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DOI: 10.1055/s-0040-1718389
Image-Guided Intratumoral Delivery of Immunotherapeutics in Gastrointestinal Malignancies
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Abstract
Intratumoral (IT) administration of immunotherapy is a promising treatment strategy under clinical development for gastrointestinal malignancies. Due to its targeted nature, IT immunotherapies can generate regional proinflammatory microenvironments that result in the focal recruitment of tumor-specific immune cells. Precision targeting of tumors via IT immunotherapy injection theoretically produces a more robust immune response to the treated tumor itself and to distant metastatic tumors that share tumor-specific antigens with those of the treated tumor, while also minimizing the priming of the adaptive immune system to nonspecific antigens. Diverse arrays of IT immunotherapeutic agents including but not limited to lyophilized bacteria, viral vectors, cellular-based agents, molecules, and peptides, both as monotherapies and in combination with systemic immunotherapies, are in various stages of preclinical and clinical development. In this review, we summarize the current state of the art for IT immunotherapy and highlight potential future directions and their relevance to image-guided interventionalists.
Publication History
Received: 05 May 2020
Accepted: 30 July 2020
Article published online:
12 January 2021
© 2021. Thieme. All rights reserved.
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References
- 1 Marabelle A, Tselikas L, de Baere T, Houot R. Intratumoral immunotherapy: using the tumor as the remedy. Ann Oncol 2017; 28 (12) (Suppl. 12) xii33-xii43
- 2 Murthy V, Minehart J, Sterman DH. Local immunotherapy of cancer: innovative approaches to harnessing tumor-specific immune responses. J Natl Cancer Inst 2017;109(12):
- 3 Singh M, Overwijk WW. Intratumoral immunotherapy for melanoma. Cancer Immunol Immunother 2015; 64 (07) 911-921
- 4 Bilusic M, Gulley JL. Editorial: local immunotherapy: a way to convert tumors from “cold” to “hot”. J Natl Cancer Inst 2017;109(12):
- 5 Sharma P, Allison JP. The future of immune checkpoint therapy. Science 2015; 348 (6230): 56-61
- 6 Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med 2017; 377 (25) 2500-2501
- 7 van Rooij N, van Buuren MM, Philips D. et al. Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J Clin Oncol 2013; 31 (32) e439-e442
- 8 Singh M, Khong H, Dai Z. et al. Effective innate and adaptive antimelanoma immunity through localized TLR7/8 activation. J Immunol 2014; 193 (09) 4722-4731
- 9 Stewart IV JH, Levine EA. Role of bacillus Calmette-Guérin in the treatment of advanced melanoma. Expert Rev Anticancer Ther 2011; 11 (11) 1671-1676
- 10 Kidner TB, Morton DL, Lee DJ. et al. Combined intralesional bacille Calmette-Guérin (BCG) and topical imiquimod for in-transit melanoma. J Immunother 2012; 35 (09) 716-720
- 11 Lonsdorf AS, Kuekrek H, Stern BV, Boehm BO, Lehmann PV, Tary-Lehmann M. Intratumor CpG-oligodeoxynucleotide injection induces protective antitumor T cell immunity. J Immunol 2003; 171 (08) 3941-3946
- 12 Houot R, Levy R. T-cell modulation combined with intratumoral CpG cures lymphoma in a mouse model without the need for chemotherapy. Blood 2009; 113 (15) 3546-3552
- 13 Temizoz B, Kuroda E, Ohata K. et al. TLR9 and STING agonists synergistically induce innate and adaptive type-II IFN. Eur J Immunol 2015; 45 (04) 1159-1169
- 14 Corrales L, McWhirter SM, Dubensky Jr TW, Gajewski TF. The host STING pathway at the interface of cancer and immunity. J Clin Invest 2016; 126 (07) 2404-2411
- 15 Au BC, Lee CJ, Lopez-Perez O. et al. Direct lymph node vaccination of lentivector/prostate-specific antigen is safe and generates tissue-specific responses in rhesus macaques. Biomedicines 2016; 4 (01) E6
- 16 Spaner DE, Astsaturov I, Vogel T. et al. Enhanced viral and tumor immunity with intranodal injection of canary pox viruses expressing the melanoma antigen, gp100. Cancer 2006; 106 (04) 890-899
- 17 Larocca C, Schlom J. Viral vector-based therapeutic cancer vaccines. Cancer J 2011; 17 (05) 359-371
- 18 Wheeler LA, Manzanera AG, Bell SD. et al. Phase II multicenter study of gene-mediated cytotoxic immunotherapy as adjuvant to surgical resection for newly diagnosed malignant glioma. Neuro-oncol 2016; 18 (08) 1137-1145
- 19 Satoh T, Teh BS, Timme TL. et al. Enhanced systemic T-cell activation after in situ gene therapy with radiotherapy in prostate cancer patients. Int J Radiat Oncol Biol Phys 2004; 59 (02) 562-571
- 20 Aguilar LK, Shirley LA, Chung VM. et al. Gene-mediated cytotoxic immunotherapy as adjuvant to surgery or chemoradiation for pancreatic adenocarcinoma. Cancer Immunol Immunother 2015; 64 (06) 727-736
- 21 Weide B, Eigentler TK, Pflugfelder A. et al. Survival after intratumoral interleukin-2 treatment of 72 melanoma patients and response upon the first chemotherapy during follow-up. Cancer Immunol Immunother 2011; 60 (04) 487-493
- 22 Yang RK, Kalogriopoulos NA, Rakhmilevich AL. et al. Intratumoral hu14.18-IL-2 (IC) induces local and systemic antitumor effects that involve both activated T and NK cells as well as enhanced IC retention. J Immunol 2012; 189 (05) 2656-2664
- 23 Yasuda K, Nirei T, Tsuno NH, Nagawa H, Kitayama J. Intratumoral injection of interleukin-2 augments the local and abscopal effects of radiotherapy in murine rectal cancer. Cancer Sci 2011; 102 (07) 1257-1263
- 24 Ray A, Williams MA, Meek SM. et al. A phase I study of intratumoral ipilimumab and interleukin-2 in patients with advanced melanoma. Oncotarget 2016; 7 (39) 64390-64399
- 25 Vom Berg J, Vrohlings M, Haller S. et al. Intratumoral IL-12 combined with CTLA-4 blockade elicits T cell-mediated glioma rejection. J Exp Med 2013; 210 (13) 2803-2811
- 26 Ugen KE, Kutzler MA, Marrero B. et al. Regression of subcutaneous B16 melanoma tumors after intratumoral delivery of an IL-15-expressing plasmid followed by in vivo electroporation. Cancer Gene Ther 2006; 13 (10) 969-974
- 27 Kirk CJ, Hartigan-O'Connor D, Mulé JJ. The dynamics of the T-cell antitumor response: chemokine-secreting dendritic cells can prime tumor-reactive T cells extranodally. Cancer Res 2001; 61 (24) 8794-8802
- 28 Yoshida R, Nagira M, Kitaura M, Imagawa N, Imai T, Yoshie O. Secondary lymphoid-tissue chemokine is a functional ligand for the CC chemokine receptor CCR7. J Biol Chem 1998; 273 (12) 7118-7122
- 29 Thompson JF, Agarwala SS, Smithers BM. et al. Phase 2 study of intralesional PV-10 in refractory metastatic melanoma. Ann Surg Oncol 2015; 22 (07) 2135-2142
- 30 Foote M, Read T, Thomas J, Wagels M, Burmeister B, Smithers BM. Results of a phase II, open-label, non-comparative study of intralesional PV-10 followed by radiotherapy for the treatment of in-transit or metastatic melanoma. J Surg Oncol 2017; 115 (07) 891-897
- 31 Predina JD, Keating J, Venegas O, Nims S, Singhal S. Neoadjuvant intratumoral immuno-gene therapy for non-small cell lung cancer. Discov Med 2016; 21 (116) 275-281
- 32 Quatromoni JG, Predina JD, Bhojnagarwala P. et al. Adenoviral-based immunotherapy provides local disease control in an orthotopic murine model of esophageal cancer. J Immunother 2014; 37 (05) 283-292
- 33 Predina JD, Kapoor V, Judy BF. et al. Cytoreduction surgery reduces systemic myeloid suppressor cell populations and restores intratumoral immunotherapy effectiveness. J Hematol Oncol 2012; 5: 34
- 34 Predina JD, Judy B, Aliperti LA. et al. Neoadjuvant in situ gene-mediated cytotoxic immunotherapy improves postoperative outcomes in novel syngeneic esophageal carcinoma models. Cancer Gene Ther 2011; 18 (12) 871-883
- 35 Andtbacka RHI. et al. OPTiM: a randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment (tx) of unresected stage IIIB/C and IV melanoma. J Clin Oncol 2013; 31 (18) LBA9008
- 36 Andtbacka RH, Kaufman HL, Collichio F. et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol 2015; 33 (25) 2780-2788
- 37 Andtbacka RH, Ross M, Puzanov I. et al. Patterns of clinical response with talimogene laherparepvec (T-VEC) in patients with melanoma treated in the OPTiM phase III clinical trial. Ann Surg Oncol 2016; 23 (13) 4169-4177
- 38 Harrington KJ, Andtbacka RH, Collichio F. et al. Efficacy and safety of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in patients with stage IIIB/C and IVM1a melanoma: subanalysis of the Phase III OPTiM trial. OncoTargets Ther 2016; 9: 7081-7093
- 39 Puzanov I, Milhem MM, Minor D. et al. Talimogene laherparepvec in combination with ipilimumab in previously untreated, unresectable stage IIIB-IV melanoma. J Clin Oncol 2016; 34 (22) 2619-2626
- 40 Palucka K, Banchereau J. Dendritic-cell-based therapeutic cancer vaccines. Immunity 2013; 39 (01) 38-48
- 41 Rozera C, Cappellini GA, D'Agostino G. et al. Intratumoral injection of IFN-alpha dendritic cells after dacarbazine activates anti-tumor immunity: results from a phase I trial in advanced melanoma. J Transl Med 2015; 13: 139
- 42 Teitz-Tennenbaum S, Li Q, Rynkiewicz S. et al. Radiotherapy potentiates the therapeutic efficacy of intratumoral dendritic cell administration. Cancer Res 2003; 63 (23) 8466-8475
- 43 Finkelstein SE, Iclozan C, Bui MM. et al. Combination of external beam radiotherapy (EBRT) with intratumoral injection of dendritic cells as neo-adjuvant treatment of high-risk soft tissue sarcoma patients. Int J Radiat Oncol Biol Phys 2012; 82 (02) 924-932
- 44 Ott PA, Hodi FS, Kaufman HL, Wigginton JM, Wolchok JD. Combination immunotherapy: a road map. J Immunother Cancer 2017; 5: 16
- 45 van den Boorn JG, Hartmann G. Turning tumors into vaccines: co-opting the innate immune system. Immunity 2013; 39 (01) 27-37
- 46 Bast Jr RC, Zbar B, Borsos T, Rapp HJ. BCG and cancer. N Engl J Med 1974; 290 (26) 1458-1469
- 47 Fox BA, Sanders KL, Chen S, Bzik DJ. Targeting tumors with nonreplicating Toxoplasma gondii uracil auxotroph vaccines. Trends Parasitol 2013; 29 (09) 431-437
- 48 Baird JR, Byrne KT, Lizotte PH. et al. Immune-mediated regression of established B16F10 melanoma by intratumoral injection of attenuated Toxoplasma gondii protects against rechallenge. J Immunol 2013; 190 (01) 469-478
- 49 Andarini S, Kikuchi T, Nukiwa M. et al. Adenovirus vector-mediated in vivo gene transfer of OX40 ligand to tumor cells enhances antitumor immunity of tumor-bearing hosts. Cancer Res 2004; 64 (09) 3281-3287
- 50 Mastrangelo MJ, Maguire Jr HC, Eisenlohr LC. et al. Intratumoral recombinant GM-CSF-encoding virus as gene therapy in patients with cutaneous melanoma. Cancer Gene Ther 1999; 6 (05) 409-422
- 51 Senzer NN, Kaufman HL, Amatruda T. et al. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second-generation oncolytic herpesvirus in patients with unresectable metastatic melanoma. J Clin Oncol 2009; 27 (34) 5763-5771
- 52 Amos SM, Pegram HJ, Westwood JA. et al. Adoptive immunotherapy combined with intratumoral TLR agonist delivery eradicates established melanoma in mice. Cancer Immunol Immunother 2011; 60 (05) 671-683
- 53 Lou Y, Liu C, Lizée G. et al. Antitumor activity mediated by CpG: the route of administration is critical. J Immunother 2011; 34 (03) 279-288
- 54 Nierkens S, den Brok MH, Roelofsen T. et al. Route of administration of the TLR9 agonist CpG critically determines the efficacy of cancer immunotherapy in mice. PLoS One 2009; 4 (12) e8368
- 55 Nierkens S, den Brok MH, Garcia Z. et al. Immune adjuvant efficacy of CpG oligonucleotide in cancer treatment is founded specifically upon TLR9 function in plasmacytoid dendritic cells. Cancer Res 2011; 71 (20) 6428-6437
- 56 Stone GW, Barzee S, Snarsky V. et al. Nanoparticle-delivered multimeric soluble CD40L DNA combined with Toll-Like Receptor agonists as a treatment for melanoma. PLoS One 2009; 4 (10) e7334
- 57 Davis MB, Vasquez-Dunddel D, Fu J, Albesiano E, Pardoll D, Kim YJ. Intratumoral administration of TLR4 agonist absorbed into a cellular vector improves antitumor responses. Clin Cancer Res 2011; 17 (12) 3984-3992
- 58 Oldford SA, Haidl ID, Howatt MA, Leiva CA, Johnston B, Marshall JS. A critical role for mast cells and mast cell-derived IL-6 in TLR2-mediated inhibition of tumor growth. J Immunol 2010; 185 (11) 7067-7076
- 59 Quetglas JI, Dubrot J, Bezunartea J. et al. Immunotherapeutic synergy between anti-CD137 mAb and intratumoral administration of a cytopathic Semliki Forest virus encoding IL-12. Mol Ther 2012; 20 (09) 1664-1675
- 60 Woo SR, Corrales L, Gajewski TF. The STING pathway and the T cell-inflamed tumor microenvironment. Trends Immunol 2015; 36 (04) 250-256
- 61 Ohkuri T, Ghosh A, Kosaka A. et al. STING contributes to antiglioma immunity via triggering type I IFN signals in the tumor microenvironment. Cancer Immunol Res 2014; 2 (12) 1199-1208
- 62 Carpentier A, Metellus P, Ursu R. et al. Intracerebral administration of CpG oligonucleotide for patients with recurrent glioblastoma: a phase II study. Neuro-oncol 2010; 12 (04) 401-408
- 63 Salazar AM, Erlich RB, Mark A, Bhardwaj N, Herberman RB. Therapeutic in situ autovaccination against solid cancers with intratumoral poly-ICLC: case report, hypothesis, and clinical trial. Cancer Immunol Res 2014; 2 (08) 720-724
- 64 Søndergaard H, Galsgaard ED, Bartholomaeussen M, Straten PT, Odum N, Skak K. Intratumoral interleukin-21 increases antitumor immunity, tumor-infiltrating CD8+ T-cell density and activity, and enlarges draining lymph nodes. J Immunother 2010; 33 (03) 236-249
- 65 Cha E, Daud A. Plasmid IL-12 electroporation in melanoma. Hum Vaccin Immunother 2012; 8 (11) 1734-1738
- 66 Chinnasamy D, Yu Z, Kerkar SP. et al. Local delivery of interleukin-12 using T cells targeting VEGF receptor-2 eradicates multiple vascularized tumors in mice. Clin Cancer Res 2012; 18 (06) 1672-1683
- 67 Pan J, Zhang M, Wang J. et al. Intratumoral injection of interferon-gamma gene-modified dendritic cells elicits potent antitumor effects: effective induction of tumor-specific CD8+ CTL response. J Cancer Res Clin Oncol 2005; 131 (07) 468-478
- 68 Van der Jeught K, Joe PT, Bialkowski L. et al. Intratumoral administration of mRNA encoding a fusokine consisting of IFN-β and the ectodomain of the TGF-β receptor II potentiates antitumor immunity. Oncotarget 2014; 5 (20) 10100-10113
- 69 Heinzerling L, Burg G, Dummer R. et al. Intratumoral injection of DNA encoding human interleukin 12 into patients with metastatic melanoma: clinical efficacy. Hum Gene Ther 2005; 16 (01) 35-48
- 70 Weide B, Eigentler TK, Pflugfelder A. et al. Intralesional treatment of stage III metastatic melanoma patients with L19-IL2 results in sustained clinical and systemic immunologic responses. Cancer Immunol Res 2014; 2 (07) 668-678
- 71 Okano S, Kondoh H, Toshima T. et al. Fas-deficient fully allogeneic dendritic cells administered via an intratumoral injection route show efficient antitumor effects in murine models. Fukuoka Igaku Zasshi 2013; 104 (01) 15-26
- 72 Liu C, Lou Y, Lizée G. et al. Plasmacytoid dendritic cells induce NK cell-dependent, tumor antigen-specific T cell cross-priming and tumor regression in mice. J Clin Invest 2008; 118 (03) 1165-1175
- 73 Fujimura T, Nakagawa S, Ohtani T, Ito Y, Aiba S. Inhibitory effect of the polyinosinic-polycytidylic acid/cationic liposome on the progression of murine B16F10 melanoma. Eur J Immunol 2006; 36 (12) 3371-3380
- 74 Shevtsov MA, Kim AV, Samochernych KA. et al. Pilot study of intratumoral injection of recombinant heat shock protein 70 in the treatment of malignant brain tumors in children. OncoTargets Ther 2014; 7: 1071-1081
- 75 Galili U. Conversion of tumors into autologous vaccines by intratumoral injection of α-Gal glycolipids that induce anti-Gal/α-Gal epitope interaction. Clin Dev Immunol 2011; 2011: 134020
- 76 Doukas J, Rolland A. Mechanisms of action underlying the immunotherapeutic activity of Allovectin in advanced melanoma. Cancer Gene Ther 2012; 19 (12) 811-817
- 77 Sandin LC, Eriksson F, Ellmark P, Loskog AS, Tötterman TH, Mangsbo SM. Local CTLA4 blockade effectively restrains experimental pancreatic adenocarcinoma growth in vivo. OncoImmunology 2014; 3 (01) e27614
- 78 Coley WB. II. Contribution to the knowledge of sarcoma. Ann Surg 1891; 14 (03) 199-220
- 79 Chou R, Selph S, Buckley DI. et al. Intravesical therapy for the treatment of nonmuscle invasive bladder cancer: a systematic review and meta-analysis. J Urol 2017; 197 (05) 1189-1199
- 80 Celikoglu F, Celikoglu SI, York AM, Goldberg EP. Intratumoral administration of cisplatin through a bronchoscope followed by irradiation for treatment of inoperable non-small cell obstructive lung cancer. Lung Cancer 2006; 51 (02) 225-236
- 81 Duvillard C, Romanet P, Cosmidis A, Beaudouin N, Chauffert B. Phase 2 study of intratumoral cisplatin and epinephrine treatment for locally recurrent head and neck tumors. Ann Otol Rhinol Laryngol 2004; 113 (3 Pt 1): 229-233
- 82 Nierenberg D, Harbaugh R, Maurer LH. et al. Continuous intratumoral infusion of methotrexate for recurrent glioblastoma: a pilot study. Neurosurgery 1991; 28 (05) 752-761
- 83 Mariani G, Cei A, Collecchi P. et al. Tumor targeting in vivo and metabolic fate of 5-[iodine-125]iodo-2′-deoxyuridine following intratumoral injection in patients with colorectal cancer. J Nucl Med 1993; 34 (07) 1175-1183
- 84 Gulley JL, Heery CR, Madan RA. et al. Phase I study of intraprostatic vaccine administration in men with locally recurrent or progressive prostate cancer. Cancer Immunol Immunother 2013; 62 (09) 1521-1531
- 85 Kim YH, Gratzinger D, Harrison C. et al. In situ vaccination against mycosis fungoides by intratumoral injection of a TLR9 agonist combined with radiation: a phase 1/2 study. Blood 2012; 119 (02) 355-363
- 86 Brody JD, Ai WZ, Czerwinski DK. et al. In situ vaccination with a TLR9 agonist induces systemic lymphoma regression: a phase I/II study. J Clin Oncol 2010; 28 (28) 4324-4332
- 87 Zamarin D, Holmgaard RB, Subudhi SK. et al. Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci Transl Med 2014; 6 (226) 226ra32
- 88 Weide B, Derhovanessian E, Pflugfelder A. et al. High response rate after intratumoral treatment with interleukin-2: results from a phase 2 study in 51 patients with metastasized melanoma. Cancer 2010; 116 (17) 4139-4146
- 89 Weide B, Eigentler TK, Elia G, Neri D, Garbe C. Limited efficacy of intratumoral IL-2 applied to large melanoma metastases. Cancer Immunol Immunother 2014; 63 (11) 1231-1232
- 90 Rao D, Parakrama R, Augustine T, Liu Q, Goel S, Maitra R. Immunotherapeutic advances in gastrointestinal malignancies. NPJ Precis Oncol 2019; 3: 4
- 91 Galon J, Mlecnik B, Bindea G. et al. Towards the introduction of the 'Immunoscore' in the classification of malignant tumours. J Pathol 2014; 232 (02) 199-209
- 92 Le DT, Uram JN, Wang H. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015; 372 (26) 2509-2520
- 93 El-Khoueiry AB, Sangro B, Yau T. et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 2017; 389 (10088): 2492-2502
- 94 Bang YJ, Ruiz EY, Van Cutsem E. et al. Phase III, randomised trial of avelumab versus physician's choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300. Ann Oncol 2018; 29 (10) 2052-2060
- 95 McGranahan N, Furness AJ, Rosenthal R. et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 2016; 351 (6280): 1463-1469
- 96 Govindan R. Cancer. Attack of the clones. Science 2014; 346 (6206): 169-170
- 97 Rao B, Gao Y, Zhou Q. et al. A recombinant adenovirus vector encoding the light chain of human coagulation factor VII and IgG1 Fc fragment to targeting tissue factor for colorectal cancer immunotherapy in the mouse model. J Cancer Res Clin Oncol 2013; 139 (06) 1015-1023
- 98 Pan WY, Lo CH, Chen CC. et al. Cancer immunotherapy using a membrane-bound interleukin-12 with B7-1 transmembrane and cytoplasmic domains. Mol Ther 2012; 20 (05) 927-937
- 99 Narvaiza I, Mazzolini G, Barajas M. et al. Intratumoral coinjection of two adenoviruses, one encoding the chemokine IFN-gamma-inducible protein-10 and another encoding IL-12, results in marked antitumoral synergy. J Immunol 2000; 164 (06) 3112-3122
- 100 Kudo-Saito C, Schlom J, Hodge JW. Induction of an antigen cascade by diversified subcutaneous/intratumoral vaccination is associated with antitumor responses. Clin Cancer Res 2005; 11 (06) 2416-2426
- 101 Endo T, Toda M, Watanabe M. et al. In situ cancer vaccination with a replication-conditional HSV for the treatment of liver metastasis of colon cancer. Cancer Gene Ther 2002; 9 (02) 142-148
- 102 Ohkuri T, Kosaka A, Ishibashi K. et al. Intratumoral administration of cGAMP transiently accumulates potent macrophages for anti-tumor immunity at a mouse tumor site. Cancer Immunol Immunother 2017; 66 (06) 705-716
- 103 Nobuoka D, Yoshikawa T, Takahashi M. et al. Intratumoral peptide injection enhances tumor cell antigenicity recognized by cytotoxic T lymphocytes: a potential option for improvement in antigen-specific cancer immunotherapy. Cancer Immunol Immunother 2013; 62 (04) 639-652
- 104 Mendiratta SK, Quezada A, Matar M. et al. Intratumoral delivery of IL-12 gene by polyvinyl polymeric vector system to murine renal and colon carcinoma results in potent antitumor immunity. Gene Ther 1999; 6 (05) 833-839
- 105 Takeda T, Wakasugi T, Katsumoto Y. et al. Effect of intratumoral injection of the mixture of OK-432 and fibrinogen (OK/fbg) on gastric cancer [in Japanese]. Gan To Kagaku Ryoho 1992; 19 (10) 1458-1460
- 106 Ogawara T, Sakai K, Sekikawa T, Kouno K, Matsumoto Y. Effect of endoscopic local injection of OK-432 on regional lymph nodes in gastric cancer patients [in Japanese]. Gan To Kagaku Ryoho 1992; 19 (10) 1601-1604
- 107 Yamane T, Sagara Y, Suzuki G. et al. Endoscopic preoperative intralesional injection of OK-432 in early gastric cancer [in Japanese]. Gan To Kagaku Ryoho 1984; 11 (04) 930-934
- 108 Inbe A, Sumii K, Haruma K. et al. Endoscopic administration of OK-432 in gastric cancer [in Japanese]. Gan To Kagaku Ryoho 1986; 13 (03) (, Pt 1): 514-519
- 109 Kobayashi G. Augmentation of cytotoxicity of regional lymph node lymphocytes of gastric cancer after intratumoral injection of OK-432 [in Japanese]. Nippon Geka Gakkai Zasshi 1990; 91 (01) 68-76
- 110 Melero I, Duarte M, Ruiz J. et al. Intratumoral injection of bone-marrow derived dendritic cells engineered to produce interleukin-12 induces complete regression of established murine transplantable colon adenocarcinomas. Gene Ther 1999; 6 (10) 1779-1784
- 111 Kikuchi T, Miyazawa N, Moore MA, Crystal RG. Tumor regression induced by intratumor administration of adenovirus vector expressing CD40 ligand and naive dendritic cells. Cancer Res 2000; 60 (22) 6391-6395
- 112 Takeda T, Makita K, Okita K, Haba A, Xianhui D. Intratumoral injection of immature dendritic cells (DC) for cancer patients [in Japanese]. Gan To Kagaku Ryoho 2005; 32 (11) 1574-1575
- 113 Kanazawa M, Yoshihara K, Abel H. et al. Two case reports on intra-tumor injection therapy of dendritic cells [in Japanese]. Gan To Kagaku Ryoho 2005; 32 (11) 1571-1573
- 114 Kanazawa M, Yoshihara K, Abe H. et al. Case report on intra-tumor injection therapy of dendritic cells in advanced gastric cancer [in Japanese]. Gan To Kagaku Ryoho 2004; 31 (11) 1773-1776
- 115 Toh U, Yamana H, Kido K. et al. Autologous tumor specific immunotherapy of refractory cancers with ex vivo-generated T cells stimulated by autologous tumor cell [in Japanese]. Gan To Kagaku Ryoho 2003; 30 (11) 1566-1570
- 116 Tanaka F, Yamaguchi H, Ohta M. et al. Intratumoral injection of dendritic cells after treatment of anticancer drugs induces tumor-specific antitumor effect in vivo. Int J Cancer 2002; 101 (03) 265-269
- 117 Kim KW, Kim SH, Shin JG. et al. Direct injection of immature dendritic cells into irradiated tumor induces efficient antitumor immunity. Int J Cancer 2004; 109 (05) 685-690
- 118 Overman MJ, McDermott R, Leach JL. et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 2017; 18 (09) 1182-1191
- 119 Zhu AX, Finn RS, Edeline J. KEYNOTE-224 investigators. et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol 2018; 19 (07) 940-952
- 120 Fuchs CS, Doi T, Jang RW. et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial. JAMA Oncol 2018; 4 (05) e180013