 Feb 06; 13(1). PMID: 12569286
Fine needle percutaneous intratumoral chemotherapy under ultrasound guidance: a feasibility study.
T Livraghi, E Bajetta, +3 authors, C Vettori.
Tumori, 1986 Feb 28; 72(1). PMID: 3513408
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.
Tumor-derived CD4(+)CD25(+) regulatory T cell suppression of dendritic cell function involves TGF-beta and IL-10.
Nicolas Larmonier, Marilyn Marron, +7 authors, Emmanuel Katsanis.
Cancer Immunol Immunother, 2006 Apr 14; 56(1). PMID: 16612596
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.
Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation.
Adam D Cohen, David A Schaer, +10 authors, Jedd D Wolchok.
PLoS One, 2010 May 11; 5(5). PMID: 20454651    Free PMC article.
Highly Cited.
Cancer immunoediting: antigens, mechanisms, and implications to cancer immunotherapy.
Matthew D Vesely, Robert D Schreiber.
Ann N Y Acad Sci, 2013 May 09; 1284. PMID: 23651186    Free PMC article.
Highly Cited.
Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity.
Fumiya Hirano, Katsumi Kaneko, +9 authors, Lieping Chen.
Cancer Res, 2005 Feb 12; 65(3). PMID: 15705911
Highly Cited.
CD8alpha+ DC are not the sole subset cross-presenting cell-associated tumor antigens from a solid tumor.
Alison M McDonnell, Amy C Prosser, +2 authors, Andrew J Currie.
Eur J Immunol, 2010 Apr 08; 40(6). PMID: 20373290
Tumour-educated macrophages promote tumour progression and metastasis.
Jeffrey W Pollard.
Nat Rev Cancer, 2004 Jan 07; 4(1). PMID: 14708027
Highly Cited. Review.
Conditional regulatory T-cell depletion releases adaptive immunity preventing carcinogenesis and suppressing established tumor growth.
Michele W L Teng, Shin Foong Ngiow, +3 authors, Mark J Smyth.
Cancer Res, 2010 Oct 07; 70(20). PMID: 20924111
Targeting macrophages rescues age-related immune deficiencies in C57BL/6J geriatric mice.
Connie Jackaman, Hannah G Radley-Crabb, +3 authors, Delia J Nelson.
Aging Cell, 2013 Feb 28; 12(3). PMID: 23442123
Phase 2 study of intratumoral cisplatin and epinephrine treatment for locally recurrent head and neck tumors.
Christian Duvillard, Philippe Romanet, +2 authors, Bruno Chauffert.
Ann Otol Rhinol Laryngol, 2004 Apr 01; 113(3 Pt 1). PMID: 15053208
Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells.
D I Gabrilovich, H L Chen, +5 authors, D P Carbone.
Nat Med, 1996 Oct 01; 2(10). PMID: 8837607
Highly Cited.
OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection.
Silvia Piconese, Barbara Valzasina, Mario P Colombo.
J Exp Med, 2008 Mar 26; 205(4). PMID: 18362171    Free PMC article.
Highly Cited.
Tumor antigen cross-presentation and the dendritic cell: where it all begins?
Alison M McDonnell, Bruce W S Robinson, Andrew J Currie.
Clin Dev Immunol, 2010 Oct 27; 2010. PMID: 20976125    Free PMC article.
ERK-dependent Bim modulation downstream of the 4-1BB-TRAF1 signaling axis is a critical mediator of CD8 T cell survival in vivo.
Laurent Sabbagh, Gayle Pulle, +2 authors, Tania H Watts.
J Immunol, 2008 Jun 05; 180(12). PMID: 18523273
Radiological findings following postsurgical intratumoral bleomycin injection for cystic craniopharyngioma.
Sang-Dae Kim, Jung-Yul Park, +3 authors, Dong-Jun Lim.
Clin Neurol Neurosurg, 2006 Oct 19; 109(3). PMID: 17046151
Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4.
Omar S Qureshi, Yong Zheng, +12 authors, David M Sansom.
Science, 2011 Apr 09; 332(6029). PMID: 21474713    Free PMC article.
Highly Cited.
Tumor-associated macrophages as a paradigm of macrophage plasticity, diversity, and polarization: lessons and open questions.
Alberto Mantovani, Massimo Locati.
Arterioscler Thromb Vasc Biol, 2013 Jun 15; 33(7). PMID: 23766387
Highly Cited.
CD40-CD40Ligand interactions and their role in cytotoxic T lymphocyte priming and anti-tumor immunity.
R E Toes, S P Schoenberger, +2 authors, C J Melief.
Semin Immunol, 1998 Nov 25; 10(6). PMID: 9826577
Intratumoral production of IL-6 in B cell chronic lymphocytic leukemia and B lymphomas.
D Emilie, M B Leger-Ravet, +5 authors, P Galanaud.
Leuk Lymphoma, 1993 Nov 01; 11(5-6). PMID: 8124214
Interleukin-10 promotes B16-melanoma growth by inhibition of macrophage functions and induction of tumour and vascular cell proliferation.
M L García-Hernández, R Hernández-Pando, P Gariglio, Jaime Berumen.
Immunology, 2002 Mar 02; 105(2). PMID: 11872099    Free PMC article.
CD40 stimulation leads to effective therapy of CD40(-) tumors through induction of strong systemic cytotoxic T lymphocyte immunity.
Geertje J D van Mierlo, Annemieke Th den Boer, +5 authors, Rene E M Toes.
Proc Natl Acad Sci U S A, 2002 Apr 04; 99(8). PMID: 11929985    Free PMC article.
Cytokine gene therapy of mesothelioma. Immune and antitumor effects of transfected interleukin-12.
I Caminschi, E Venetsanakos, +3 authors, B Scott.
Am J Respir Cell Mol Biol, 1999 Aug 26; 21(3). PMID: 10460752
Dendritic cells infected with a vaccinia virus interleukin-2 vector secrete high levels of IL-2 and can become efficient antigen presenting cells that secrete high levels of the immunostimulatory cytokine IL-12.
Sutapa Mukherjee, John W Upham, +4 authors, Delia J Nelson.
Cancer Gene Ther, 2003 Jul 23; 10(8). PMID: 12872141
Direct intratumoral chemotherapy with carboplatin and epinephrine in a recurrent cervical chordoma: case report.
Séverine Guiu, Boris Guiu, Sylvaine Feutray, Bruno Chauffert.
Neurosurgery, 2009 Aug 19; 65(3). PMID: 19687674
Combining anaerobic bacterial oncolysis with vaccination that blocks interleukin-10 signaling may achieve better outcomes for late stage cancer management.
Guoying Ni, Tianfang Wang, +3 authors, Ming Q Wei.
Hum Vaccin Immunother, 2015 Sep 15; 12(3). PMID: 26367244    Free PMC article.
The immunohistochemical analysis of membrane-bound CD55, CD59 and fluid-phase FH and FH-like complement inhibitors in cancers of ovary and corpus uteri origin.
Lucyna Kapka-Skrzypczak, Ewa Wolinska, +2 authors, Maciej Skrzypczak.
Cent Eur J Immunol, 2015 Dec 10; 40(3). PMID: 26648780    Free PMC article.
Natural Killer Cell-Based Therapies Targeting Cancer: Possible Strategies to Gain and Sustain Anti-Tumor Activity.
Carin I M Dahlberg, Dhifaf Sarhan, +2 authors, Evren Alici.
Front Immunol, 2015 Dec 10; 6. PMID: 26648934    Free PMC article.
Long-Term Clinical Responses of Neoadjuvant Dendritic Cell Infusions and Radiation in Soft Tissue Sarcoma.
Shailaja Raj, Marilyn M Bui, +11 authors, Scott J Antonia.
Sarcoma, 2016 Feb 18; 2015. PMID: 26880867    Free PMC article.
Harnessing immunosurveillance: current developments and future directions in cancer immunotherapy.
Maureen L Drakes, Patrick J Stiff.
Immunotargets Ther, 2014 Jan 01; 3. PMID: 27471706    Free PMC article.
Immunologic Function and Molecular Insight of Recombinant Interleukin-18.
Jirakrit Saetang, Aekkachai Puseenam, +3 authors, Varomyalin Tipmanee.
PLoS One, 2016 Aug 03; 11(8). PMID: 27483370    Free PMC article.
Tumour-associated mesenchymal stem/stromal cells: emerging therapeutic targets.
Yufang Shi, Liming Du, Liangyu Lin, Ying Wang.
Nat Rev Drug Discov, 2016 Nov 05; 16(1). PMID: 27811929
Highly Cited. Review.
Effect of IL-17 in the development of colon cancer in mice.
Lijuan Yang, Hao Liu, +6 authors, Yixin Qi.
Oncol Lett, 2017 Jan 20; 12(6). PMID: 28101230    Free PMC article.
Soluble NKG2D ligands are biomarkers associated with the clinical outcome to immune checkpoint blockade therapy of metastatic melanoma patients.
Cristina Maccalli, Diana Giannarelli, +13 authors, Michele Maio.
Oncoimmunology, 2017 Aug 16; 6(7). PMID: 28811958    Free PMC article.
Clinical characteristics of patient selection and imaging predictors of outcome in solid tumors treated with checkpoint-inhibitors.
Sabrina Rossi, Luca Toschi, +3 authors, Egesta Lopci.
Eur J Nucl Med Mol Imaging, 2017 Aug 18; 44(13). PMID: 28815334
Immediate breast reconstruction with omental flap for luminal breast cancer patients: Ten clinical case reports.
Nanlin Li, Zhao Zheng, +9 authors, Rui Ling.
Medicine (Baltimore), 2017 Aug 18; 96(33). PMID: 28816969    Free PMC article.
The Oncopig Cancer Model: An Innovative Large Animal Translational Oncology Platform.
Kyle M Schachtschneider, Regina M Schwind, +14 authors, Lawrence B Schook.
Front Oncol, 2017 Sep 08; 7. PMID: 28879168    Free PMC article.
Coley's immunotherapy revived: Innate immunity as a link in priming cancer cells for an attack by adaptive immunity.
Ondrej Uher, Veronika Caisova, +5 authors, Karel Pacak.
Semin Oncol, 2019 Nov 20; 46(4-5). PMID: 31739997    Free PMC article.
Phase I dose-escalation study to determine the safety, tolerability, preliminary efficacy and pharmacokinetics of an intratumoral injection of tigilanol tiglate (EBC-46).
Benedict J Panizza, Paul de Souza, +3 authors, Jason D Lickliter.
EBioMedicine, 2019 Dec 08; 50. PMID: 31810818    Free PMC article.
Therapeutic Mesenchymal Stromal Cells for Immunotherapy and for Gene and Drug Delivery.
Graça Almeida-Porada, Anthony J Atala, Christopher D Porada.
Mol Ther Methods Clin Dev, 2020 Feb 20; 16. PMID: 32071924    Free PMC article.
Nanomedicine and Onco-Immunotherapy: From the Bench to Bedside to Biomarkers.
Vanessa Acebes-Fernández, Alicia Landeria-Viñuela, +5 authors, Manuel Fuentes.
Nanomaterials (Basel), 2020 Jul 03; 10(7). PMID: 32610601    Free PMC article.
Local Injection of Submicron Particle Docetaxel is Associated with Tumor Eradication, Reduced Systemic Toxicity and an Immunologic Response in Uro-Oncologic Xenografts.
Holly A Maulhardt, Lauren Hylle, +6 authors, Gere S diZerega.
Cancers (Basel), 2019 Apr 27; 11(4). PMID: 31022918    Free PMC article.
Submicron particle docetaxel intratumoral injection in combination with anti-mCTLA-4 into 4T1-Luc orthotopic implants reduces primary tumor and metastatic pulmonary lesions.
Holly Maulhardt, Alyson Marin, Holly Hesseltine, Gere diZerega.
Med Oncol, 2021 Aug 01; 38(9). PMID: 34331595    Free PMC article.
Leukemic stem cell signatures in Acute myeloid leukemia- targeting the Guardians with novel approaches.
Deepshi Thakral, Ritu Gupta, Aafreen Khan.
Stem Cell Rev Rep, 2022 Apr 13;. PMID: 35412219
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.