Journal Article
. 2014 Apr; 20(7):1747-56.
doi: 10.1158/1078-0432.CCR-13-2116.

Intratumoral immunization: a new paradigm for cancer therapy

Aurélien Marabelle 1 Holbrook Kohrt  Christophe Caux  Ronald Levy  
  • PMID: 24691639
  •     76 References
  •     91 citations


Immune cell infiltration in the tumor microenvironment is of prognostic and therapeutic import. These immune cell subsets can be heterogeneous and are composed of mature antigen-presenting cells, helper and effector cytotoxic T cells, toleragenic dendritic cells, tumor-associated macrophages, and regulatory T cells, among other cell types. With the development of novel drugs that target the immune system rather than the cancer cells, the tumor immune microenvironment is not only prognostic for overall patient outcome, but also predictive for likelihood of response to these immune-targeted therapies. Such therapies aim to reverse the cancer immunotolerance and trigger an effective antitumor immune response. Two major families of immunostimulatory drugs are currently in clinical development: pattern recognition receptor agonists (PRRago) and immunostimulatory monoclonal antibodies (ISmAb). Despite their immune-targeted design, these agents have so far been developed clinically as if they were typical anticancer drugs. Here, we review the limitations of this conventional approach, specifically addressing the shortcomings of the usual schedules of intravenous infusions every 2 or 3 weeks. If the new modalities of immunotherapy target specific immune cells within the tumor microenvironment, it might be preferable to deliver them locally into the tumor rather than systemically. There is preclinical and clinical evidence that a therapeutic systemic antitumor immune response can be generated upon intratumoral immunomodulation. Moreover, preclinical results have shown that therapeutic synergy can be obtained by combining PRRagos and ISmAbs to the local tumor site.

Antitumor activity of the DNA fraction from Mycobacterium bovis BCG. II. Effects on various syngeneic mouse tumors.
S Shimada, O Yano, +5 authors, T Tokunaga.
J Natl Cancer Inst, 1985 Mar 01; 74(3). PMID: 3856070
CpG DNA increases primary malignant B cell expression of costimulatory molecules and target antigens.
B Jahrsdörfer, G Hartmann, +7 authors, G J Weiner.
J Leukoc Biol, 2001 Feb 24; 69(1). PMID: 11200072
Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial.
Byeong-Ho Park, Taeho Hwang, +16 authors, David H Kirn.
Lancet Oncol, 2008 May 23; 9(6). PMID: 18495536
Highly Cited.
Cytosolic DNA sensors regulating type I interferon induction.
Sinead E Keating, Marcin Baran, Andrew G Bowie.
Trends Immunol, 2011 Sep 24; 32(12). PMID: 21940216
Controlled local delivery of CTLA-4 blocking antibody induces CD8+ T-cell-dependent tumor eradication and decreases risk of toxic side effects.
Marieke F Fransen, Tetje C van der Sluis, +2 authors, Cornelis J M Melief.
Clin Cancer Res, 2013 Jun 22; 19(19). PMID: 23788581
Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions.
Nobuyoshi Hiraoka, Kaoru Onozato, Tomoo Kosuge, Setsuo Hirohashi.
Clin Cancer Res, 2006 Sep 27; 12(18). PMID: 17000676
Highly Cited.
Combined intralesional Bacille Calmette-Guérin (BCG) and topical imiquimod for in-transit melanoma.
Travis B Kidner, Donald L Morton, +4 authors, Mark B Faries.
J Immunother, 2012 Oct 24; 35(9). PMID: 23090081    Free PMC article.
Management of nonmelanoma skin cancer in 2007.
Julie A Neville, Erin Welch, David J Leffell.
Nat Clin Pract Oncol, 2007 Jul 28; 4(8). PMID: 17657251
Predominant infiltration of macrophages and CD8(+) T Cells in cancer nests is a significant predictor of survival in stage IV nonsmall cell lung cancer.
Osamu Kawai, Genichiro Ishii, +9 authors, Atsushi Ochiai.
Cancer, 2008 Aug 02; 113(6). PMID: 18671239
Highly Cited.
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.
Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells.
Mark J Selby, John J Engelhardt, +4 authors, Alan J Korman.
Cancer Immunol Res, 2014 Apr 30; 1(1). PMID: 24777248
Highly Cited.
Prognostic value of tumor-infiltrating dendritic cells in colorectal cancer: role of maturation status and intratumoral localization.
Maro H Sandel, Alisher R Dadabayev, +9 authors, Peter J K Kuppen.
Clin Cancer Res, 2005 Apr 09; 11(7). PMID: 15814636
Lymphoma immunotherapy with CpG oligodeoxynucleotides requires TLR9 either in the host or in the tumor itself.
Jiali Li, Wenru Song, +5 authors, Ronald Levy.
J Immunol, 2007 Aug 07; 179(4). PMID: 17675511
Toll-like receptor 3 signaling converts tumor-supporting myeloid cells to tumoricidal effectors.
Hiroaki Shime, Misako Matsumoto, +6 authors, Tsukasa Seya.
Proc Natl Acad Sci U S A, 2012 Feb 07; 109(6). PMID: 22308357    Free PMC article.
Highly Cited.
Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer.
Jeong Heo, Tony Reid, +23 authors, David H Kirn.
Nat Med, 2013 Feb 12; 19(3). PMID: 23396206    Free PMC article.
Highly Cited.
Localized immunotherapy via liposome-anchored Anti-CD137 + IL-2 prevents lethal toxicity and elicits local and systemic antitumor immunity.
Brandon Kwong, S Annie Gai, +2 authors, Darrell J Irvine.
Cancer Res, 2013 Feb 26; 73(5). PMID: 23436794    Free PMC article.
Macrophage infiltration predicts a poor prognosis for human ewing sarcoma.
Toshifumi Fujiwara, Jun-ichi Fukushi, +13 authors, Yukihide Iwamoto.
Am J Pathol, 2011 Jul 21; 179(3). PMID: 21771572    Free PMC article.
CXC chemokine receptor 3 expression by activated CD8+ T cells is associated with survival in melanoma patients with stage III disease.
Irene M Mullins, Craig L Slingluff, +6 authors, David W Mullins.
Cancer Res, 2004 Nov 03; 64(21). PMID: 15520172
Molecular pathways: toll-like receptors in the tumor microenvironment--poor prognosis or new therapeutic opportunity.
Lisa A Ridnour, Robert Y S Cheng, +6 authors, David A Wink.
Clin Cancer Res, 2012 Dec 29; 19(6). PMID: 23271799    Free PMC article.
Abscopal effect in a patient with melanoma.
Susan M Hiniker, Daniel S Chen, Susan J Knox.
N Engl J Med, 2012 May 25; 366(21). PMID: 22621637
The toll-like receptor repertoire of human B lymphocytes: inducible and selective expression of TLR9 and TLR10 in normal and transformed cells.
Emer Bourke, Daniela Bosisio, +2 authors, Alberto Mantovani.
Blood, 2003 Apr 12; 102(3). PMID: 12689944
Highly Cited.
Plasmacytoid dendritic cells infiltrating ovarian cancer are associated with poor prognosis.
Sana Intidhar Labidi-Galy, Isabelle Treilleux, +5 authors, Nathalie Bendriss-Vermare.
Oncoimmunology, 2012 Jun 28; 1(3). PMID: 22737622    Free PMC article.
Tumor-infiltrating macrophages are associated with metastasis suppression in high-grade osteosarcoma: a rationale for treatment with macrophage activating agents.
Emilie P Buddingh, Marieke L Kuijjer, +8 authors, Anne-Marie Cleton-Jansen.
Clin Cancer Res, 2011 Mar 05; 17(8). PMID: 21372215
Highly Cited.
Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling.
Nikhil Wagle, Caroline Emery, +9 authors, Levi A Garraway.
J Clin Oncol, 2011 Mar 09; 29(22). PMID: 21383288    Free PMC article.
Highly Cited.
S100 positive dendritic cells in human lung tumors associated with cell differentiation and enhanced survival.
N A Zeid, H K Muller.
Pathology, 1993 Oct 01; 25(4). PMID: 8164994
Activating Fc γ receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies.
Yannick Bulliard, Rose Jolicoeur, +6 authors, Jennifer L Brogdon.
J Exp Med, 2013 Jul 31; 210(9). PMID: 23897982    Free PMC article.
Highly Cited.
Tumor promotion by intratumoral plasmacytoid dendritic cells is reversed by TLR7 ligand treatment.
Isabelle Le Mercier, Dominique Poujol, +12 authors, Nadège Goutagny.
Cancer Res, 2013 Jun 01; 73(15). PMID: 23722543
Immunotherapy with BCG administered by scarification: standardization of reactions and management of side effects.
G N Hortobagyi, S P Richman, +3 authors, E M Hersh.
Cancer, 1978 Nov 01; 42(5). PMID: 363257
Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection.
Qiang Gao, Shuang-Jian Qiu, +6 authors, Zhao-You Tang.
J Clin Oncol, 2007 Jun 20; 25(18). PMID: 17577038
Highly Cited.
Immunostimulatory oligodeoxynucleotides containing CpG motifs enhance the efficacy of monoclonal antibody therapy of lymphoma.
J E Wooldridge, Z Ballas, A M Krieg, G J Weiner.
Blood, 1997 Apr 15; 89(8). PMID: 9108420
Tumor infiltrating Foxp3+ regulatory T-cells are associated with recurrence in pathologic stage I NSCLC patients.
Rebecca P Petersen, Michael J Campa, +4 authors, Edward F Patz.
Cancer, 2006 Nov 14; 107(12). PMID: 17099880
Highly Cited.
In situ vaccination against mycosis fungoides by intratumoral injection of a TLR9 agonist combined with radiation: a phase 1/2 study.
Youn H Kim, Dita Gratzinger, +13 authors, Ronald Levy.
Blood, 2011 Nov 03; 119(2). PMID: 22045986    Free PMC article.
Phase I/II study of topical imiquimod and intralesional interleukin-2 in the treatment of accessible metastases in malignant melanoma.
D S Green, M D Bodman-Smith, A G Dalgleish, M D Fischer.
Br J Dermatol, 2007 Jan 17; 156(2). PMID: 17223875
Imiquimod clears tumors in mice independent of adaptive immunity by converting pDCs into tumor-killing effector cells.
Barbara Drobits, Martin Holcmann, +5 authors, Maria Sibilia.
J Clin Invest, 2012 Jan 19; 122(2). PMID: 22251703    Free PMC article.
Highly Cited.
Density of DC-LAMP(+) mature dendritic cells in combination with activated T lymphocytes infiltrating primary cutaneous melanoma is a strong independent prognostic factor.
Andrea Ladányi, Judit Kiss, +5 authors, József Tímár.
Cancer Immunol Immunother, 2007 Feb 07; 56(9). PMID: 17279413
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.
T-cell modulation combined with intratumoral CpG cures lymphoma in a mouse model without the need for chemotherapy.
Roch Houot, Ronald Levy.
Blood, 2008 Oct 23; 113(15). PMID: 18941113    Free PMC article.
Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens.
Sarah L Jongbloed, Andrew J Kassianos, +10 authors, Kristen J Radford.
J Exp Med, 2010 May 19; 207(6). PMID: 20479116    Free PMC article.
Highly Cited.
Localisation pattern of Foxp3+ regulatory T cells is associated with clinical behaviour in gastric cancer.
Y Mizukami, K Kono, +4 authors, H Fujii.
Br J Cancer, 2007 Dec 19; 98(1). PMID: 18087278    Free PMC article.
Immunogenic cell death in cancer therapy.
Guido Kroemer, Lorenzo Galluzzi, Oliver Kepp, Laurence Zitvogel.
Annu Rev Immunol, 2012 Nov 20; 31. PMID: 23157435
Highly Cited. Review.
The HIF-1α hypoxia response in tumor-infiltrating T lymphocytes induces functional CD137 (4-1BB) for immunotherapy.
Asís Palazón, Iván Martínez-Forero, +11 authors, Ignacio Melero.
Cancer Discov, 2012 Jun 22; 2(7). PMID: 22719018
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.
Tumor-associated macrophages as potential diagnostic and prognostic biomarkers in breast cancer.
Xiaoqiang Tang.
Cancer Lett, 2013 Jan 26; 332(1). PMID: 23348699
Highly Cited. Review.
Intralesional injection of the methanol extraction residue of Bacillus Calmette-Guerin (MER) into cutaneous metastases of malignant melanoma.
S E Krown, E Y Hilal, +5 authors, H F Oettgen.
Cancer, 1978 Dec 01; 42(6). PMID: 728866
Feedback loop of immune regulation by CD4+CD25+ Treg.
Yun-Jae Jung, Ju-Young Seoh.
Immunobiology, 2009 Mar 31; 214(4). PMID: 19327546
Dendritic cell infiltration and prognosis of early stage breast cancer.
Isabelle Treilleux, Jean-Yves Blay, +8 authors, Serge Lebecque.
Clin Cancer Res, 2004 Dec 01; 10(22). PMID: 15569976
Highly Cited.
The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases. 1893.
W B Coley.
Clin Orthop Relat Res, 1991 Jan 01; (262). PMID: 1984929
Highly Cited.
BCG and cancer.
R C Bast, B Zbar, T Borsos, H J Rapp.
N Engl J Med, 1974 Jun 27; 290(26). PMID: 4598691
Prognostic significance of CD83 positive tumor-infiltrating dendritic cells and expression of TGF-beta 1 in human gastric cancer.
Julian Ananiev, Maya Vladova Gulubova, Irena Manolova Manolova.
Hepatogastroenterology, 2011 Nov 17; 58(110-111). PMID: 22086706
Reprogrammed foxp3(+) regulatory T cells provide essential help to support cross-presentation and CD8(+) T cell priming in naive mice.
Madhav D Sharma, De-Yan Hou, +6 authors, David H Munn.
Immunity, 2010 Dec 15; 33(6). PMID: 21145762    Free PMC article.
Highly Cited.
Immunologic correlates of the abscopal effect in a patient with melanoma.
Michael A Postow, Margaret K Callahan, +18 authors, Jedd D Wolchok.
N Engl J Med, 2012 Mar 09; 366(10). PMID: 22397654    Free PMC article.
Highly Cited.
Abscopal effects of radiation therapy: a clinical review for the radiobiologist.
Shankar Siva, Michael P MacManus, Roger F Martin, Olga A Martin.
Cancer Lett, 2013 Oct 16; 356(1). PMID: 24125863
Highly Cited. Review.
Clinical significance of tumor-associated inflammatory cells in metastatic neuroblastoma.
Shahab Asgharzadeh, Jill A Salo, +15 authors, Robert C Seeger.
J Clin Oncol, 2012 Aug 29; 30(28). PMID: 22927533    Free PMC article.
Highly Cited.
Proapoptotic signaling induced by RIG-I and MDA-5 results in type I interferon-independent apoptosis in human melanoma cells.
Robert Besch, Hendrik Poeck, +8 authors, Gunther Hartmann.
J Clin Invest, 2009 Jul 22; 119(8). PMID: 19620789    Free PMC article.
Highly Cited.
Malignant melanoma metastatic to the bladder. Regression following intratumor injection of BCG vaccine.
M J Silverstein, J DeKernion, D L Morton.
JAMA, 1974 Aug 05; 229(6). PMID: 4408302
The immune contexture in human tumours: impact on clinical outcome.
Wolf Herman Fridman, Franck Pagès, Catherine Sautès-Fridman, Jérôme Galon.
Nat Rev Cancer, 2012 Mar 16; 12(4). PMID: 22419253
Highly Cited. Review.
Cancer immunotherapy comes of age.
Ira Mellman, George Coukos, Glenn Dranoff.
Nature, 2011 Dec 24; 480(7378). PMID: 22193102    Free PMC article.
Highly Cited. Review.
Intraepithelial CD8-positive T lymphocytes predict survival for patients with serous stage III ovarian carcinomas: relevance of clonal selection of T lymphocytes.
M Stumpf, A Hasenburg, +9 authors, S Lassmann.
Br J Cancer, 2009 Oct 29; 101(9). PMID: 19861998    Free PMC article.
The abscopal effect associated with a systemic anti-melanoma immune response.
Emily F Stamell, Jedd D Wolchok, +2 authors, Isaac Brownell.
Int J Radiat Oncol Biol Phys, 2012 May 09; 85(2). PMID: 22560555    Free PMC article.
Highly Cited.
Turning tumors into vaccines: co-opting the innate immune system.
Jasper G van den Boorn, Gunther Hartmann.
Immunity, 2013 Jul 31; 39(1). PMID: 23890061
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.
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.
How BCG led to the discovery of immunostimulatory DNA.
T Tokunaga, T Yamamoto, S Yamamoto.
Jpn J Infect Dis, 2000 May 16; 52(1). PMID: 10808252
In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer.
Franck Pagès, Amos Kirilovsky, +12 authors, Jérôme Galon.
J Clin Oncol, 2009 Oct 28; 27(35). PMID: 19858404
Highly Cited.
TLR ligand suppression or enhancement of Treg cells? A double-edged sword in immunity to tumours.
H Conroy, N A Marshall, K H G Mills.
Oncogene, 2008 Jan 08; 27(2). PMID: 18176598
Prognostic significance of CD83 positive, mature dendritic cells in the gallbladder carcinoma.
Makoto Furihata, Yuko Ono, +3 authors, Keiichi Kubota.
Oncol Rep, 2005 Jul 14; 14(2). PMID: 16012714
Intratumoral injection of interferon-α and systemic delivery of agonist anti-CD137 monoclonal antibodies synergize for immunotherapy.
Juan Dubrot, Asis Palazón, +9 authors, Ignacio Melero.
Int J Cancer, 2010 Mar 24; 128(1). PMID: 20309938
In situ vaccination with a TLR9 agonist induces systemic lymphoma regression: a phase I/II study.
Joshua D Brody, Weiyun Z Ai, +10 authors, Ronald Levy.
J Clin Oncol, 2010 Aug 11; 28(28). PMID: 20697067    Free PMC article.
Highly Cited.
BCG immunotherapy of malignant melanoma: summary of a seven-year experience.
D L Morton, F R Eilber, +4 authors, F C Sparks.
Ann Surg, 1974 Oct 01; 180(4). PMID: 4412271    Free PMC article.
Highly Cited.
Toll-like receptors in tumor immunotherapy.
Chrystal M Paulos, Andrew Kaiser, +11 authors, Nicholas P Restifo.
Clin Cancer Res, 2007 Sep 19; 13(18 Pt 1). PMID: 17875756    Free PMC article.
Intralesional treatment of recurrent metastatic cutaneous malignant melanoma: a randomized prospective study of intralesional Bacillus Calmette-Guerin versus intralesional dinitrochlorobenzene.
M H Cohen, J M Jessup, +2 authors, R B Herberman.
Cancer, 1978 Jun 01; 41(6). PMID: 657108
Immunotherapy of cancer: regression of tumors after intralesional injection of living Mycobacterium bovis.
B Zbar, T Tanaka.
Science, 1971 Apr 16; 172(3980). PMID: 4323415
Highly Cited.
Local secretion of anti-CTLA-4 enhances the therapeutic efficacy of a cancer immunotherapy with reduced evidence of systemic autoimmunity.
Andrew D Simmons, Marina Moskalenko, +5 authors, Karin Jooss.
Cancer Immunol Immunother, 2008 Feb 01; 57(8). PMID: 18236040
CpG motifs in bacterial DNA trigger direct B-cell activation.
A M Krieg, A K Yi, +5 authors, D M Klinman.
Nature, 1995 Apr 06; 374(6522). PMID: 7700380
Highly Cited.
The number of intratumoral dendritic cells and zeta-chain expression in T cells as prognostic and survival biomarkers in patients with oral carcinoma.
T E Reichert, C Scheuer, +2 authors, T L Whiteside.
Cancer, 2001 Jun 08; 91(11). PMID: 11391595
Viral evasion and subversion of pattern-recognition receptor signalling.
Andrew G Bowie, Leonie Unterholzner.
Nat Rev Immunol, 2008 Nov 08; 8(12). PMID: 18989317    Free PMC article.
Highly Cited. Review.
Regression of human papillomavirus intraepithelial lesions is induced by MVA E2 therapeutic vaccine.
Ricardo Rosales, Mario López-Contreras, +10 authors, Freddy Villarreal.
Hum Gene Ther, 2014 Oct 03; 25(12). PMID: 25275724    Free PMC article.
Intratumoral administration of mRNA encoding a fusokine consisting of IFN-β and the ectodomain of the TGF-β receptor II potentiates antitumor immunity.
Kevin Van der Jeught, Patrick Tjok Joe, +6 authors, Karine Breckpot.
Oncotarget, 2014 Oct 23; 5(20). PMID: 25338019    Free PMC article.
Intratumoral dendritic cells in the anti-tumor immune response.
Yang Liu, Xuetao Cao.
Cell Mol Immunol, 2015 Jan 20; 12(4). PMID: 25597333    Free PMC article.
Targeting the tumor microenvironment to enhance antitumor immune responses.
Kevin Van der Jeught, Lukasz Bialkowski, +7 authors, Karine Breckpot.
Oncotarget, 2015 Feb 16; 6(3). PMID: 25682197    Free PMC article.
Antigen specificity can be irrelevant to immunocytokine efficacy and biodistribution.
Alice Tzeng, Byron H Kwan, +2 authors, K Dane Wittrup.
Proc Natl Acad Sci U S A, 2015 Mar 04; 112(11). PMID: 25733854    Free PMC article.
Cytokine-Enhanced Vaccine and Interferon-β plus Suicide Gene Therapy as Surgery Adjuvant Treatments for Spontaneous Canine Melanoma.
Liliana M E Finocchiaro, Chiara Fondello, +4 authors, Gerardo C Glikin.
Hum Gene Ther, 2015 Mar 13; 26(6). PMID: 25762364    Free PMC article.
Mutant allele tumor heterogeneity (MATH) and head and neck squamous cell carcinoma.
James W Rocco.
Head Neck Pathol, 2015 Mar 26; 9(1). PMID: 25804377    Free PMC article.
Selective cell elimination in vitro and in vivo from tissues and tumors using antibodies conjugated with a near infrared phthalocyanine.
Kazuhide Sato, Takahito Nakajima, Peter L Choyke, Hisataka Kobayashi.
RSC Adv, 2015 Apr 14; 5(32). PMID: 25866624    Free PMC article.
In-situ tumor vaccination: Bringing the fight to the tumor.
Robert H Pierce, Jean S Campbell, +2 authors, Holbrook E K Kohrt.
Hum Vaccin Immunother, 2015 Jun 10; 11(8). PMID: 26055074    Free PMC article.
Kick-starting the cancer-immunity cycle by targeting CD40.
P Ellmark, S M Mangsbo, +2 authors, P Norlén.
Oncoimmunology, 2015 Jul 04; 4(7). PMID: 26140231    Free PMC article.
Intratumoral delivery of mRNA: Overcoming obstacles for effective immunotherapy.
Kevin Van der Jeught, Sandra Van Lint, Kris Thielemans, Karine Breckpot.
Oncoimmunology, 2015 Jul 15; 4(5). PMID: 26155403    Free PMC article.
Evolving synergistic combinations of targeted immunotherapies to combat cancer.
Ignacio Melero, David M Berman, +3 authors, John Haanen.
Nat Rev Cancer, 2015 Jul 25; 15(8). PMID: 26205340
Highly Cited. Review.
Enhancing Cancer Immunotherapy Via Activation of Innate Immunity.
Jacob L Goldberg, Paul M Sondel.
Semin Oncol, 2015 Sep 01; 42(4). PMID: 26320061    Free PMC article.
Immunodynamics: a cancer immunotherapy trials network review of immune monitoring in immuno-oncology clinical trials.
Holbrook E Kohrt, Paul C Tumeh, +33 authors, Cancer Immunotherapy Trials Network (CITN).
J Immunother Cancer, 2016 Mar 17; 4. PMID: 26981245    Free PMC article.
Flagellin is a strong vaginal adjuvant of a therapeutic vaccine for genital cancer.
Shee Eun Lee, Seol Hee Hong, +9 authors, Joon Haeng Rhee.
Oncoimmunology, 2016 Apr 09; 5(2). PMID: 27057462    Free PMC article.
The oncolytic peptide LTX-315 overcomes resistance of cancers to immunotherapy with CTLA4 checkpoint blockade.
T Yamazaki, J M Pitt, +5 authors, L Zitvogel.
Cell Death Differ, 2016 Apr 16; 23(6). PMID: 27082453    Free PMC article.
Emerging Opportunities and Challenges in Cancer Immunotherapy.
Theresa L Whiteside, Sandra Demaria, +2 authors, Ignacio Melero.
Clin Cancer Res, 2016 Apr 17; 22(8). PMID: 27084738    Free PMC article.
Highly Cited. Review.
Have lessons from past failures brought us closer to the success of immunotherapy in metastatic pancreatic cancer?
Laura Rosa Brunet, Thorsten Hagemann, +2 authors, Aurelien Marabelle.
Oncoimmunology, 2016 May 04; 5(4). PMID: 27141395    Free PMC article.
Histologic Assessment of Intratumoral Lymphoplasmacytic Infiltration Is Useful in Predicting Prognosis of Patients with Hepatocellular Carcinoma.
Akimasa Hayashi, Junji Shibahara, +5 authors, Masashi Fukayama.
PLoS One, 2016 May 20; 11(5). PMID: 27195977    Free PMC article.
In Situ Tumor Vaccination by Combining Local Radiation and Tumor-Specific Antibody or Immunocytokine Treatments.
Zachary S Morris, Emily I Guy, +13 authors, Paul M Sondel.
Cancer Res, 2016 May 20; 76(13). PMID: 27197149    Free PMC article.
Breaking Free of Control: How Conventional T Cells Overcome Regulatory T Cell Suppression.
Emily R Mercadante, Ulrike M Lorenz.
Front Immunol, 2016 Jun 01; 7. PMID: 27242798    Free PMC article.
Intratumoral Infection with Murine Cytomegalovirus Synergizes with PD-L1 Blockade to Clear Melanoma Lesions and Induce Long-term Immunity.
Dan A Erkes, Guangwu Xu, +5 authors, Christopher M Snyder.
Mol Ther, 2016 Jul 20; 24(8). PMID: 27434584    Free PMC article.
A hypofractionated radiation regimen avoids the lymphopenia associated with neoadjuvant chemoradiation therapy of borderline resectable and locally advanced pancreatic adenocarcinoma.
Todd Crocenzi, Benjamin Cottam, +12 authors, Marka R Crittenden.
J Immunother Cancer, 2016 Aug 18; 4. PMID: 27532020    Free PMC article.
Targeting Antitumor Immune Response for Enhancing the Efficacy of Photodynamic Therapy of Cancer: Recent Advances and Future Perspectives.
Yamin Yang, Yue Hu, Hongjun Wang.
Oxid Med Cell Longev, 2016 Sep 28; 2016. PMID: 27672421    Free PMC article.
Intratumoral injection of a CpG oligonucleotide reverts resistance to PD-1 blockade by expanding multifunctional CD8+ T cells.
Shu Wang, Jose Campos, +5 authors, Cristiana Guiducci.
Proc Natl Acad Sci U S A, 2016 Nov 02; 113(46). PMID: 27799536    Free PMC article.
Highly Cited.
Double-stranded RNA promotes CTL-independent tumor cytolysis mediated by CD11b+Ly6G+ intratumor myeloid cells through the TICAM-1 signaling pathway.
Hiroaki Shime, Misako Matsumoto, Tsukasa Seya.
Cell Death Differ, 2016 Nov 12; 24(3). PMID: 27834952    Free PMC article.
Vectorization in an oncolytic vaccinia virus of an antibody, a Fab and a scFv against programmed cell death -1 (PD-1) allows their intratumoral delivery and an improved tumor-growth inhibition.
Patricia Kleinpeter, Laetitia Fend, +16 authors, Jean-Baptiste Marchand.
Oncoimmunology, 2016 Nov 18; 5(10). PMID: 27853644    Free PMC article.
Intralesional treatment of metastatic melanoma: a review of therapeutic options.
Benjamin Weide, Dario Neri, Giuliano Elia.
Cancer Immunol Immunother, 2017 Jan 13; 66(5). PMID: 28078357    Free PMC article.
Delivering safer immunotherapies for cancer.
Lauren Milling, Yuan Zhang, Darrell J Irvine.
Adv Drug Deliv Rev, 2017 May 27; 114. PMID: 28545888    Free PMC article.
Highly Cited. Review.
Intratumoral infection by CMV may change the tumor environment by directly interacting with tumor-associated macrophages to promote cancer immunity.
Dan A Erkes, Nicole A Wilski, Christopher M Snyder.
Hum Vaccin Immunother, 2017 Jun 13; 13(8). PMID: 28604162    Free PMC article.
Serum IgG4:IgG Ratio Predicts Recurrence of Patients with Hepatocellular Carcinoma after Curative Resection.
Jiong Wu, Xiao-Lu Ma, +12 authors, Wei Guo.
J Cancer, 2017 Jun 24; 8(8). PMID: 28638447    Free PMC article.
A Natural CCR2 Antagonist Relieves Tumor-associated Macrophage-mediated Immunosuppression to Produce a Therapeutic Effect for Liver Cancer.
Wenbo Yao, Qian Ba, +8 authors, Hui Wang.
EBioMedicine, 2017 Jul 30; 22. PMID: 28754304    Free PMC article.
Synthetic immune niches for cancer immunotherapy.
Jorieke Weiden, Jurjen Tel, Carl G Figdor.
Nat Rev Immunol, 2017 Aug 31; 18(3). PMID: 28853444
Manipulation of Innate Immunity for Cancer Therapy in Dogs.
Daniel Regan, Steven Dow.
Vet Sci, 2015 Dec 01; 2(4). PMID: 29061951    Free PMC article.
Cancer cell-expressed B7-H3 regulates the differentiation of tumor-associated macrophages in human colorectal carcinoma.
Yong Mao, Lujun Chen, +4 authors, Jing Sun.
Oncol Lett, 2017 Nov 09; 14(5). PMID: 29113264    Free PMC article.
CD215+ Myeloid Cells Respond to Interleukin 15 Stimulation and Promote Tumor Progression.
Shouheng Lin, Guohua Huang, +21 authors, Peng Li.
Front Immunol, 2017 Dec 20; 8. PMID: 29255466    Free PMC article.
Intratumoral administration of IL2- and TNF-based fusion proteins cures cancer without establishing protective immunity.
Barbara Ziffels, Francesca Pretto, Dario Neri.
Immunotherapy, 2018 Jan 27; 10(3). PMID: 29370721    Free PMC article.
Cancer vaccine based on a combination of an infection-enhanced adenoviral vector and pro-inflammatory allogeneic DCs leads to sustained antigen-specific immune responses in three melanoma models.
Grammatiki Fotaki, Chuan Jin, +5 authors, Magnus Essand.
Oncoimmunology, 2018 Feb 06; 7(3). PMID: 29399398    Free PMC article.
Imaging activated T cells predicts response to cancer vaccines.
Israt S Alam, Aaron T Mayer, +7 authors, Sanjiv S Gambhir.
J Clin Invest, 2018 Mar 30; 128(6). PMID: 29596062    Free PMC article.
Highly Cited.
The revival of CpG oligonucleotide-based cancer immunotherapies.
Tomasz Adamus, Marcin Kortylewski.
Contemp Oncol (Pozn), 2018 Apr 10; 22(1A). PMID: 29628795    Free PMC article.
Induction of necrotic cell death and activation of STING in the tumor microenvironment via cationic silica nanoparticles leading to enhanced antitumor immunity.
Myunggi An, Chunsong Yu, +4 authors, Haipeng Liu.
Nanoscale, 2018 May 09; 10(19). PMID: 29737353    Free PMC article.
Tumor-Specific Inhibition of In Situ Vaccination by Distant Untreated Tumor Sites.
Zachary S Morris, Emily I Guy, +15 authors, Paul M Sondel.
Cancer Immunol Res, 2018 May 12; 6(7). PMID: 29748391    Free PMC article.
Editorial: Local Immunotherapy: A Way to Convert Tumors From "Cold" to "Hot".
Marijo Bilusic, James L Gulley.
J Natl Cancer Inst, 2018 Jul 28; 109(12). PMID: 30053078    Free PMC article.
Drug resistance and new therapies in colorectal cancer.
Kevin Van der Jeught, Han-Chen Xu, +2 authors, Guang Ji.
World J Gastroenterol, 2018 Sep 20; 24(34). PMID: 30228778    Free PMC article.
Highly Cited. Review.
Diprovocims: A New and Exceptionally Potent Class of Toll-like Receptor Agonists.
Matthew D Morin, Ying Wang, +7 authors, Dale L Boger.
J Am Chem Soc, 2018 Oct 03; 140(43). PMID: 30272974    Free PMC article.
Dual CCR5/CCR2 targeting: opportunities for the cure of complex disorders.
Laura Fantuzzi, Maria Tagliamonte, Maria Cristina Gauzzi, Lucia Lopalco.
Cell Mol Life Sci, 2019 Aug 05; 76(24). PMID: 31377844    Free PMC article.
An inhalable nanoparticulate STING agonist synergizes with radiotherapy to confer long-term control of lung metastases.
Yang Liu, William N Crowe, +4 authors, Dawen Zhao.
Nat Commun, 2019 Nov 11; 10(1). PMID: 31704921    Free PMC article.
Microparticle Depots for Controlled and Sustained Release of Endosomolytic Nanoparticles.
Kyle M Garland, Sema Sevimli, +3 authors, John T Wilson.
Cell Mol Bioeng, 2019 Nov 14; 12(5). PMID: 31719925    Free PMC article.
Modeling multi-needle injection into solid tumor.
Vladimir Subbotin, Gennady Fiksel.
Am J Cancer Res, 2019 Nov 14; 9(10). PMID: 31720083    Free PMC article.
Beneficial modulation of the tumor microenvironment and generation of anti-tumor responses by TLR9 agonist lefitolimod alone and in combination with checkpoint inhibitors.
Kerstin Kapp, Barbara Volz, +3 authors, Manuel Schmidt.
Oncoimmunology, 2019 Nov 20; 8(12). PMID: 31741757    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.
A Novel C Type CpG Oligodeoxynucleotide Exhibits Immunostimulatory Activity In Vitro and Enhances Antitumor Effect In Vivo.
Tete Li, Jing Wu, +10 authors, Jingtao Chen.
Front Pharmacol, 2020 Mar 03; 11. PMID: 32116691    Free PMC article.
Engineering Targeting Materials for Therapeutic Cancer Vaccines.
Priscilla S Briquez, Sylvie Hauert, +4 authors, Jeffrey A Hubbell.
Front Bioeng Biotechnol, 2020 Mar 03; 8. PMID: 32117911    Free PMC article.
In vitro evolution of enhanced RNA replicons for immunotherapy.
Yingzhong Li, Brian Teague, +6 authors, Ron Weiss.
Sci Rep, 2019 May 08; 9(1). PMID: 31061426    Free PMC article.
Starting the fight in the tumor: expert recommendations for the development of human intratumoral immunotherapy (HIT-IT).
A Marabelle, R Andtbacka, +21 authors, J Brody.
Ann Oncol, 2018 Oct 09; 29(11). PMID: 30295695    Free PMC article.
The Emerging World of TCR-T Cell Trials Against Cancer: A Systematic Review.
Jianxiang Zhang, Lingyu Wang.
Technol Cancer Res Treat, 2019 Feb 26; 18. PMID: 30798772    Free PMC article.
Highly Cited. Systematic Review.
Bispecific CD3-HAC carried by E1A-engineered mesenchymal stromal cells against metastatic breast cancer by blocking PD-L1 and activating T cells.
Yuanyuan Yang, Xiaolong Zhang, +11 authors, Dongsheng Xiong.
J Hematol Oncol, 2019 Apr 27; 12(1). PMID: 31023384    Free PMC article.
Immunotherapeutic effects of intratumoral nanoplexed poly I:C.
M Angela Aznar, Lourdes Planelles, +13 authors, Ignacio Melero.
J Immunother Cancer, 2019 May 03; 7(1). PMID: 31046839    Free PMC article.
Combining alpha radiation-based brachytherapy with immunomodulators promotes complete tumor regression in mice via tumor-specific long-term immune response.
Vered Domankevich, Adi Cohen, +6 authors, Yona Keisari.
Cancer Immunol Immunother, 2019 Oct 23; 68(12). PMID: 31637474    Free PMC article.
Potent STING activation stimulates immunogenic cell death to enhance antitumor immunity in neuroblastoma.
Lihong Wang-Bishop, Mohamed Wehbe, +7 authors, John T Wilson.
J Immunother Cancer, 2020 Mar 15; 8(1). PMID: 32169869    Free PMC article.
Deciphering the Biological Activities of Dunaliella sp. Aqueous Extract from Stressed Conditions on Breast Cancer: from in Vitro to in Vivo Investigations.
Fatma Elleuch, Patrick Baril, +4 authors, Chantal Pichon.
Int J Mol Sci, 2020 Mar 07; 21(5). PMID: 32138292    Free PMC article.
Pickering emulsions with ethiodized oil and nanoparticles for slow release of intratumoral anti-CTLA4 immune checkpoint antibodies.
Lambros Tselikas, Thierry de Baere, +9 authors, Aurélien Marabelle.
J Immunother Cancer, 2020 Jun 24; 8(1). PMID: 32571995    Free PMC article.
Nanoparticle delivery of immunostimulatory oligonucleotides enhances response to checkpoint inhibitor therapeutics.
Colin G Buss, Sangeeta N Bhatia.
Proc Natl Acad Sci U S A, 2020 Jun 05; 117(24). PMID: 32493746    Free PMC article.
Targeting Prostate Cancer Using Intratumoral Cytotopically Modified Interleukin-15 Immunotherapy in a Syngeneic Murine Model.
Efthymia Papaevangelou, Dorota Smolarek, +2 authors, Christine Galustian.
Immunotargets Ther, 2020 Aug 18; 9. PMID: 32802803    Free PMC article.
In situ Vaccine Plus Checkpoint Blockade Induces Memory Humoral Response.
Claire C Baniel, Clinton M Heinze, +13 authors, Zachary S Morris.
Front Immunol, 2020 Aug 28; 11. PMID: 32849544    Free PMC article.
Design of an Interferon-Resistant Oncolytic HSV-1 Incorporating Redundant Safety Modalities for Improved Tolerability.
Edward M Kennedy, Terry Farkaly, +16 authors, Lorena Lerner.
Mol Ther Oncolytics, 2020 Sep 22; 18. PMID: 32953982    Free PMC article.
Enhancing cancer immunotherapy with nanomedicine.
Darrell J Irvine, Eric L Dane.
Nat Rev Immunol, 2020 Feb 02; 20(5). PMID: 32005979    Free PMC article.
Revisiting Immunotherapy: A Focus on Prostate Cancer.
Ha-Ram Cha, Joo Hyoung Lee, Selvarangan Ponnazhagan.
Cancer Res, 2020 Feb 19; 80(8). PMID: 32066566    Free PMC article.
Intratumoral injection reduces toxicity and antibody-mediated neutralization of immunocytokine in a mouse melanoma model.
Claire C Baniel, Elizabeth G Sumiec, +8 authors, Paul M Sondel.
J Immunother Cancer, 2020 Oct 30; 8(2). PMID: 33115944    Free PMC article.
Ex vivo Live Cell Imaging of Nanoparticle-Cell Interactions in the Mouse Lung.
Fernanda Ramos-Gomes, Nathalia Ferreira, +2 authors, M Andrea Markus.
Front Bioeng Biotechnol, 2020 Nov 17; 8. PMID: 33195152    Free PMC article.
Click Chemistry as a Tool for Cell Engineering and Drug Delivery.
Yukiya Takayama, Kosuke Kusamori, Makiya Nishikawa.
Molecules, 2019 Jan 10; 24(1). PMID: 30621193    Free PMC article.
Advances in engineering local drug delivery systems for cancer immunotherapy.
Peter Abdou, Zejun Wang, +4 authors, Zhen Gu.
Wiley Interdiscip Rev Nanomed Nanobiotechnol, 2020 Apr 08; 12(5). PMID: 32255276    Free PMC article.
Modulation of intratumoural myeloid cells, the hallmark of the anti-tumour efficacy induced by a triple combination: tumour-associated peptide, TLR-3 ligand and α-PD-1.
Sara Zalba, Virginia Belsúe, +5 authors, María J Garrido.
Br J Cancer, 2021 Feb 04; 124(7). PMID: 33531689    Free PMC article.
Development and External Validation of a Novel Immune Checkpoint-Related Gene Signature for Prediction of Overall Survival in Hepatocellular Carcinoma.
Enfa Zhao, Shimin Chen, Ying Dang.
Front Mol Biosci, 2021 Feb 09; 7. PMID: 33553243    Free PMC article.
In Situ Crosslinked Hydrogel Depot for Sustained Antibody Release Improves Immune Checkpoint Blockade Cancer Immunotherapy.
Jihoon Kim, David M Francis, Susan N Thomas.
Nanomaterials (Basel), 2021 Mar 07; 11(2). PMID: 33673289    Free PMC article.
PD-1 blockade synergizes with intratumoral vaccination of a therapeutic HPV protein vaccine and elicits regression of tumor in a preclinical model.
Shiwen Peng, Marietta Tan, +7 authors, T-C Wu.
Cancer Immunol Immunother, 2020 Oct 28; 70(4). PMID: 33108473    Free PMC article.
Immunotherapy Goes Local: The Central Role of Lymph Nodes in Driving Tumor Infiltration and Efficacy.
Kim M van Pul, Marieke F Fransen, Rieneke van de Ven, Tanja D de Gruijl.
Front Immunol, 2021 Mar 19; 12. PMID: 33732264    Free PMC article.
Identification and external validation of a prognostic signature associated with DNA repair genes in gastric cancer.
Shimin Chen, Wenbo Liu, Yu Huang.
Sci Rep, 2021 Apr 01; 11(1). PMID: 33785812    Free PMC article.
Genomic profile and immune contexture in colorectal cancer-relevance for prognosis and immunotherapy.
Sandra Meršaková, Zora Lasabová, +7 authors, Peter Mikolajčík.
Clin Exp Med, 2020 Jul 29; 21(2). PMID: 32720224
A blocking antibody against canine CSF-1R maturated by limited CDR mutagenesis.
Breno C B Beirão, Teresa P Raposo, +4 authors, David J Argyle.
Antib Ther, 2021 May 04; 3(3). PMID: 33937625    Free PMC article.
Low-Temperature Photothermal Therapy: Strategies and Applications.
Xiulin Yi, Qiu-Yi Duan, Fu-Gen Wu.
Research (Wash D C), 2021 May 28; 2021. PMID: 34041494    Free PMC article.
ABC triblock bottlebrush copolymer-based injectable hydrogels: design, synthesis, and application to expanding the therapeutic index of cancer immunochemotherapy.
Farrukh Vohidov, Lauren E Milling, +5 authors, Jeremiah A Johnson.
Chem Sci, 2021 Jun 08; 11(23). PMID: 34094088    Free PMC article.
Low-Dose Radiation Potentiates the Propagation of Anti-Tumor Immunity against Melanoma Tumor in the Brain after In Situ Vaccination at a Tumor outside the Brain.
Paul A Clark, Raghava N Sriramaneni, +17 authors, Zachary S Morris.
Radiat Res, 2021 Apr 08; 195(6). PMID: 33826741    Free PMC article.
Implantable optical fibers for immunotherapeutics delivery and tumor impedance measurement.
Ai Lin Chin, Shan Jiang, +4 authors, Rong Tong.
Nat Commun, 2021 Aug 28; 12(1). PMID: 34446702    Free PMC article.
Multifunctional oncolytic nanoparticles deliver self-replicating IL-12 RNA to eliminate established tumors and prime systemic immunity.
Yingzhong Li, Zhijun Su, +7 authors, Ron Weiss.
Nat Cancer, 2021 Aug 28; 1(9). PMID: 34447945    Free PMC article.
Intratumoral injection of TLR9 agonist promotes an immunopermissive microenvironment transition and causes cooperative antitumor activity in combination with anti-PD1 in pancreatic cancer.
Carmine Carbone, Geny Piro, +12 authors, Giampaolo Tortora.
J Immunother Cancer, 2021 Sep 05; 9(9). PMID: 34479922    Free PMC article.
Intratumoral co-injection of the poly I:C-derivative BO-112 and a STING agonist synergize to achieve local and distant anti-tumor efficacy.
Maite Alvarez, Carmen Molina, +14 authors, Ignacio Melero.
J Immunother Cancer, 2021 Nov 27; 9(11). PMID: 34824158    Free PMC article.
Intratumourally injected alum-tethered cytokines elicit potent and safer local and systemic anticancer immunity.
Yash Agarwal, Lauren E Milling, +11 authors, K Dane Wittrup.
Nat Biomed Eng, 2022 Jan 12; 6(2). PMID: 35013574
Interleukin-12 as an in situ cancer vaccine component: a review.
Emily M Cheng, Noah W Tsarovsky, Paul M Sondel, Alexander L Rakhmilevich.
Cancer Immunol Immunother, 2022 Jan 14;. PMID: 35024897
Novel Cellular Therapies for Hepatocellular Carcinoma.
Harriet Roddy, Tim Meyer, Claire Roddie.
Cancers (Basel), 2022 Feb 16; 14(3). PMID: 35158772    Free PMC article.
Nanoparticle delivery improves the pharmacokinetic properties of cyclic dinucleotide STING agonists to open a therapeutic window for intravenous administration.
Mohamed Wehbe, Lihong Wang-Bishop, +7 authors, John T Wilson.
J Control Release, 2020 Nov 16; 330. PMID: 33189789    Free PMC article.