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Immunomodulation Within a Single Tumor Site to Induce Systemic Antitumor Immunity: In Situ Vaccination for Cancer

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Novel Immunotherapeutic Approaches to the Treatment of Cancer

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Abstract

Prophylactic vaccinations have been one of the greatest advances in modern medicine, both eradicating disease and reducing mortality. The translation of this advance into cancer therapy has been challenging and dates back to the turn of the twentieth century (Currie, Br J Cancer 26: 141–153, 1972). Cancer cells, derived from an aberrant clone, bear predominantly self-antigens and thus avoid alerting the immune system. In addition, the tumor microenvironment can be severely immunosuppressive; adding an extra layer of protection against the host immune response. Tumor cells can actively suppress immune responses through the downregulation of antigen presentation and the production of membrane-bound and secreted immuneregulatory molecules (Upadhyay et al, Cancers (Basel), 7: 736-62, 2015). To overcome such obstacles, a successful cancer vaccine must be able to induce a powerful immune response against tumor-associated antigens (TAAs) while avoiding normal host cells. This strategy has proven difficult because TAAs are highly variable in their immunogenicity and undergo immune editing to escape recognition. In addition, they can differ between tumor types and more importantly between individuals (Escors, New J Sci, 2014: 25, 2014). The presence of antigen-presenting cells (APCs) is generally low in the tumor microenvironment. Some efficacy in the treatment of cancer has been demonstrated by the use of autologous dendritic cells (DCs) pulsed with tumor cell lysates containing a whole array of antigens as well as single TAAs (Reichardt et al, Blood Rev: 18, 235-43, 2004). DC can be differentiated and expanded from peripheral blood ex vivo, and a resected tumor mass can be used to subsequently load the DC with TAAs. These strategies, while successful in developing a patient-specific vaccine, are labor and time intensive limiting the ability to experiment with numerous iterations to optimize the approach.

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Abbreviations

APC:

Antigen-presenting cell

CNS:

Central nervous system

CTL:

Cytotoxic T-lymphocyte

CTLA-4:

Cytotoxic T-lymphocyte-associated protein 4

DC:

Dendritic cell

ECM:

Extracellular matrix

EGFR:

Epidermal growth factor receptor

FLT3L:

Fms-like tyrosine kinase 3 ligand

GM-CSF:

Granulocyte-macrophage colony-stimulating factor

HSPs:

Heat shock proteins

IFN:

Interferon

IL:

Interleukin

LPS:

Lipopolysaccharide

PD-1:

Programmed death 1

Rb:

Retinoblastoma

TAA:

Tumor-associated antigen

TLR:

Toll-like receptor

TNF:

Tumor necrosis factor

VEGF:

Vascular endothelial growth factor

VSV:

Vesicular stomatitis virus

References

  • Adams, S., Kozhaya, L., Martiniuk, F., Meng, T.C., Chiriboga, L., Liebes, L., Hochman, T., Shuman, N., Axelrod, D., Speyer, J., Novik, Y., Tiersten, A., Goldberg, J.D., Formenti, S.C., Bhardwaj, N., Unutmaz, D., Demaria, S.: Topical TLR7 agonist imiquimod can induce immune-mediated rejection of skin metastases in patients with breast cancer. Clin. Cancer Res. 18, 6748–6757 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Agrawal, N., Bettegowda, C., Cheong, I., Geschwind, J.F., Drake, C.G., Hipkiss, E.L., Tatsumi, M., Dang, L.H., Diaz Jr., L.A., Pomper, M., Abusedera, M., Wahl, R.L., Kinzler, K.W., Zhou, S., Huso, D.L., Vogelstein, B.: Bacteriolytic therapy can generate a potent immune response against experimental tumors. Proc Natl Acad Sci U S A 101, 15172–15177 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Alemany, R.: Oncolytic adenoviruses in cancer treatment. Biomedicines 2, 36–49 (2014)

    Article  Google Scholar 

  • Amos, S.M., Pegram, H.J., Westwood, J.A., John, L.B., Devaud, C., Clarke, C.J., Restifo, N.P., Smyth, M.J., Darcy, P.K., Kershaw, M.H.: Adoptive immunotherapy combined with intratumoral TLR agonist delivery eradicates established melanoma in mice. Cancer Immunol. Immunother. 60, 671–683 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Andtbacka, R.H., Kaufman, H.L., Collichio, F., Amatruda, T., Senzer, N., Chesney, J., Delman, K.A., Spitler, L.E., Puzanov, I., Agarwala, S.S., Milhem, M., Cranmer, L., Curti, B., Lewis, K., Ross, M., Guthrie, T., Linette, G.P., Daniels, G.A., Harrington, K., Middleton, M.R., Miller Jr., W.H., Zager, J.S., Ye, Y., Yao, B., Li, A., Doleman, S., VanderWalde, A., Gansert, J., Coffin, R.S.: Talimogene Laherparepvec improves durable response rate in patients with advanced Melanoma. J Clin Oncol 33(25), 2780–8 (2015). doi:10.1200/JCO.2014.58.3377

    Article  CAS  PubMed  Google Scholar 

  • AJ Clin Oncol. 2015 Sep 1;33(25):2780-8. doi: 10.1200/JCO.2014.58.3377. Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma.Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, Delman KA, Spitler LE, Puzanov I, Agarwala SS, Milhem M, Cranmer L, Curti B, Lewis K, Ross M, Guthrie T, Linette GP, Daniels GA, Harrington K, Middleton MR, Miller WH Jr, Zager JS, Ye Y, Yao B, Li A, Doleman S,VanderWalde A, Gansert J, Coffin RS. (2015b)

    Google Scholar 

  • Andtbacka, R.H.I., Curti, B.D., Kaufman, H., Daniels, G.A., Nemunaitis, J.J., Spitler, L.E., Hallmeyer, S., Lutzky, J., Schultz, S.M., Whitman, E.D., Zhou, K., Karpathy, R., Weisberg, J.I., Grose, M., Shafren, D.:. Final data from CALM: a phase II study of Coxsackievirus A21 (CVA21) oncolytic virus immunotherapy in patients with advanced melanoma. J. Clin. Oncol. (Meeting Abstracts) 33(15_suppl) (May 20 Supplement) 9030 (2015c)

    Google Scholar 

  • Anwer, K., Barnes, M.N., Fewell, J., Lewis, D.H., Alvarez, R.D.: Phase-I clinical trial of IL-12 plasmid/lipopolymer complexes for the treatment of recurrent ovarian cancer. Gene Ther. 17, 360–369 (2010)

    Article  CAS  PubMed  Google Scholar 

  • Appledorn, D.M., Patial, S., McBride, A., Godbehere, S., van Rooijen, N., Parameswaran, N., Amalfitano, A.: Adenovirus vector-induced innate inflammatory mediators, MAPK signaling, as well as adaptive immune responses are dependent upon both TLR2 and TLR9 in vivo. J. Immunol. 181, 2134–2144 (2008)

    Article  CAS  PubMed  Google Scholar 

  • Ardigo, M., Cota, C., Berardesca, E.: Unilesional mycosis fungoides successfully treated with imiquimod. Eur. J. Dermatol. 16, 446 (2006)

    PubMed  Google Scholar 

  • Ariffin, N., Khorshid, M.: Treatment of mycosis fungoides with imiquimod 5% cream. Clin. Exp. Dermatol. 31, 822–823 (2006)

    Article  CAS  PubMed  Google Scholar 

  • Atkins, M.B., Lotze, M.T., Dutcher, J.P., Fisher, R.I., Weiss, G., Margolin, K., Abrams, J., Sznol, M., Parkinson, D., Hawkins, M., Paradise, C., Kunkel, L., Rosenberg, S.A.: High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J. Clin. Oncol. 17, 2105–2116 (1999)

    CAS  PubMed  Google Scholar 

  • Atkins, M.B., Robertson, M.J., Gordon, M., Lotze, M.T., Decoste, M., Dubois, J.S., Ritz, J., Sandler, A.B., Edington, H.D., Garzone, P.D., Mier, J.W., Canning, C.M., Battiato, L., Tahara, H., Sherman, M.L.: Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies. Clin. Cancer Res. 3, 409–417 (1997)

    CAS  PubMed  Google Scholar 

  • Banchereau, R., Baldwin, N., Cepika, A.M., Athale, S., Xue, Y., Yu, C.I., Metang, P., Cheruku, A., Berthier, I., Gayet, I., Wang, Y., Ohouo, M., Snipes, L., Xu, H., Obermoser, G., Blankenship, D., Oh, S., Ramilo, O., Chaussabel, D., Palucka, K., Pascual, V.: Transcriptional specialization of human dendritic cell subsets in response to microbial vaccines. Nat. Commun. 5, 5283 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Banissi, C., Ghiringhelli, F., Chen, L., Carpentier, A.F.: Treg depletion with a low-dose metronomic temozolomide regimen in a rat glioma model. Cancer Immunol. Immunother. 58, 1627–1634 (2009)

    Article  CAS  PubMed  Google Scholar 

  • Bartlett, D.L., Liu, Z., Sathaiah, M., Ravindranathan, R., Guo, Z., He, Y., Guo, Z.S.: Oncolytic viruses as therapeutic cancer vaccines. Mol. Cancer 12, 103 (2013)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Benencia, F., Courreges, M.C., Conejo-Garcia, J.R., Mohamed-Hadley, A., Zhang, L., Buckanovich, R.J., Carroll, R., Fraser, N., Coukos, G.: HSV oncolytic therapy upregulates interferon-inducible chemokines and recruits immune effector cells in ovarian cancer. Mol. Ther. 12, 789–802 (2005)

    Article  CAS  PubMed  Google Scholar 

  • Benencia, F., Courreges, M.C., Fraser, N.W., Coukos, G.: Herpes virus oncolytic therapy reverses tumor immune dysfunction and facilitates tumor antigen presentation. Cancer Biol. Ther. 7, 1194–1205 (2008)

    Article  CAS  PubMed  Google Scholar 

  • Bennett, J.J., Malhotra, S., Wong, R.J., Delman, K., Zager, J., St-Louis, M., Johnson, P., Fong, Y.: Interleukin 12 secretion enhances antitumor efficacy of oncolytic herpes simplex viral therapy for colorectal cancer. Ann. Surg. 233, 819–826 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Berendt, M.J., North, R.J., Kirstein, D.P.: The immunological basis of endotoxin-induced tumor regression. Requirement for T-cell-mediated immunity. J. Exp. Med. 148, 1550–1559 (1978)

    Article  CAS  PubMed  Google Scholar 

  • Bhardwaj, N., Merad, M., Kim-Schulze, S., Crowley, B., Davis, T., Salazar, A., Brody, J.: Converting tumors into vaccine manufacturing factories: DC recruitment, activation and clinical responses with a flt3L-primed in situ vaccine for low-grade lymphoma [nct01976585]. J. Immunother. Cancer 2(Suppl 3), 45 (2014)

    Article  Google Scholar 

  • Blander, J.M., Medzhitov, R.: Toll-dependent selection of microbial antigens for presentation by dendritic cells. Nature 440, 808–812 (2006)

    Article  CAS  PubMed  Google Scholar 

  • Bourke, E., Bosisio, D., Golay, J., Polentarutti, N., Mantovani, A.: The toll-like receptor repertoire of human B lymphocytes: inducible and selective expression of TLR9 and TLR10 in normal and transformed cells. Blood 102, 956–963 (2003)

    Article  PubMed  Google Scholar 

  • Braidwood, L., Dunn, P.D., Hardy, S., Evans, T.R., Brown, S.M.: Antitumor activity of a selectively replication competent herpes simplex virus (HSV) with enzyme prodrug therapy. Anticancer Res 29, 2159–2166 (2009)

    CAS  PubMed  Google Scholar 

  • Breitbach, C.J., Arulanandam, R., de Silva, N., Thorne, S.H., Patt, R., Daneshmand, M., Moon, A., Ilkow, C., Burke, J., Hwang, T.H., Heo, J., Cho, M., Chen, H., Angarita, F.A., Addison, C., Mccart, J.A., Bell, J.C., Kirn, D.H.: Oncolytic vaccinia virus disrupts tumor-associated vasculature in humans. Cancer Res. 73, 1265–1275 (2013)

    Article  CAS  PubMed  Google Scholar 

  • Breitbach, C.J., Burke, J., Jonker, D., Stephenson, J., Haas, A.R., Chow, L.Q., Nieva, J., Hwang, T.H., Moon, A., Patt, R., Pelusio, A., le Boeuf, F., Burns, J., Evgin, L., de Silva, N., Cvancic, S., Robertson, T., Je, J.E., Lee, Y.S., Parato, K., Diallo, J.S., Fenster, A., Daneshmand, M., Bell, J.C., Kirn, D.H.: Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans. Nature 477, 99–102 (2011)

    Article  CAS  PubMed  Google Scholar 

  • Breitbach, C.J., Moon, A., Burke, J., Hwang, T.H., Kirn, D.H.: A phase 2, open-label, randomized study of Pexa-Vec (JX-594) administered by intratumoral injection in patients with unresectable primary hepatocellular carcinoma. Methods Mol. Biol. 1317, 343–357 (2015)

    Article  PubMed  Google Scholar 

  • Bridle, B.W., Boudreau, J.E., Lichty, B.D., Brunellière, J., Stephenson, K., Koshy, S., Bramson, J.L., Wan, Y.: Vesicular stomatitis virus as a novel cancer vaccine vector to prime antitumor immunity amenable to rapid boosting with adenovirus. Mol. Ther. 17, 1814–1821 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bridle, B.W., Stephenson, K.B., Boudreau, J.E., Koshy, S., Kazdhan, N., Pullenayegum, E., Brunellière, J., Bramson, J.L., Lichty, B.D., Wan, Y.: Potentiating cancer immunotherapy using an oncolytic virus. Mol. Ther. 18, 1430–1439 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brody, J.D., Ai, W.Z., Czerwinski, D.K., Torchia, J.A., Levy, M., Advani, R.H., Kim, Y.H., Hoppe, R.T., Knox, S.J., Shin, L.K., Wapnir, I., Tibshirani, R.J., Levy, R.: In situ vaccination with a TLR9 agonist induces systemic lymphoma regression: a phase I/II study. J. Clin. Oncol. 28, 4324–4332 (2010)

    Article  PubMed  PubMed Central  Google Scholar 

  • Brody, J.D., Goldstein, M.J., Czerwinski, D.K., Levy, R.: Immunotransplantation preferentially expands T-effector cells over T-regulatory cells and cures large lymphoma tumors. Blood 113, 85–94 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Broz, M.L., Binnewies, M., Boldajipour, B., Nelson, A.E., Pollack, J.L., Erle, D.J., Barczak, A., Rosenblum, M.D., Daud, A., Barber, D.L., Amigorena, S., Van’t Veer, L.J., Sperling, A.I., Wolf, D.M., Krummel, M.F.: Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell 26, 638–652 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brunda, M.J., Luistro, L., Warrier, R.R., Wright, R.B., Hubbard, B.R., Murphy, M., Wolf, S.F., Gately, M.K.: Antitumor and antimetastatic activity of interleukin 12 against murine tumors. J. Exp. Med. 178, 1223–1230 (1993)

    Article  CAS  PubMed  Google Scholar 

  • Calista, D., Riccioni, L., Bagli, L., Valenzano, F.: Long-term remission of primary cutaneous neutrophil-rich CD30+ anaplastic large cell lymphoma treated with topical imiquimod. A case report. J. Eur. Acad. Dermatol. Venereol. (2015). doi:10.1111/jdv.13070

    PubMed  Google Scholar 

  • Carpentier, A., Metellus, P., Ursu, R., Zohar, S., Lafitte, F., Barrie, M., Meng, Y., Richard, M., Parizot, C., Laigle-Donadey, F., Gorochov, G., Psimaras, D., Sanson, M., Tibi, A., Chinot, O., Carpentier, A.F.: Intracerebral administration of CpG oligonucleotide for patients with recurrent glioblastoma: a phase II study. Neuro Oncol. 12, 401–408 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cerullo, V., Diaconu, I., Kangasniemi, L., Rajecki, M., Escutenaire, S., Koski, A., Romano, V., Rouvinen, N., Tuuminen, T., Laasonen, L., Partanen, K., Kauppinen, S., Joensuu, T., Oksanen, M., Holm, S.L., Haavisto, E., Karioja-Kallio, A., Kanerva, A., Pesonen, S., Arstila, P.T., Hemminki, A.: Immunological effects of low-dose cyclophosphamide in cancer patients treated with oncolytic adenovirus. Mol. Ther. 19, 1737–1746 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cerullo, V., Diaconu, I., Romano, V., Hirvinen, M., Ugolini, M., Escutenaire, S., Holm, S.L., Kipar, A., Kanerva, A., Hemminki, A.: An oncolytic adenovirus enhanced for toll-like receptor 9 stimulation increases antitumor immune responses and tumor clearance. Mol. Ther. 20, 2076–2086 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheema, T.A., Wakimoto, H., Fecci, P.E., Ning, J., Kuroda, T., Jeyaretna, D.S., Martuza, R.L., Rabkin, S.D.: Multifaceted oncolytic virus therapy for glioblastoma in an immunocompetent cancer stem cell model. Proc. Natl. Acad. Sci. U. S. A. 110, 12006–12011 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chicoine, M.R., Won, E.K., Zahner, M.C.: Intratumoral injection of lipopolysaccharide causes regression of subcutaneously implanted mouse glioblastoma multiforme. Neurosurgery 48, 607–614 (2001). discussion 614–615

    Article  CAS  PubMed  Google Scholar 

  • Choi, K.J., Kim, J.H., Lee, Y.S., Kim, J., Suh, B.S., Kim, H., Cho, S., Sohn, J.H., Kim, G.E., Yun, C.O.: Concurrent delivery of GM-CSF and B7-1 using an oncolytic adenovirus elicits potent antitumor effect. Gene Ther. 13, 1010–1020 (2006)

    Article  CAS  PubMed  Google Scholar 

  • Chong, A., Loo, W.J., Banney, L., Grant, J.W., Norris, P.G.: Imiquimod 5% cream in the treatment of mycosis fungoides—a pilot study. J. Dermatolog. Treat. 15, 118–119 (2004)

    Article  CAS  PubMed  Google Scholar 

  • Colombo, M.P., Trinchieri, G.: Interleukin-12 in anti-tumor immunity and immunotherapy. Cytokine Growth Factor Rev. 13, 155–168 (2002)

    Article  CAS  PubMed  Google Scholar 

  • Conner, J., Braidwood, L.: Expression of inhibitor of growth 4 by HSV1716 improves oncolytic potency and enhances efficacy. Cancer Gene Ther. 19, 499–507 (2012)

    Article  CAS  PubMed  Google Scholar 

  • Coors, E.A., Schuler, G., von den Driesch, P.: Topical imiquimod as treatment for different kinds of cutaneous lymphoma. Eur. J. Dermatol. 16, 391–393 (2006)

    CAS  PubMed  Google Scholar 

  • Cripe, T.P., Ngo, M.C., Geller, J.I., Louis, C.U., Currier, M.A., Racadio, J.M., Towbin, A.J., Rooney, C.M., Pelusio, A., Moon, A., Hwang, T.H., Burke, J.M., Bell, J.C., Kirn, D.H., Breitbach, C.J.: Phase 1 study of intratumoral Pexa-Vec (JX-594), an oncolytic and immunotherapeutic vaccinia virus, in pediatric cancer patients. Mol. Ther. 23, 602–608 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Currie, G.A.: Eighty years of immunotherapy: a review of immunological methods used for the treatment of human cancer. Br. J. Cancer 26, 141–153 (1972)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • D’Andrea, A., Rengaraju, M., Valiante, N.M., Chehimi, J., Kubin, M., Aste, M., Chan, S.H., Kobayashi, M., Young, D., Nickbarg, E., et al.: Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells. J. Exp. Med. 176, 1387–1398 (1992)

    Article  PubMed  Google Scholar 

  • Davis, M.B., Vasquez-Dunddel, D., Fu, J., Albesiano, E., Pardoll, D., Kim, Y.J.: Intratumoral administration of TLR4 agonist absorbed into a cellular vector improves antitumor responses. Clin. Cancer Res. 17, 3984–3992 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Deeths, M.J., Chapman, J.T., Dellavalle, R.P., Zeng, C., Aeling, J.L.: Treatment of patch and plaque stage mycosis fungoides with imiquimod 5% cream. J. Am. Acad. Dermatol. 52, 275–280 (2005)

    Article  PubMed  Google Scholar 

  • Dewan, M.Z., Vanpouille-Box, C., Kawashima, N., Dinapoli, S., Babb, J.S., Formenti, S.C., Adams, S., Demaria, S.: Synergy of topical toll-like receptor 7 agonist with radiation and low-dose cyclophosphamide in a mouse model of cutaneous breast cancer. Clin. Cancer Res. 18, 6668–6678 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • di Nicola, M., Zappasodi, R., Carlostella, C., Mortarini, R., Pupa, S.M., Magni, M., Devizzi, L., Matteucci, P., Baldassari, P., Ravagnani, F., Cabras, A., Anichini, A., Gianni, A.M.: Vaccination with autologous tumor-loaded dendritic cells induces clinical and immunological responses in indolent B cell lymphoma patients with relapsed and measurable disease: a pilot study. Blood 113, 6668–6678 (2008)

    Google Scholar 

  • Diaconu, I., Cerullo, V., Hirvinen, M.L., Escutenaire, S., Ugolini, M., Pesonen, S.K., Bramante, S., Parviainen, S., Kanerva, A., Loskog, A.S., Eliopoulos, A.G., Pesonen, S., Hemminki, A.: Immune response is an important aspect of the antitumor effect produced by a CD40L-encoding oncolytic adenovirus. Cancer Res. 72, 2327–2338 (2012)

    Article  CAS  PubMed  Google Scholar 

  • Dias, J.D., Hemminki, O., Diaconu, I., Hirvinen, M., Bonetti, A., Guse, K., Escutenaire, S., Kanerva, A., Pesonen, S., Löskog, A., Cerullo, V., Hemminki, A.: Targeted cancer immunotherapy with oncolytic adenovirus coding for a fully human monoclonal antibody species for C TLA-4. Gene Ther. 10, 988–998 (2012)

    Article  CAS  Google Scholar 

  • Didona, B., Benucci, R., Amerio, P., Canzona, F., Rienzo, O., Cavalieri, R.: Primary cutaneous CD30+ T-cell lymphoma responsive to topical imiquimod (Aldara). Br. J. Dermatol. 150, 1198–1201 (2004)

    Article  CAS  PubMed  Google Scholar 

  • Dovedi, S.J., Melis, M.H., Wilkinson, R.W., Adlard, A.L., Stratford, I.J., Honeychurch, J., Illidge, T.M.: Systemic delivery of a TLR7 agonist in combination with radiation primes durable antitumor immune responses in mouse models of lymphoma. Blood 121, 251–259 (2013)

    Article  CAS  PubMed  Google Scholar 

  • Dranoff, G., Jaffee, E., Lazenby, A., Golumbek, P., Levitsky, H., Brose, K., Jackson, V., Hamada, H., Pardoll, D., Mulligan, R.C.: Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc. Natl. Acad. Sci. U. S. A. 90, 3539–3543 (1993)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Du, T., Shi, G., Li, Y.M., Zhang, J.F., Tian, H.W., Wei, Y.Q., Deng, H., Yu, D.C.: Tumor-specific oncolytic adenoviruses expressing granulocyte macrophage colony-stimulating factor or anti-CTLA4 antibody for the treatment of cancers. Cancer Gene Ther. 21, 340–348 (2014)

    Article  CAS  PubMed  Google Scholar 

  • Dummer, R., Urosevic, M., Kempf, W., Kazakov, D., Burg, G.: Imiquimod induces complete clearance of a PUVA-resistant plaque in mycosis fungoides. Dermatology 207, 116–118 (2003)

    Article  PubMed  Google Scholar 

  • Egilmez, N.K., Jong, Y.S., Sabel, M.S., Jacob, J.S., Mathiowitz, E., Bankert, R.B.: In situ tumor vaccination with interleukin-12-encapsulated biodegradable microspheres: induction of tumor regression and potent antitumor immunity. Cancer Res. 60, 3832–3837 (2000)

    CAS  PubMed  Google Scholar 

  • Ehst, B.D., Dreno, B., Vonderheid, E.C.: Primary cutaneous CD30+ anaplastic large cell lymphoma responds to imiquimod cream. Eur. J. Dermatol. 18, 467–468 (2008)

    PubMed  Google Scholar 

  • Elsedawy, N.B., Russell, S.J.: Oncolytic vaccines. Expert Rev. Vaccines 12, 1155–1172 (2013)

    Article  CAS  PubMed  Google Scholar 

  • Engeland, C.E., Grossardt, C., Veinalde, R., Bossow, S., Lutz, D., Kaufmann, J.K., Shevchenko, I., Umansky, V., Nettelbeck, D.M., Weichert, W., Jäger, D., von Kalle, C., Ungerechts, G.: CTLA-4 and PD-L1 checkpoint blockade enhances oncolytic measles virus therapy. Mol. Ther. 22, 1949–1959 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Engelhardt, R., Mackensen, A., Galanos, C., Andreesen, R.: Biological response to intravenously administered endotoxin in patients with advanced cancer. J. Biol. Response Mod. 9, 480–491 (1990)

    CAS  PubMed  Google Scholar 

  • Escors, D.: Tumour immunogenicity, antigen presentation and immunological barriers in cancer immunotherapy. New J. Sci. 2014, 25 (2014)

    Article  CAS  Google Scholar 

  • Fan, R., Wang, C., Wang, Y., Ren, P., Gan, P., Ji, H., Xia, Z., Hu, S., Zeng, Q., Huang, W., Jiang, Y., Huang, X.: Enhanced antitumoral efficacy and immune response following conditionally replicative adenovirus containing constitutive HSF1 delivery to rodent tumors. J. Transl. Med. 10, 101 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fiszer-Maliszewska, L., den Otter, W., Madej, J.A., Mordarski, M.: Therapeutic potential of biological response modifiers against transplantable mouse tumors of spontaneous origin. II. Local interleukin 2 treatment of tumors of different immunogenic strength. Arch. Immunol. Ther. Exp. (Warsz.) 46, 293–300 (1998)

    CAS  Google Scholar 

  • Formenti, S.C., Demaria, S.: Systemic effects of local radiotherapy. Lancet Oncol. 10, 718–726 (2009)

    Article  PubMed  PubMed Central  Google Scholar 

  • Fransen, M.F., Sluijter, M., Morreau, H., Arens, R., Melief, C.J.: Local activation of CD8 T cells and systemic tumor eradication without toxicity via slow release and local delivery of agonistic CD40 antibody. Clin. Cancer Res. 17, 2270–2280 (2011)

    Article  CAS  PubMed  Google Scholar 

  • Fransen, M.F., van der Sluis, T.C., Ossendorp, F., Arens, R., Melief, C.J.: Controlled local delivery of CTLA-4 blocking antibody induces CD8+ T-cell-dependent tumor eradication and decreases risk of toxic side effects. Clin. Cancer Res. 19, 5381–5389 (2013)

    Article  CAS  PubMed  Google Scholar 

  • 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. 36, 3371–3380 (2006)

    Article  CAS  PubMed  Google Scholar 

  • Fukuhara, H., Ino, Y., Kuroda, T., Martuza, R.L., Todo, T.: Triple gene-deleted oncolytic herpes simplex virus vector double-armed with interleukin 18 and soluble B7-1 constructed by bacterial artificial chromosome-mediated system. Cancer Res. 65, 10663–10668 (2005)

    Article  CAS  PubMed  Google Scholar 

  • Furumoto, K., Soares, L., Engleman, E.G., Merad, M.: Induction of potent antitumor immunity by in situ targeting of intratumoral DCs. J. Clin. Invest. 113, 774–783 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fyfe, G., Fisher, R.I., Rosenberg, S.A., Sznol, M., Parkinson, D.R., Louie, A.C.: Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J. Clin. Oncol. 13, 688–696 (1995)

    CAS  PubMed  Google Scholar 

  • Galanis, E., Hersh, E.M., Stopeck, A.T., Gonzalez, R., Burch, P., Spier, C., Akporiaye, E.T., Rinehart, J.J., Edmonson, J., Sobol, R.E., Forscher, C., Sondak, V.K., Lewis, B.D., Unger, E.C., O’Driscoll, M., Selk, L., Rubin, J.: Immunotherapy of advanced malignancy by direct gene transfer of an interleukin-2 DNA/DMRIE/DOPE lipid complex: phase I/II experience. J. Clin. Oncol. 17, 3313–3323 (1999)

    CAS  PubMed  Google Scholar 

  • Gitlin, L., Barchet, W., Gilfillan, S., Cella, M., Beutler, B., Flavell, R.A., Diamond, M.S., Colonna, M.: Essential role of mda-5 in type I IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picornavirus. Proc. Natl. Acad. Sci. U. S. A. 103, 8459–8464 (2006)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goshima, F., Esaki, S., Luo, C., Kamakura, M., Kimura, H., Nishiyama, Y.: Oncolytic viral therapy with a combination of HF10, a herpes simplex virus type 1 variant and granulocyte-macrophage colony-stimulating factor for murine ovarian cancer. Int. J. Cancer 134, 2865–2877 (2014)

    Article  CAS  PubMed  Google Scholar 

  • Goto, S., Sakai, S., Kera, J., Suma, Y., Soma, G.I., Takeuchi, S.: Intradermal administration of lipopolysaccharide in treatment of human cancer. Cancer Immunol. Immunother. 42, 255–261 (1996)

    Article  CAS  PubMed  Google Scholar 

  • Grauer, O.M., Molling, J.W., Bennink, E., Toonen, L.W., Sutmuller, R.P., Nierkens, S., Adema, G.J.: TLR ligands in the local treatment of established intracerebral murine gliomas. J. Immunol. 181, 6720–6729 (2008)

    Article  CAS  PubMed  Google Scholar 

  • Gudmundsdottir, H., Wells, A.D., Turka, L.A.: Dynamics and requirements of T cell clonal expansion in vivo at the single-cell level: effector function is linked to proliferative capacity. J. Immunol. 162, 5212–5223 (1999)

    CAS  PubMed  Google Scholar 

  • Guo, J., Zhu, J., Sheng, X., Wang, X., Qu, L., Han, Y., Liu, Y., Zhang, H., Huo, L., Zhang, S., Lin, B., Yang, Z.: Intratumoral injection of dendritic cells in combination with local hyperthermia induces systemic antitumor effect in patients with advanced melanoma. Int. J. Cancer 120, 2418–2425 (2007)

    Article  CAS  PubMed  Google Scholar 

  • Gutwald, J.G., Groth, W., Mahrle, G.: Peritumoral injections of interleukin 2 induce tumour regression in metastatic malignant melanoma. Br. J. Dermatol. 130, 541–542 (1994)

    Article  CAS  PubMed  Google Scholar 

  • Harrington, K.J., Hingorani, M., Tanay, M.A., Hickey, J., Bhide, S.A., Clarke, P.M., Renouf, L.C., Thway, K., Sibtain, A., Mcneish, I.A., Newbold, K.L., Goldsweig, H., Coffin, R., Nutting, C.M.: Phase I/II study of oncolytic HSV GM-CSF in combination with radiotherapy and cisplatin in untreated stage III/IV squamous cell cancer of the head and neck. Clin. Cancer Res. 16, 4005–4015 (2010)

    Article  CAS  PubMed  Google Scholar 

  • Henriques, L., Palumbo, M., Guay, M.P., Bahoric, B., Basik, M., Kavan, P., Batist, G.: Imiquimod in the treatment of breast cancer skin metastasis. J. Clin. Oncol. 32, e22–e25 (2014)

    Article  PubMed  Google Scholar 

  • Heo, J., Reid, T., Ruo, L., Breitbach, C.J., Rose, S., Bloomston, M., Cho, M., Lim, H.Y., Chung, H.C., Kim, C.W., Burke, J., Lencioni, R., Hickman, T., Moon, A., Lee, Y.S., Kim, M.K., Daneshmand, M., Dubois, K., Longpre, L., Ngo, M., Rooney, C., Bell, J.C., Rhee, B.G., Patt, R., Hwang, T.H., Kirn, D.H.: Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat. Med. 19, 329–336 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hodi, F.S., O’Day, S.J., McDermott, D.F., Weber, R.W., Sosman, J.A., Haanen, J.B., Gonzalez, R., Robert, C., Schadendorf, D., Hassel, J.C., Akerley, W., van den Eertwegh, A.J., Lutzky, J., Lorigan, P., Vaubel, J.M., Linette, G.P., Hogg, D., Ottensmeier, C.H., Lebbé, C., Peschel, C., Quirt, I., Clark, J.I., Wolchok, J.D., Weber, J.S., Tian, J., Yellin, M.J., Nichol, G.M., Hoos, A., Urba, W.J.: Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hoeller, C., Jansen, B., Heere-Ress, E., Pustelnik, T., Mossbacher, U., Schlagbauer-Wadl, H., Wolff, K., Pehamberger, H.: Perilesional injection of r-GM-CSF in patients with cutaneous melanoma metastases. J. Invest. Dermatol. 117, 371–374 (2001)

    Article  CAS  PubMed  Google Scholar 

  • Hoffman, D.M., Figlin, R.A.: Intratumoral interleukin 2 for renal-cell carcinoma by direct gene transfer of a plasmid DNA/DMRIE/DOPE lipid complex. World J. Urol. 18, 152–156 (2000)

    Article  CAS  PubMed  Google Scholar 

  • Horton, H.M., Dorigo, O., Hernandez, P., Anderson, D., Berek, J.S., Parker, S.E.: IL-2 plasmid therapy of murine ovarian carcinoma inhibits the growth of tumor ascites and alters its cytokine profile. J. Immunol. 163, 6378–6385 (1999)

    CAS  PubMed  Google Scholar 

  • Hou, S., Kou, G., Fan, X., Wang, H., Qian, W., Zhang, D., Li, B., Dai, J., Zhao, J., Ma, J., Li, J., Lin, B., Wu, M., Guo, Y.: Eradication of hepatoma and colon cancer in mice with Flt3L gene therapy in combination with 5-FU. Cancer Immunol. Immunother. 56, 1605–1613 (2007)

    Article  CAS  PubMed  Google Scholar 

  • Houot, R., Levy, R.: T-cell modulation combined with intratumoral CpG cures lymphoma in a mouse model without the need for chemotherapy. Blood 113, 3546–3552 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hu, J.C., Coffin, R.S., Davis, C.J., Graham, N.J., Groves, N., Guest, P.J., Harrington, K.J., James, N.D., Love, C.A., Mcneish, I., Medley, L.C., Michael, A., Nutting, C.M., Pandha, H.S., Shorrock, C.A., Simpson, J., Steiner, J., Steven, N.M., Wright, D., Coombes, R.C.: A phase I study of OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor. Clin. Cancer Res. 12, 6737–6747 (2006)

    Article  CAS  PubMed  Google Scholar 

  • Huang, X.F., Ren, W., Rollins, L., Pittman, P., Shah, M., Shen, L., Gu, Q., Strube, R., Hu, F., Chen, S.Y.: A broadly applicable, personalized heat shock protein-mediated oncolytic tumor vaccine. Cancer Res. 63, 7321–7329 (2003)

    CAS  PubMed  Google Scholar 

  • Hwang, T.H., Moon, A., Burke, J., Ribas, A., Stephenson, J., Breitbach, C.J., Daneshmand, M., de Silva, N., Parato, K., Diallo, J.S., Lee, Y.S., Liu, T.C., Bell, J.C., Kirn, D.H.: A mechanistic proof-of-concept clinical trial with JX-594, a targeted multi-mechanistic oncolytic poxvirus, in patients with metastatic melanoma. Mol. Ther. 19, 1913–1922 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ino, Y., Saeki, Y., Fukuhara, H., Todo, T.: Triple combination of oncolytic herpes simplex virus-1 vectors armed with interleukin-12, interleukin-18, or soluble B7-1 results in enhanced antitumor efficacy. Clin. Cancer Res. 12, 643–652 (2006)

    Article  CAS  PubMed  Google Scholar 

  • Ishihara, M., Seo, N., Mitsui, J., Muraoka, D., Tanaka, M., Mineno, J., Ikeda, H., Shiku, H.: Systemic CD8+ T cell-mediated tumoricidal effects by intratumoral treatment of oncolytic herpes simplex virus with the agonistic monoclonal antibody for murine glucocorticoid-induced tumor necrosis factor receptor. PLoS One 9, e104669 (2014)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jackaman, C., Bundell, C.S., Kinnear, B.F., Smith, A.M., Filion, P., van Hagen, D., Robinson, B.W., Nelson, D.J.: IL-2 intratumoral immunotherapy enhances CD8+ T cells that mediate destruction of tumor cells and tumor-associated vasculature: a novel mechanism for IL-2. J. Immunol. 171, 5051–5063 (2003)

    Article  CAS  PubMed  Google Scholar 

  • Jahrsdörfer, B., Hartmann, G., Racila, E., Jackson, W., Mühlenhoff, L., Meinhardt, G., Endres, S., Link, B.K., Krieg, A.M., Weiner, G.J.: CpG DNA increases primary malignant B cell expression of costimulatory molecules and target antigens. J. Leukoc. Biol. 69, 81–88 (2001)

    PubMed  Google Scholar 

  • Jahrsdorfer, B., Muhlenhoff, L., Blackwell, S.E., Wagner, M., Poeck, H., Hartmann, E., Jox, R., Giese, T., Emmerich, B., Endres, S., Weiner, G.J., Hartmann, G.: B-cell lymphomas differ in their responsiveness to CpG oligodeoxynucleotides. Clin. Cancer Res. 11, 1490–1499 (2005)

    Article  CAS  PubMed  Google Scholar 

  • Kashiwagi, I., Morita, R., Schichita, T., Komai, K., Saeki, K., Matsumoto, M., Takeda, K., Nomura, M., Hayashi, A., Kanai, T., Yoshimura, A.: Smad2 and Smad3 inversely regulate TGF-beta autoinduction in Clostridium butyricum-activated dendritic cells. Immunity 43, 65–79 (2015)

    Article  CAS  PubMed  Google Scholar 

  • Kaufman, H.L., Ingemar Andtbacka, R.H., Collichio, F.A., Amatruda, T., Senzer, N.N., Chesney, J., Delman, K.A., Spitler, L.E., Puzanov, I., Ye, Y., Li, A., Gansert, J.L., Coffin, R., Ross, M.I.: Primary overall survival (OS) from 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. 32, 5s (2014) (suppl; abstr 9008a)

    Article  CAS  Google Scholar 

  • Kaufman, H.L., Kim, D.W., Deraffele, G., Mitcham, J., Coffin, R.S., Kim-Schulze, S.: Local and distant immunity induced by intralesional vaccination with an oncolytic herpes virus encoding GM-CSF in patients with stage IIIc and IV melanoma. Ann. Surg. Oncol. 17, 718–730 (2010)

    Article  PubMed  Google Scholar 

  • Kerkmann, M., Rothenfusser, S., Hornung, V., Towarowski, A., Wagner, M., Sarris, A., Giese, T., Endres, S., Hartmann, G.: Activation with CpG-A and CpG-B oligonucleotides reveals two distinct regulatory pathways of type I IFN synthesis in human plasmacytoid dendritic cells. J. Immunol. 170, 4465–4474 (2003)

    Article  CAS  PubMed  Google Scholar 

  • Kim, J.H., Oh, J.Y., Park, B.H., Lee, D.E., Kim, J.S., Park, H.E., Roh, M.S., Je, J.E., Yoon, J.H., Thorne, S.H., Kirn, D., Hwang, T.H.: Systemic armed oncolytic and immunologic therapy for cancer with JX-594, a targeted poxvirus expressing GM-CSF. Mol. Ther. 14, 361–730 (2006)

    Article  CAS  PubMed  Google Scholar 

  • Kim, Y.H., Gratzinger, D., Harrison, C., Brody, J.D., Czerwinski, D.K., Ai, W.Z., Morales, A., Abdulla, F., Xing, L., Navi, D., Tibshirani, R.J., Advani, R.H., Lingala, B., Shah, S., Hoppe, R.T., Levy, R.: In situ vaccination against mycosis fungoides by intratumoral injection of a TLR9 agonist combined with radiation: a phase 1/2 study. Blood 119, 355–63 (2012)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kimata, H., Imai, T., Kikumori, T., Teshigahara, O., Nagasaka, T., Goshima, F., Nishiyama, Y., Nakao, A.: Pilot study of oncolytic viral therapy using mutant herpes simplex virus (HF10) against recurrent metastatic breast cancer. Ann. Surg. Oncol. 13, 1078–1084 (2006)

    Article  PubMed  Google Scholar 

  • Kobayashi, T., Walsh, P.T., Walsh, M.C., Speirs, K.M., Chiffoleau, E., King, C.G., Hancock, W.W., Caamano, J.H., Hunter, C.A., Scott, P., Turka, L.A., Choi, Y.: TRAF6 is a critical factor for dendritic cell maturation and development. Immunity 19, 353–363 (2003)

    Article  CAS  PubMed  Google Scholar 

  • Kohrt, H.E., Chu, J., Brody, J., Czerwinski, D.K., Chester, C., Sadaram, M., Advani, R., Kim, Y.H., Hoppe, R.T., Knox, S.J., Wapnir, I., Tibshirani, R.J., Levy, R.: Dose-escalated, intratumoral TLR9 agonist and low-dose radiation induce abscopal effects in follicular lymphoma. Blood 124, 3092 (2014)

    Article  CAS  Google Scholar 

  • Kolstad, A., Kumari, S., Walczak, M., Madsbu, U., Hagtvedt, T., Bogsrud, T.V., Kvalheim, G., Holte, H., Aurlien, E., Delabie, J., Tierens, A., Olweus, J.: Sequential intranodal immunotherapy induces antitumor immunity and correlated regression of disseminated follicular lymphoma. Blood 125, 82–89 (2015)

    Article  CAS  PubMed  Google Scholar 

  • Kreiter, S., Diken, M., Selmi, A., Diekmann, J., Attig, S., Hüsemann, Y., Koslowski, M., Huber, C., Türeci, Ö., Sahin, U.: FLT3 ligand enhances the cancer therapeutic potency of naked RNA vaccines. Cancer Res. 71, 6132–6142 (2011)

    Article  CAS  PubMed  Google Scholar 

  • Kuang, M., Liu, S.Q., Saijo, K., Uchimura, E., Huang, L., Leong, K.W., Lu, M.D., Huang, J.F., Ohno, T.: Microwave tumour coagulation plus in situ treatment with cytokine-microparticles: induction of potent anti-residual tumour immunity. Int. J. Hyperthermia 21, 247–257 (2005)

    Article  CAS  PubMed  Google Scholar 

  • Lang, F.F., Conrad, C., Gomez-Manzano, C., Tufaro, F., Yung, W., Sawaya, R., Weinberg, J., Prabhu, S., Fuller, G., Aldape, K., Fueyo, J.: First-in-human phase I clinical trial of oncolytic Delta-24-RGD (DNX-2401) with biological endpoints: implications for Viro-immunotherapy. Neuro-Oncology 16, iii39 (2014)

    Article  PubMed Central  Google Scholar 

  • Lee, Y.S., Kim, J.H., Choi, K.J., Choi, I.K., Kim, H., Cho, S., Cho, B.C., Yun, C.O.: Enhanced antitumor effect of oncolytic adenovirus expressing interleukin-12 and B7-1 in an immunocompetent murine model. Clin. Cancer Res. 12, 5859–5868 (2006)

    Article  CAS  PubMed  Google Scholar 

  • Leonard, J.P., Sherman, M.L., Fisher, G.L., Buchanan, L.J., Larsen, G., Atkins, M.B., Sosman, J.A., Dutcher, J.P., Vogelzang, N.J., Ryan, J.L.: Effects of single-dose interleukin-12 exposure on interleukin-12-associated toxicity and interferon-gamma production. Blood 90, 2541–2548 (1997)

    CAS  PubMed  Google Scholar 

  • Li, J., Song, W., Czerwinski, D.K., Varghese, B., Uematsu, S., Akira, S., Krieg, A.M., Levy, R.: Lymphoma immunotherapy with CpG oligodeoxynucleotides requires TLR9 either in the host or in the tumor itself. J. Immunol. 179, 2493–500 (2007)

    Article  CAS  PubMed  Google Scholar 

  • Li, J.L., Liu, H.L., Zhang, X.R., Xu, J.P., Hu, W.K., Liang, M., Chen, S.Y., Hu, F., Chu, D.T.: A phase I trial of intratumoral administration of recombinant oncolytic adenovirus overexpressing HSP70 in advanced solid tumor patients. Gene Ther. 16, 376–82 (2009)

    Article  CAS  PubMed  Google Scholar 

  • Liu, B.L., Robinson, M., Han, Z.Q., Branston, R.H., English, C., Reay, P., Mcgrath, Y., Thomas, S.K., Thornton, M., Bullock, P., Love, C.A., Coffin, R.S.: ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties. Gene Ther. 10, 292–303 (2003)

    Article  CAS  PubMed  Google Scholar 

  • London, C.A., Lodge, M.P., Abbas, A.K.: Functional responses and costimulator dependence of memory CD4+ T cells. J. Immunol. 164, 265–272 (2000)

    Article  CAS  PubMed  Google Scholar 

  • Lu, Y.C., Yeh, W.C., Ohashi, P.S.: LPS/TLR4 signal transduction pathway. Cytokine 42, 145–151 (2008)

    Article  CAS  PubMed  Google Scholar 

  • Ma, D.Y., Clarke, E.A.: The role of CD40 and CD154/CD40L in dendritic cells. Semin. Immunol. 21, 265–272 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mach, N., Gillessen, S., Wilson, S.B., Sheehan, C., Mihm, M., Dranoff, G.: Differences in dendritic cells stimulated in vivo by tumors engineered to secrete granulocyte-macrophage colony-stimulating factor or Flt3-ligand. Cancer Res. 60, 3239–3246 (2000)

    CAS  PubMed  Google Scholar 

  • Mackie, R.M., Stewart, B., Brown, S.M.: Intralesional injection of herpes simplex virus 1716 in metastatic melanoma. Lancet 357, 525–526 (2001)

    Article  CAS  PubMed  Google Scholar 

  • Mahvi, D.M., Henry, M.B., Albertini, M.R., Weber, S., Meredith, K., Schalch, H., Rakhmilevich, A., Hank, J., Sondel, P.: Intratumoral injection of IL-12 plasmid DNA—results of a phase I/IB clinical trial. Cancer Gene Ther. 14, 717–723 (2007)

    Article  CAS  PubMed  Google Scholar 

  • Maito, F.L.D.M., Souza, A.P.D.D., Pereira, L., Smithey, M., Hinrichs, D., Bouwer, A., Bonorino, C.: Intratumoral TLR-4 agonist injection is critical for modulation of tumor microenvironment and tumor rejection. ISRN Immunol. 2012, 926817 (2012)

    Article  CAS  Google Scholar 

  • Maloney, D.G., Liles, T.M., Czerwinski, D.K., Waldichuk, C., Rosenberg, J., Grillo-Lopez, A., Levy, R.: Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood 84, 2457–2466 (1994)

    CAS  PubMed  Google Scholar 

  • Mangsbo, S.M., Broos, S., Fletcher, E., Veitonmaki, N., Furebring, C., Dahlen, E., Norlen, P., Lindstedt, M., Totterman, T.H., Ellmark, P.: The human agonistic CD40 antibody ADC-1013 eradicates bladder tumors and generates T-cell-dependent tumor immunity. Clin. Cancer Res. 21, 1115–1126 (2015)

    Article  CAS  PubMed  Google Scholar 

  • Marabelle, A., Kohrt, H., Sagiv-Barfi, I., Ajami, B., Axtell, R.C., Zhou, G., Rajapaksa, R., Green, M.R., Torchia, J., Brody, J., Luong, R., Rosenblum, M.D., Steinman, L., Levitsky, H.I., Tse, V., Levy, R.: Depleting tumor-specific Tregs at a single site eradicates disseminated tumors. J. Clin. Invest. 123, 2447–2463 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mariani, C.L., Rajon, D., Bova, F.J., Streit, W.J.: Nonspecific immunotherapy with intratumoral lipopolysaccharide and zymosan A but not GM-CSF leads to an effective anti-tumor response in subcutaneous RG-2 gliomas. J. Neurooncol 85, 231–240 (2007)

    Article  CAS  PubMed  Google Scholar 

  • Marron, T., Bhardwaj, N., Crowley, E., Keler, T., Davis, T.A., Brody, J.: Turning a tumor into a vaccine factory: in situ vaccination for low-grade lymphoma. Cancer Immunol. Res. 3, IA03 (2014)

    Article  Google Scholar 

  • Marroquin, C.E., Westwood, J.A., Lapointe, R., Mixon, A., Wunderlich, J.R., Caron, D., Rosenberg, S.A., Hwu, P.: Mobilization of dendritic cell precursors in patients with cancer by flt3 ligand allows the generation of higher yields of cultured dendritic cells. J. Immunother. 25, 278–288 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meshii, N., Takahashi, G., Okunaga, S., Hamada, M., Iwai, S., Takasu, A., Ogawa, Y., Yura, Y.: Enhancement of systemic tumor immunity for squamous cell carcinoma cells by an oncolytic herpes simplex virus. Cancer Gene Ther. 20, 493–498 (2013)

    Article  CAS  PubMed  Google Scholar 

  • Miller, R.L., Gerster, J.F., Owens, M.L., Slade, H.B., Tomai, M.A.: Imiquimod applied topically: a novel immune response modifier and new class of drug. Int. J. Immunopharmacol. 21, 1–14 (1999)

    Article  CAS  PubMed  Google Scholar 

  • Ming Lim, C., Stephenson, R., Salazar, A.M., Ferris, R.L.: TLR3 agonists improve the immunostimulatory potential of cetuximab against EGFR head and neck cancer cells. Oncoimmunology 2, e24677 (2013)

    Article  PubMed  PubMed Central  Google Scholar 

  • Morse, M.A., Nair, S., Fernandez-Casal, M., Deng, Y., St Peter, M., Williams, R., Hobeika, A., Mosca, P., Clay, T., Cumming, R.I., Fisher, E., Clavien, P., Proia, A.D., Niedzwiecki, D., Caron, D., Lyerly, H.K.: Preoperative mobilization of circulating dendritic cells by Flt3 ligand administration to patients with metastatic colon cancer. J. Clin. Oncol. 18, 3883–93 (2000)

    CAS  PubMed  Google Scholar 

  • Motoyoshi, Y., Kaminoda, K., Saitoh, O., Hamasaki, K., Nakao, K., Ishii, N., Nagayama, Y., Eguchi, K.: Different mechanisms for anti-tumor effects of low- and high-dose cyclophosphamide. Oncol. Rep. 16, 141–146 (2006)

    CAS  PubMed  Google Scholar 

  • Nakao, A., Kasuya, H., Sahin, T.T., Nomura, N., Kanzaki, A., Misawa, M., Shirota, T., Yamada, S., Fujii, T., Sugimoto, H., Shikano, T., Nomoto, S., Takeda, S., Kodera, Y., Nishiyama, Y.: A phase I dose-escalation clinical trial of intraoperative direct intratumoral injection of HF10 oncolytic virus in non-resectable patients with advanced pancreatic cancer. Cancer Gene Ther. 18, 167–175 (2011)

    Article  CAS  PubMed  Google Scholar 

  • Nasi, M.L., Lieberman, P., Busam, K.J., Prieto, V., Panageas, K.S., Lewis, J.J., Houghton, A.N., Chapman, P.B.: Intradermal injection of granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with metastatic melanoma recruits dendritic cells. Cytokines Cell. Mol. Ther. 5, 139–144 (1999)

    CAS  PubMed  Google Scholar 

  • Nemunaitis, J.: Oncolytic viruses. Invest. New Drugs 17, 375–386 (1999)

    Article  CAS  PubMed  Google Scholar 

  • Nemunaitis, J.J., Linette, G.P., Ali, H., Lebel, F., Barrett, J.A., Reed, T., Krishnan, S., Lewis, J.: Ad-RTS-hIL-12+ veledimex regulation of IL-12 expression in advanced breast cancer (BC) and melanoma patients. AACR—Tumor Immunology and Immunotherapy: A New Chapter Poster Session B (meeting abstract) (2014)

    Google Scholar 

  • Neville, M.E., Robb, R.J., Popescu, M.C.: In situ vaccination against a non-immunogenic tumour using intratumoural injections of liposomal interleukin 2. Cytokine 16, 239–250 (2001)

    Article  CAS  PubMed  Google Scholar 

  • Noessner, E., Gastpar, R., Milani, V., Brandl, A., Hutzler, P.J., Kuppner, M.C., Roos, M., Kremmer, E., Asea, A., Calderwood, S.K., Issels, R.D.: Tumor-derived heat shock protein 70 peptide complexes are cross-presented by human dendritic cells. J. Immunol. 169, 5424–5432 (2002)

    Article  CAS  PubMed  Google Scholar 

  • Okuda, H., Kobayashi, A., Xia, B., Watabe, M., Pai, S.K., Hirota, S., Xing, F., Liu, W., Pandey, P.R., Fukuda, K., Modur, V., Ghosh, A., Wilber, A., Watabe, K.: Hyaluronan synthase HAS2 promotes tumor progression in bone by stimulating the interaction of breast cancer stem-like cells with macrophages and stromal cells. Cancer Res. 72, 537–547 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Otto, F., Schmid, P., Mackensen, A., Wehr, U., Seiz, A., Braun, M., Galanos, C., Mertelsmann, R., Engelhardt, R.: Phase II trial of intravenous endotoxin in patients with colorectal and non-small cell lung cancer. Eur. J. Cancer 32A, 1712–1718 (1996)

    Article  CAS  PubMed  Google Scholar 

  • Papanastassiou, V., Rampling, R., Fraser, M., Petty, R., Hadley, D., Nicoll, J., Harland, J., Mabbs, R., Brown, M.: The potential for efficacy of the modified (ICP 34.5(−)) herpes simplex virus HSV1716 following intratumoural injection into human malignant glioma: a proof of principle study. Gene Ther. 9, 398–406 (2002)

    Article  CAS  PubMed  Google Scholar 

  • Parato, K.A., Breitbach, C.J., le Boeuf, F., Wang, J., Storbeck, C., Ilkow, C., Diallo, J.S., Falls, T., Burns, J., Garcia, V., Kanji, F., Evgin, L., Hu, K., Paradis, F., Knowes, S., Hwang, T.H., Vanderhyden, B.C., Auer, R., Kirn, D.H., Bell, J.C.: The oncolytic poxvirus JX-594 selectively replicates in and destroys cancer cells driven by genetic pathways commonly activated in cancers. Mol. Ther. 20, 749–758 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park, B.H., Hwang, T., Liu, T.C., Sze, D.Y., Kim, J.S., Kwon, H.C., Oh, S.Y., Han, S.Y., Yoon, J.H., Hong, S.H., Moon, A., Speth, K., Park, C., Ahn, Y.J., Daneshmand, M., Rhee, B.G., Pinedo, H.M., Bell, J.C., Kirn, D.H.: Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial. Lancet Oncol 9, 533–542 (2008)

    Article  CAS  PubMed  Google Scholar 

  • Pawlowska, A.B., Hashino, S., McKenna, H., Weigel, B.J., Taylor, P.A., Blazar, B.R.: In vitro tumor-pulsed or in vivo Flt3 ligand-generated dendritic cells provide protection against acute myelogenous leukemia in nontransplanted or syngeneic bone marrow-transplanted mice. Blood 97, 1474–1482 (2001)

    Article  CAS  PubMed  Google Scholar 

  • Pesonen, S., Diaconu, I., Kangasniemi, L., Ranki, T., Kanerva, A., Pesonen, S.K., Gerdemann, U., Leen, A.M., Kairemo, K., Oksanen, M., Haavisto, E., Holm, S.L., Karioja-Kallio, A., Kauppinen, S., Partanen, K.P., Laasonen, L., Joensuu, T., Alanko, T., Cerullo, V., Hemminki, A.: Oncolytic immunotherapy of advanced solid tumors with a CD40L-expressing replicating adenovirus: assessment of safety and immunologic responses in patients. Cancer Res. 72, 1621–1631 (2012)

    Article  CAS  PubMed  Google Scholar 

  • Postow, M.A., Chesney, J., Pavlick, A.C., Robert, C., Grossmann, K., McDermott, D., Linette, G.P., Meyer, N., Giguere, J.K., Agarwala, S.S., Shaheen, M., Ernstoff, M.S., Minor, D., Salama, A.K., Taylor, M., Ott, P.A., Rollin, L.M., Horak, C., Gagnier, P., Wolchok, J.D., Hodi, F.S.: Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N. Engl. J. Med. 372, 2006–2017 (2015)

    Article  PubMed  Google Scholar 

  • Pullen, S.S., Dang, T.T., Crute, J.J., Kehry, M.R.: CD40 signaling through tumor necrosis factor receptor-associated factors (TRAFs). Binding site specificity and activation of downstream pathways by distinct TRAFs. J. Biol. Chem. 274, 14246–14254 (1999)

    Article  CAS  PubMed  Google Scholar 

  • Puzanov, I., Milhem, M.M., Ingemar Andtbacka, R.H., Minor, D.R., Hamid, O., Li, A., Chastain, M., Gorski, K., Anderson, A., Vanderwalde, A.M., Chou, J., Kaufman, H.L.: Primary analysis of a phase 1b multicenter trial to evaluate safety and efficacy of talimogene laherparepvec (T-VEC) and ipilimumab (ipi) in previously untreated, unresected stage IIIB-IV melanoma. J. Clin. Oncol. 32, 5 (2014) (suppl; abstr 9029^)

    Article  CAS  Google Scholar 

  • Radny, P., Caroli, U.M., Bauer, J., Paul, T., Schlegel, C., Eigentler, T.K., Weide, B., Schwarz, M., Garbe, C.: Phase II trial of intralesional therapy with interleukin-2 in soft-tissue melanoma metastases. Br. J. Cancer 89, 1620–1626 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Raykov, Z., Grekova, S., Leuchs, B., Aprahamian, M., Rommelaere, J.: Arming parvoviruses with CpG motifs to improve their oncosuppressive capacity. Int. J. Cancer 122, 2880–2884 (2008)

    Article  CAS  PubMed  Google Scholar 

  • Reichardt, V.L., Brossart, P., Kanz, L.: Dendritic cells in vaccination therapies of human malignant disease. Blood Rev. 18, 235–243 (2004)

    Article  PubMed  Google Scholar 

  • Richmond, H.M., Lozano, A., Jones, D., Duvic, M.: Primary cutaneous follicle center lymphoma associated with alopecia areata. Clin. Lymphoma Myeloma 8, 121–124 (2008)

    Article  PubMed  Google Scholar 

  • Riediger, C., Wingender, G., Knolle, P., Aulmann, S., Stremmel, W., Encke, J.: Fms-like tyrosine kinase 3 receptor ligand (Flt3L)-based vaccination administered with an adenoviral vector prevents tumor growth of colorectal cancer in a BALB/c mouse model. J. Cancer Res. Clin. Oncol. 139, 2097–2110 (2013)

    Article  CAS  PubMed  Google Scholar 

  • Robert, C., Thomas, L., Bondarenko, I., O’Day, S., Weber, J., Garbe, C., Lebbe, C., Baurain, J.F., Testori, A., Grob, J.J., Davidson, N., Richards, J., Maio, M., Hauschild, A., Miller, W.H., Gascon, P., Lotem, M., Harmankaya, K., Ibrahim, R., Francis, S., Chen, T.T., Humphrey, R., Hoos, A., Wolchok, J.D.: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364, 2517–2526 (2011)

    Article  CAS  PubMed  Google Scholar 

  • Roberts, N.J., Zhang, L., Janku, F., Collins, A., Bai, R.Y., Staedtke, V., Rusk, A.W., Tung, D., Miller, M., Roix, J., Khanna, K.V., Murthy, R., Benjamin, R.S., Helgason, T., Szvalb, A.D., Bird, J.E., Roy-Chowdhuri, S., Zhang, H.H., Qiao, Y., Karim, B., Mcdaniel, J., Elpiner, A., Sahora, A., Lachowicz, J., Phillips, B., Turner, A., Klein, M.K., Post, G., Diaz Jr., L.A., Riggins, G.J., Papadopoulos, N., Kinzler, K.W., Vogelstein, B., Bettegowda, C., Huso, D.L., Varterasian, M., Saha, S., Zhou, S.: Intratumoral injection of Clostridium novyi-NT spores induces antitumor responses. Sci. Transl. Med. 6, 249ra111 (2014)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Rodríguez-García, A., Giménez-Alejandre, M., Rojas, J.J., Moreno, R., Bazan-Peregrino, M., Cascalló, M., Alemany, R.: Safety and efficacy of VCN-01, an oncolytic adenovirus combining fiber HSG-binding domain replacement with RGD and hyaluronidase expression. Clin. Cancer Res. 21, 1406–1418 (2015)

    Article  PubMed  CAS  Google Scholar 

  • Rommelfanger, D.M., Compte, M., Grau, M.C., Diaz, R.M., Ilett, E., Alvarez-Vallina, L., Thompson, J.M., Kottke, T.J., Melcher, A., Vile, R.G.: The efficacy versus toxicity profile of combination virotherapy and TLR immunotherapy highlights the danger of administering TLR agonists to oncolytic virus-treated mice. Mol. Ther. 21, 348–357 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rook, A.H., Wood, G.S., Yoo, E.K., Elenitsas, R., Kao, D.M., Sherman, M.L., Witmer, W.K., Rockwell, K.A., Shane, R.B., Lessin, S.R., Vonderheid, E.C.: Interleukin-12 therapy of cutaneous T-cell lymphoma induces lesion regression and cytotoxic T-cell responses. Blood 94, 902–908 (1999)

    CAS  PubMed  Google Scholar 

  • Rosenfeld, M.R., Chamberlain, M.C., Grossman, S.A., Peereboom, D.M., Lesser, G.J., Batchelor, T.T., Desideri, S., Salazar, A.M., Ye, X.: A multi-institution phase II study of poly-ICLC and radiotherapy with concurrent and adjuvant temozolomide in adults with newly diagnosed glioblastoma. Neuro Oncol. 12, 1071–1077 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sahin, T.T., Kasuya, H., Nomura, N., Shikano, T., Yamamura, K., Gewen, T., Kanzaki, A., Fujii, T., Sugae, T., Imai, T., Nomoto, S., Takeda, S., Sugimoto, H., Kikumori, T., Kodera, Y., Nishiyama, Y., Nakao, A.: Impact of novel oncolytic virus HF10 on cellular components of the tumor microenviroment in patients with recurrent breast cancer. Cancer Gene Ther. 19, 229–237 (2012)

    Article  CAS  PubMed  Google Scholar 

  • Saji, H., Song, W., Furumoto, K., Kato, H., Engleman, E.G.: Systemic antitumor effect of intratumoral injection of dendritic cells in combination with local photodynamic therapy. Clin. Cancer Res. 12, 2568–2574 (2006)

    Article  CAS  PubMed  Google Scholar 

  • Salazar, A.M., Erlich, R.B., Mark, A., Bhardwaj, N., Herberman, R.B.: Therapeutic in situ autovaccination against solid cancers with intratumoral poly-ICLC: case report, hypothesis, and clinical trial. Cancer Immunol. Res. 2, 720–724 (2014)

    Article  PubMed  Google Scholar 

  • Salem, M.L., El-Naggar, S.A., Kadima, A., Gillanders, W.E., Cole, D.J.: The adjuvant effects of the toll-like receptor 3 ligand polyinosinic-cytidylic acid poly (I:C) on antigen-specific CD8+ T cell responses are partially dependent on NK cells with the induction of a beneficial cytokine milieu. Vaccine 24, 5119–5132 (2006)

    Article  CAS  PubMed  Google Scholar 

  • Salem, M.L., Kadima, A.N., Cole, D.J., Gillanders, W.E.: Defining the antigen-specific T-cell response to vaccination and poly(I:C)/TLR3 signaling: evidence of enhanced primary and memory CD8 T-cell responses and antitumor immunity. J. Immunother. 28, 220–228 (2005)

    Article  CAS  PubMed  Google Scholar 

  • Salmon, H.E.A.: Expansion and activation of CD103+ DC progenitors at the tumor site promote T cell accumulation in melanoma lesions and transform clinical response to BRAF and PD-L1 blockade. Immunity (2016) (in press)

    Google Scholar 

  • Sangro, B., Mazzolini, G., Ruiz, J., Herraiz, M., Quiroga, J., Herrero, I., Benito, A., Larrache, J., Pueyo, J., Subtil, J.C., Olagüe, C., Sola, J., Sádaba, B., Lacasa, C., Melero, I., Qian, C., Prieto, J.: Phase I trial of intratumoral injection of an adenovirus encoding interleukin-12 for advanced digestive tumors. J. Clin. Oncol. 22, 1389–1397 (2004)

    Article  CAS  PubMed  Google Scholar 

  • Schuster, S.J., Neelapu, S.S., Gause, B.L., Janik, J.E., Muggia, F.M., Gockerman, J.P., Winter, J.N., Flowers, C.R., Nikcevich, D.A., Sotomayor, E.M., Mcgaughey, D.S., Jaffe, E.S., Chong, E.A., Reynolds, C.W., Berry, D.A., Santos, C.F., Popa, M.A., McCord, A.M., Kwak, L.W.: Vaccination with patient-specific tumor-derived antigen in first remission improves disease-free survival in follicular lymphoma. J. Clin. Oncol. 29, 2787–2794 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Senzer, N.N., Kaufman, H.L., Amatruda, T., Nemunaitis, M., Reid, T., Daniels, G., Gonzalez, R., Glaspy, J., Whitman, E., Harrington, K., Goldsweig, H., Marshall, T., Love, C., Coffin, R., Nemunaitis, J.J.: 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. 27, 5763–5771 (2009)

    Article  CAS  PubMed  Google Scholar 

  • Serrone, L., Zeuli, M., Sega, F.M., Cognetti, F.: Dacarbazine-based chemotherapy for metastatic melanoma: thirty-year experience overview. J. Exp. Clin. Cancer Res. 19, 21–34 (2000)

    CAS  PubMed  Google Scholar 

  • Shafren, D., Quah, M., Wong, Y., Andtbacka, R.H.I., Kaufman, H.L., Au, G.G.: Combination of a novel oncolytic immunotherapeutic agent, CAVATAK (coxsackievirus A21) and immune-checkpoint blockade significantly reduces tumor growth and improves survival in an immune competent mouse melanoma model. J. Immunother. Cancer 2, 125–P125 (2014)

    Article  Google Scholar 

  • Sharma, P., Allison, J.P.: The future of immune checkpoint therapy. Science 348, 56–61 (2015)

    Article  CAS  PubMed  Google Scholar 

  • Sharma, S., Dominguez, A.L., Hoelzinger, D.B., Lustgarten, J.: CpG-ODN but not other TLR-ligands restore the antitumor responses in old mice: the implications for vaccinations in the aged. Cancer Immunol. Immunother. 57, 549–561 (2008)

    Article  CAS  PubMed  Google Scholar 

  • Shortman, K., Naik, S.H.: Steady-state and inflammatory dendritic-cell development. Nat. Rev. Immunol. 7, 19–30 (2007)

    Article  CAS  PubMed  Google Scholar 

  • Si, Z., Hersey, P., Coates, A.S.: Clinical responses and lymphoid infiltrates in metastatic melanoma following treatment with intralesional GM-CSF. Melanoma Res. 6, 247–255 (1996)

    Article  CAS  PubMed  Google Scholar 

  • Siders, W.M., Garron, C., Shields, J., Kaplan, J.M.: Induction of antitumor immunity by semi-allogeneic and fully allogeneic electrofusion products of tumor cells and dendritic cells. Clin. Transl. Sci. 2, 75–79 (2009)

    Article  PubMed  CAS  Google Scholar 

  • Sidky, Y.A., Borden, E.C., Weeks, C.E., Reiter, M.J., Hatcher, J.F., Bryan, G.T.: Inhibition of murine tumor growth by an interferon-inducing imidazoquinolinamine. Cancer Res. 52, 3528–3533 (1992)

    CAS  PubMed  Google Scholar 

  • Simmons, A.D., Moskalenko, M., Creson, J., Fang, J., Yi, S., Vanroey, M.J., Allison, J.P., Jooss, K.: Local secretion of anti-CTLA-4 enhances the therapeutic efficacy of a cancer immunotherapy with reduced evidence of systemic autoimmunity. Cancer Immunol. Immunother. 57, 1263–1270 (2008)

    Article  CAS  PubMed  Google Scholar 

  • Singh-Jasuja, H., Toes, R.E., Spee, P., Münz, C., Hilf, N., Schoenberger, S.P., Ricciardi-Castagnoli, P., Neefjes, J., Rammensee, H.G., Arnold-Schild, D., Schild, H.: Cross-presentation of glycoprotein 96-associated antigens on major histocompatibility complex class I molecules requires receptor-mediated endocytosis. J. Exp. Med. 191, 1965–1974 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Singh, M., Khong, H., Dai, Z., Huang, X.F., Wargo, J.A., Cooper, Z.A., Vasilakos, J.P., Hwu, P., Overwijk, W.W.: Effective innate and adaptive antimelanoma immunity through localized TLR7/8 activation. J. Immunol. 193, 4722–4731 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Slos, P., de Meyer, M., Leroy, P., Rousseau, C., Acres, B.: Immunotherapy of established tumors in mice by intratumoral injection of an adenovirus vector harboring the human IL-2 cDNA: induction of CD8(+) T-cell immunity and NK activity. Cancer Gene Ther. 8, 321–332 (2001)

    Article  CAS  PubMed  Google Scholar 

  • Smyth, E.C., Flavin, M., Pulitzer, M.P., Gardner, G.J., Costantino, P.D., Chi, D.S., Bogatch, K., Chapman, P.B., Wolchok, J.D., Schwartz, G.K., Carvajal, R.D.: Treatment of locally recurrent mucosal melanoma with topical imiquimod. J. Clin. Oncol. 29, e809–e811 (2011)

    Article  PubMed  Google Scholar 

  • Soiffer, R., Lynch, T., Mihm, M., Jung, K., Rhuda, C., Schmollinger, J.C., Hodi, F.S., Liebster, L., Lam, P., Mentzer, S., Singer, S., Tanabe, K.K., Cosimi, A.B., Duda, R., Sober, A., Bhan, A., Daley, J., Neuberg, D., Parry, G., Rokovich, J., Richards, L., Drayer, J., Berns, A., Clift, S., Cohen, L.K., Mulligan, R.C., Dranoff, G.: Vaccination with irradiated autologous melanoma cells engineered to secrete human granulocyte-macrophage colony-stimulating factor generates potent antitumor immunity in patients with metastatic melanoma. Proc. Natl. Acad. Sci. U S A 95(22), 13141–13146 (1998)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Song, W., Levy, R.: Therapeutic vaccination against murine lymphoma by intratumoral injection of naive dendritic cells. Cancer Res. 65, 5958–5964 (2005)

    Article  CAS  PubMed  Google Scholar 

  • Spaner, D.E., Miller, R.L., Mena, J., Grossman, L., Sorrenti, V., Shi, Y.: Regression of lymphomatous skin deposits in a chronic lymphocytic leukemia patient treated with the Toll-like receptor-7/8 agonist, imiquimod. Leuk. Lymphoma 46, 935–939 (2005)

    Article  PubMed  Google Scholar 

  • Stavrakoglou, A., Brown, V.L., Coutts, I.: Successful treatment of primary cutaneous follicle centre lymphoma with topical 5 % imiquimod. Br. J. Dermatol. 157, 620–622 (2007)

    Article  CAS  PubMed  Google Scholar 

  • Stone, G.W., Barzee, S., Snarsky, V., Santucci, C., Tran, B., Kornbluth, R.S.: Regression of established AB1 murine mesothelioma induced by peritumoral injections of CpG oligodeoxynucleotide either alone or in combination with poly(I:C) and CD40 ligand plasmid DNA. J. Thorac. Oncol. 4, 802–808 (2009a)

    Article  PubMed  Google Scholar 

  • Stone, G.W., Barzee, S., Snarsky, V., Santucci, C., Tran, B., Langer, R., Zugates, G.T., Anderson, D.G., Kornbluth, R.S.: Nanoparticle-delivered multimeric soluble CD40L DNA combined with Toll-Like Receptor agonists as a treatment for melanoma. PLoS One 4, e7334 (2009b)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Suchin, K.R., Junkins-Hopkins, J.M., Rook, A.H.: Treatment of stage IA cutaneous T-Cell lymphoma with topical application of the immune response modifier imiquimod. Arch. Dermatol. 138, 1137–1139 (2002)

    Article  PubMed  Google Scholar 

  • Suresh, M., Whitmire, J.K., Harrington, L.E., Larsen, C.P., Pearson, T.C., Altman, J.D., Ahmed, R.: Role of CD28-B7 interactions in generation and maintenance of CD8 T cell memory. J. Immunol. 167, 5565–5573 (2001)

    Article  CAS  PubMed  Google Scholar 

  • Tan, G., Kasuya, H., Sahin, T.T., Yamamura, K., Wu, Z., Koide, Y., Hotta, Y., Shikano, T., Yamada, S., Kanzaki, A., Fujii, T., Sugimoto, H., Nomoto, S., Nishikawa, Y., Tanaka, M., Tsurumaru, N., Kuwahara, T., Fukuda, S., Ichinose, T., Kikumori, T., Takeda, S., Nakao, A., Kodera, Y.: Combination therapy of oncolytic herpes simplex virus HF10 and bevacizumab against experimental model of human breast carcinoma xenograft. Int. J. Cancer 136, 1718–30 (2015)

    Article  CAS  PubMed  Google Scholar 

  • Thaker, P.H., Brady, W.E., Bradley, W.H., Anwer, K., Alvarez, R.D.: Phase I study of intraperitoneal IL-12 plasmid formulated with PEG-PEI-cholesterol lipopolymer administered in combination with pegylated liposomal doxorubicin in recurrent or persistent epithelial ovarian, Fallopian tube, or primary peritoneal cancer patients: an NRG/GOG study. J. Clin. Oncol. (Meeting Abstracts) 33(Suppl; abstr 5541) (2015)

    Google Scholar 

  • Timmerman, J.M., Czerwinski, D.K., Davis, T.A., Hsu, F.J., Benike, C., Hao, Z.M., Taidi, B., Rajapaksa, R., Caspar, C.B., Okada, C.Y., van Beckhoven, A., Liles, T.M., Engleman, E.G., Levy, R.: Idiotype-pulsed dendritic cell vaccination for B-cell lymphoma: clinical and immune responses in 35 patients. Blood 99, 1517–1526 (2002)

    Article  CAS  PubMed  Google Scholar 

  • Toda, M., Martuza, R.L., Kojima, H., Rabkin, S.D.: In situ cancer vaccination: an IL-12 defective vector/replication-competent herpes simplex virus combination induces local and systemic antitumor activity. J. Immunol. 160, 4457–4464 (1998)

    CAS  PubMed  Google Scholar 

  • Todo, T., Martuza, R.L., Dallman, M.J., Rabkin, S.D.: In situ expression of soluble B7-1 in the context of oncolytic herpes simplex virus induces potent antitumor immunity. Cancer Res. 61, 153–161 (2001)

    CAS  PubMed  Google Scholar 

  • Tong, Y., Song, W., Crystal, R.G.: Combined intratumoral injection of bone marrow-derived dendritic cells and systemic chemotherapy to treat pre-existing murine tumors. Cancer Res. 61, 7530–7535 (2001)

    CAS  PubMed  Google Scholar 

  • Tumeh, P.C., Harview, C.L., Yearley, J.H., Shintaku, I.P., Taylor, E.J., Robert, L., Chmielowski, B., Spasic, M., Henry, G., Ciobanu, V., West, A.N., Carmona, M., Kivork, C., Seja, E., Cherry, G., Gutierrez, A.J., Grogan, T.R., Mateus, C., Tomasic, G., Glaspy, J.A., Emerson, R.O., Robins, H., Pierce, R.H., Elashoff, D.A., Robert, C., Ribas, A.: PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tuve, S., Chen, B.M., Liu, Y., Cheng, T.L., Toure, P., Sow, P.S., Feng, Q., Kiviat, N., Strauss, R., Ni, S., Li, Z.Y., Roffler, S.R., Lieber, A.: Combination of tumor site-located CTL-associated antigen-4 blockade and systemic regulatory T-cell depletion induces tumor-destructive immune responses. Cancer Res. 67, 5929–5939 (2007)

    Article  CAS  PubMed  Google Scholar 

  • Upadhyay, R., Hammerich, L., Peng, P., Brown, B., Merad, M., Brody, J.D.: Lymphoma: immune evasion strategies. Cancers (Basel) 7, 736–762 (2015)

    Article  Google Scholar 

  • Varghese, S., Rabkin, S.D., Liu, R., Nielsen, P.G., Ipe, T., Martuza, R.L.: Enhanced therapeutic efficacy of IL-12, but not GM-CSF, expressing oncolytic herpes simplex virus for transgenic mouse derived prostate cancers. Cancer Gene Ther. 13, 253–265 (2006)

    Article  CAS  PubMed  Google Scholar 

  • Vom Berg, J., Vrohlings, M., Haller, S., Haimovici, A., Kulig, P., Sledzinska, A., Weller, M., Becher, B.: Intratumoral IL-12 combined with CTLA-4 blockade elicits T cell-mediated glioma rejection. J. Exp. Med. 210, 2803–2811 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vonderheide, R.H., Glennie, M.J.: Agonistic CD40 antibodies and cancer therapy. Clin. Cancer Res. 19, 1035–1043 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Voskens, C.J., Goldinger, S.M., Loquai, C., Robert, C., Kaehler, K.C., Berking, C., Bergmann, T., Bockmeyer, C.L., Eigentler, T., Fluck, M., Garbe, C., Gutzmer, R., Grabbe, S., Hauschild, A., Hein, R., Hundorfean, G., Justich, A., Keller, U., Klein, C., Mateus, C., Mohr, P., Paetzold, S., Satzger, I., Schadendorf, D., Schlaeppi, M., Schuler, G., Schuler-Thurner, B., Trefzer, U., Ulrich, J., Vaubel, J., von Moos, R., Weder, P., Wilhelm, T., Göppner, D., Dummer, R., Heinzerling, L.M.: The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network. PLoS One 8, e53745 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wallgren, A.C., Andersson, B., Backer, A., Karlsson-Parra, A.: Direct allorecognition promotes activation of bystander dendritic cells and licenses them for Th1 priming: a functional link between direct and indirect allosensitization. Scand. J. Immunol. 62, 234–242 (2005)

    Article  CAS  PubMed  Google Scholar 

  • Wang, C., Dai, Z., Fan, R., Deng, Y., Lv, G., Lu, G.: HSF1 overexpression enhances oncolytic effect of replicative adenovirus. J. Transl. Med. 8, 44 (2010)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Weide, B., Derhovanessian, E., Pflugfelder, A., Eigentler, T.K., Radny, P., Zelba, H., Pföhler, C., Pawelec, G., Garbe, C.: High response rate after intratumoral treatment with interleukin-2: results from a phase 2 study in 51 patients with metastasized melanoma. Cancer 116, 4139–4146 (2010)

    Article  CAS  PubMed  Google Scholar 

  • Won, E.K., Zahner, M.C., Grant, E.A., Gore, P., Chicoine, M.R.: Analysis of the antitumoral mechanisms of lipopolysaccharide against glioblastoma multiforme. Anticancer Drugs 14, 457–466 (2003)

    Article  CAS  PubMed  Google Scholar 

  • Wood, C., Srivastava, P., Bukowski, R., Lacombe, L., Gorelov, A.I., Gorelov, S., Mulders, P., Zielinski, H., Hoos, A., Teofilovici, F., Isakov, L., Flanigan, R., Figlin, R., Gupta, R., Escudier, B., C-100-12 RCC Study Group: An adjuvant autologous therapeutic vaccine (HSPPC-96; vitespen) versus observation alone for patients at high risk of recurrence after nephrectomy for renal cell carcinoma: a multicentre, open-label, randomised phase III trial. Lancet 372, 145–154 (2008)

    Article  CAS  PubMed  Google Scholar 

  • Wu, C.Y., Monie, A., Pang, X., Hung, C.F., Wu, T.C.: Improving therapeutic HPV peptide-based vaccine potency by enhancing CD4+ T help and dendritic cell activation. J. Biomed. Sci. 17, 88 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yizhi, Y., Xuetao, C., Hong, L., Quanxing, W., Qun, T.: The therapeutic effect of intratumoral injection of GM-CSF gene-modified allogenic macrophages on tumor-bearing mice. Chin. J. Cancer Res. 10, 1–5 (1998)

    Article  Google Scholar 

  • Zamarin, D., Holmgaard, R.B., Subudhi, S.K., Park, J.S., Mansour, M., Palese, P., Merghoub, T., Wolchok, J.D., Allison, J.P.: Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci. Transl. Med. 6, 226ra32 (2014)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zapała, Ł., Wolny, R., Wachowska, M., Jakóbisiak, M., Lasek, W.: Synergistic antitumor effect of JAWSII dendritic cells and interleukin 12 in a melanoma mouse model. Oncol. Rep. 29, 1208–1214 (2013)

    PubMed  Google Scholar 

  • Zhang, H., Liu, L., Yu, D., Kandimalla, E.R., Sun, H.B., Agrawal, S., Guha, C.: An in situ autologous tumor vaccination with combined radiation therapy and TLR9 agonist therapy. PLoS One 7, e38111 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang, W., Fulci, G., Wakimoto, H., Cheema, T.A., Buhrman, J.S., Jeyaretna, D.S., Stemmer Rachamimov, A.O., Rabkin, S.D., Martuza, R.L.: Combination of oncolytic herpes simplex viruses armed with angiostatin and IL-12 enhances antitumor efficacy in human glioblastoma models. Neoplasia 15, 591–599 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu, J., Huang, X., Yang, Y.: Innate immune response to adenoviral vectors is mediated by both Toll-like receptor-dependent and -independent pathways. J. Virol. 81, 3170–3180 (2007a)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu, X., Fallert-Junecko, B.A., Fujita, M., Ueda, R., Kohanbash, G., Kastenhuber, E.R., McDonald, H.A., Liu, Y., Kalinski, P., Reinhart, T.A., Salazar, A.M., Okada, H.: Poly-ICLC promotes the infiltration of effector T cells into intracranial gliomas via induction of CXCL10 in IFN-alpha and IFN-gamma dependent manners. Cancer Immunol. Immunother. 59, 1401–1409 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu, X., Nishimura, F., Sasaki, K., Fujita, M., Dusak, J.E., Eguchi, J., Fellows-Mayle, W., Storkus, W.J., Walker, P.R., Salazar, A.M., Okada, H.: Toll like receptor-3 ligand poly-ICLC promotes the efficacy of peripheral vaccinations with tumor antigen-derived peptide epitopes in murine CNS tumor models. J. Transl. Med. 5, 10 (2007b)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Linda Hammerich Ph.D.

  2. Lymphoma Immunotherapy Program, Division of Hematology and Medical OncologyIcahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Joshua D. Brody M.D.

Authors
  1. Linda Hammerich Ph.D.
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  2. Joshua D. Brody M.D.
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Correspondence to Joshua D. Brody M.D. .

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  1. SugarCone Biotech LLC, Holliston, Massachusetts, USA

    Paul D. Rennert

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Hammerich, L., Brody, J.D. (2016). Immunomodulation Within a Single Tumor Site to Induce Systemic Antitumor Immunity: In Situ Vaccination for Cancer. In: Rennert, P. (eds) Novel Immunotherapeutic Approaches to the Treatment of Cancer. Springer, Cham. https://doi.org/10.1007/978-3-319-29827-6_6

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