Skip to main content

Advertisement

SpringerLink
Log in

Intratumoral immunotherapy for melanoma

  • Focussed Research Review
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Selection of suitable tumor-associated antigens is a major challenge in the development of effective cancer vaccines. Intratumoral (i.t.) immunotherapy empowers the immune system to mount T cell responses against tumor-associated antigens which are most immunogenic. To mediate systemic tumor regression, i.t. immunotherapy must generate systemic T cell responses that can target distant metastases beyond the initially treated tumor mass. Now that promising preclinical results and some initial success in clinical trials have been obtained, we here review i.t. immunotherapy-related preclinical and clinical studies, their mechanisms of action and future prospects.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

APC:

Antigen-presenting cells

BCG:

Bacillus Calmette–Guerin

CTLA-4:

Cytotoxic T lymphocyte antigen-4

DCs:

Dendritic cells

IFN:

Interferon

IT:

Intratumoral

MDSC:

Myeloid-derived suppressor cells

NDV:

Newcastle disease virus

ODNs:

Oligodeoxynucleotides

PD-1:

Programmed death-1

PD-L1:

Programmed death-ligand

pDCs:

Plasmacytoid dendritic cells

poly-ICLC:

Polyinosinic-polycytidylicacid-polylysine-carboxymethylcellulose

TAAs:

Tumor-associated antigens

TLR:

Toll-like receptor

References

  1. Rosenberg SA, Yang JC, Restifo NP (2004) Cancer immunotherapy: moving beyond current vaccines. Nat Med 10:909–915. doi:10.1038/nm1100

    CAS  PubMed Central  PubMed  Google Scholar 

  2. van den Boorn JG, Hartmann G (2013) Turning tumors into vaccines: co-opting the innate immune system. Immunity 39:27–37. doi:10.1016/j.immuni.2013.07.011

    PubMed  Google Scholar 

  3. Singh M, Khong H, Dai Z, Huang XF, Wargo JA, Cooper ZA, Vasilakos JP, Hwu P, Overwijk WW (2014) Effective innate and adaptive antimelanoma immunity through localized TLR7/8 activation. J Immunol 193:4722–4731. doi:10.4049/jimmunol.1401160

    CAS  PubMed  Google Scholar 

  4. Nauts HC, Swift WE, Coley BL (1946) The treatment of malignant tumors by bacterial toxins as developed by the late William B. Coley, M.D., reviewed in the light of modern research. Cancer Res 6:205–216

    CAS  PubMed  Google Scholar 

  5. Stewart JH, Levine EA (2011) Role of bacillus Calmette–Guerin in the treatment of advanced melanoma. Expert Rev Anticancer Ther 11:1671–1676. doi:10.1586/era.11.163

    PubMed  Google Scholar 

  6. Kidner TB, Morton DL, Lee DJ, Hoban M, Foshag LJ, Turner RR, Faries MB (2012) Combined intralesional Bacille Calmette–Guerin (BCG) and topical imiquimod for in-transit melanoma. J Immunother 35:716–720. doi:10.1097/CJI.0b013e31827457bd

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Bast RC Jr, Zbar B, Borsos T, Rapp HJ (1974) BCG and cancer. N Engl J Med 290:1458–1469. doi:10.1056/NEJM197406272902605

    PubMed  Google Scholar 

  8. Paterson AH, Willans DJ, Jerry LM, Hanson J, McPherson TA (1984) Adjuvant BCG immunotherapy for malignant melanoma. Can Med Assoc J 131:744–748

    CAS  PubMed Central  PubMed  Google Scholar 

  9. Akazawa T, Masuda H, Saeki Y et al (2004) Adjuvant-mediated tumor regression and tumor-specific cytotoxic response are impaired in MyD88-deficient mice. Cancer Res 64:757–764

    CAS  PubMed  Google Scholar 

  10. Freedman VH, Gorrell TE, Nathan CF, Copeland CS, Silverstein SC (1984) Bacillus Calmette–Guerin-activated murine macrophages kill syngeneic melanoma cells under strict anaerobic conditions. J Exp Med 160:94–107

    CAS  PubMed  Google Scholar 

  11. Duda RB, Yang H, Dooley DD, Abu-Jawdeh G (1995) Recombinant BCG therapy suppresses melanoma tumor growth. Ann Surg Oncol 2:542–549

    CAS  PubMed  Google Scholar 

  12. Udagawa M, Kudo-Saito C, Hasegawa G et al (2006) Enhancement of immunologic tumor regression by intratumoral administration of dendritic cells in combination with cryoablative tumor pretreatment and Bacillus Calmette–Guerin cell wall skeleton stimulation. Clin Cancer Res 12:7465–7475. doi:10.1158/1078-0432.CCR-06-1840

    CAS  PubMed  Google Scholar 

  13. Hong EH, Chang SY, Lee BR, Pyun AR, Kim JW, Kweon MN, Ko HJ (2013) Intratumoral injection of attenuated Salmonella vaccine can induce tumor microenvironmental shift from immune suppressive to immunogenic. Vaccine 31:1377–1384. doi:10.1016/j.vaccine.2013.01.006

    CAS  PubMed  Google Scholar 

  14. Fox BA, Sanders KL, Chen S, Bzik DJ (2013) Targeting tumors with nonreplicating Toxoplasma gondii uracil auxotroph vaccines. Trends Parasitol 29:431–437. doi:10.1016/j.pt.2013.07.001

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Baird JR, Byrne KT, Lizotte PH et al (2013) Immune-mediated regression of established B16F10 melanoma by intratumoral injection of attenuated Toxoplasma gondii protects against rechallenge. J Immunol 190:469–478. doi:10.4049/jimmunol.1201209

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Alemany R (2013) Viruses in cancer treatment. Clin Transl Oncol 15:182–188. doi:10.1007/s12094-012-0951-7

    CAS  PubMed  Google Scholar 

  17. Ayala-Breton C, Barber GN, Russell SJ, Peng KW (2012) Retargeting vesicular stomatitis virus using measles virus envelope glycoproteins. Hum Gene Ther 23:484–491. doi:10.1089/hum.2011.146

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Sinkovics JG, Horvath JC (2000) Newcastle disease virus (NDV): brief history of its oncolytic strains. J Clin Virol 16:1–15

    CAS  PubMed  Google Scholar 

  19. Maass G, Bogedain C, Scheer U et al (1998) Recombinant adeno-associated virus for the generation of autologous, gene-modified tumor vaccines: evidence for a high transduction efficiency into primary epithelial cancer cells. Hum Gene Ther 9:1049–1059. doi:10.1089/hum.1998.9.7-1049

    CAS  PubMed  Google Scholar 

  20. Russell SJ, Peng KW, Bell JC (2012) Oncolytic virotherapy. Nat Biotechnol 30:658–670. doi:10.1038/nbt.2287

    CAS  PubMed  Google Scholar 

  21. van Rikxoort M, Michaelis M, Wolschek M, Muster T, Egorov A, Seipelt J, Doerr HW, Cinatl J Jr (2012) Oncolytic effects of a novel influenza A virus expressing interleukin-15 from the NS reading frame. PLoS ONE 7:e36506. doi:10.1371/journal.pone.0036506

    PubMed Central  PubMed  Google Scholar 

  22. Au GG, Beagley LG, Haley ES, Barry RD, Shafren DR (2011) Oncolysis of malignant human melanoma tumors by Coxsackieviruses A13, A15 and A18. Virol J. 8:22. doi:10.1186/1743-422X-8-22

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Prestwich RJ, Errington F, Ilett EJ et al (2008) Tumor infection by oncolytic reovirus primes adaptive antitumor immunity. Clin Cancer Res 14:7358–7366. doi:10.1158/1078-0432.CCR-08-0831

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Wongthida P, Diaz RM, Galivo F, Kottke T, Thompson J, Melcher A, Vile R (2011) VSV oncolytic virotherapy in the B16 model depends upon intact MyD88 signaling. Mol Ther 19:150–158. doi:10.1038/mt.2010.225

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Moehler MH, Zeidler M, Wilsberg V, Cornelis JJ, Woelfel T, Rommelaere J, Galle PR, Heike M (2005) Parvovirus H-1-induced tumor cell death enhances human immune response in vitro via increased phagocytosis, maturation, and cross-presentation by dendritic cells. Hum Gene Ther 16:996–1005. doi:10.1089/hum.2005.16.996

    CAS  PubMed  Google Scholar 

  26. Brun J, Mahoney DJ, Le Boeuf F, Lefebvre C, Sanaei CA, Falls T, McCart JA, Stojdl DF (2013) Oncolytic Vaccinia virus safely and effectively treats skin tumors in mouse models of xeroderma pigmentosum. Int J Cancer 132:726–731. doi:10.1002/ijc.27695

    CAS  PubMed  Google Scholar 

  27. MacTavish H, Diallo JS, Huang B et al (2010) Enhancement of vaccinia virus based oncolysis with histone deacetylase inhibitors. PLoS ONE 5:e14462. doi:10.1371/journal.pone.0014462

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Donnelly OG, Errington-Mais F, Steele L et al (2013) Measles virus causes immunogenic cell death in human melanoma. Gene Ther 20:7–15. doi:10.1038/gt.2011.205

    CAS  PubMed Central  PubMed  Google Scholar 

  29. Stanford MM, Shaban M, Barrett JW et al (2008) Myxoma virus oncolysis of primary and metastatic B16F10 mouse tumors in vivo. Mol Ther 16:52–59. doi:10.1038/sj.mt.6300348

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Prestwich RJ, Ilett EJ, Errington F et al (2009) Immune-mediated antitumor activity of reovirus is required for therapy and is independent of direct viral oncolysis and replication. Clin Cancer Res 15:4374–4381. doi:10.1158/1078-0432.CCR-09-0334

    CAS  PubMed  Google Scholar 

  31. Cerullo V, Seiler MP, Mane V, Brunetti-Pierri N, Clarke C, Bertin TK, Rodgers JR, Lee B (2007) Toll-like receptor 9 triggers an innate immune response to helper-dependent adenoviral vectors. Mol Ther 15:378–385. doi:10.1038/sj.mt.6300031

    CAS  PubMed  Google Scholar 

  32. Andoniou CE, van Dommelen SL, Voigt V et al (2005) Interaction between conventional dendritic cells and natural killer cells is integral to the activation of effective antiviral immunity. Nat Immunol 6:1011–1019. doi:10.1038/ni1244

    CAS  PubMed  Google Scholar 

  33. Edukulla R, Woller N, Mundt B et al (2009) Antitumoral immune response by recruitment and expansion of dendritic cells in tumors infected with telomerase-dependent oncolytic viruses. Cancer Res 69:1448–1458. doi:10.1158/0008-5472.CAN-08-1160

    PubMed  Google Scholar 

  34. Wongthida P, Diaz RM, Pulido C et al (2011) Activating systemic T-cell immunity against self tumor antigens to support oncolytic virotherapy with vesicular stomatitis virus. Hum Gene Ther 22:1343–1353. doi:10.1089/hum.2010.216

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Bridle BW, Stephenson KB, Boudreau JE et al (2010) Potentiating cancer immunotherapy using an oncolytic virus. Mol Ther 18:1430–1439. doi:10.1038/mt.2010.98

    CAS  PubMed Central  PubMed  Google Scholar 

  36. Shafren DR, Au GG, Nguyen T, Newcombe NG, Haley ES, Beagley L, Johansson ES, Hersey P, Barry RD (2004) Systemic therapy of malignant human melanoma tumors by a common cold-producing enterovirus, coxsackievirus a21. Clin Cancer Res 10:53–60

    CAS  PubMed  Google Scholar 

  37. Hersey P, Gallagher S (2014) Intralesional immunotherapy for melanoma. J Surg Oncol 109:320–326. doi:10.1002/jso.23494

    CAS  PubMed  Google Scholar 

  38. Galivo F, Diaz RM, Thanarajasingam U et al (2010) Interference of CD40L-mediated tumor immunotherapy by oncolytic vesicular stomatitis virus. Hum Gene Ther 21:439–450. doi:10.1089/hum.2009.143

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Diaconu I, Cerullo V, Hirvinen ML et al (2012) Immune response is an important aspect of the antitumor effect produced by a CD40L-encoding oncolytic adenovirus. Cancer Res 72:2327–2338. doi:10.1158/0008-5472.CAN-11-2975

    CAS  PubMed  Google Scholar 

  40. Andarini S, Kikuchi T, Nukiwa M et al (2004) Adenovirus vector-mediated in vivo gene transfer of OX40 ligand to tumor cells enhances antitumor immunity of tumor-bearing hosts. Cancer Res 64:3281–3287

    CAS  PubMed  Google Scholar 

  41. Hayata K, Iwahashi M, Ojima T et al (2013) Inhibition of IL-17A in tumor microenvironment augments cytotoxicity of tumor-infiltrating lymphocytes in tumor-bearing mice. PLoS ONE 8:e53131. doi:10.1371/journal.pone.0053131

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Rommelfanger DM, Compte M, Diaz RM, Ilett E, Alvarez-Vallina L, Thompson JM, Kottke TJ, Melcher A, Vile RG (2013) 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. doi:10.1038/mt.2012.204

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Zamarin D, Holmgaard RB, Subudhi SK, Park JS, Mansour M, Palese P, Merghoub T, Wolchok JD, Allison JP (2014) Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci Transl Med 6:226ra32. doi:10.1126/scitranslmed.3008095

    PubMed Central  PubMed  Google Scholar 

  44. Mastrangelo MJ, Maguire HC Jr, Eisenlohr LC, Laughlin CE, Monken CE, McCue PA, Kovatich AJ, Lattime EC (1999) Intratumoral recombinant GM-CSF-encoding virus as gene therapy in patients with cutaneous melanoma. Cancer Gene Ther 6:409–422. doi:10.1038/sj.cgt.7700066

    CAS  PubMed  Google Scholar 

  45. Senzer NN, Kaufman HL, Amatruda T et al (2009) 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. doi:10.1200/JCO.2009.24.3675

    CAS  PubMed  Google Scholar 

  46. Goins WF, Huang S, Cohen JB, Glorioso JC (2014) Engineering HSV-1 vectors for gene therapy. Methods Mol Biol 1144:63–79. doi:10.1007/978-1-4939-0428-0_5

    CAS  PubMed  Google Scholar 

  47. Dummer R, Rochlitz C, Velu T et al (2008) Intralesional adenovirus-mediated interleukin-2 gene transfer for advanced solid cancers and melanoma. Mol Ther 16:985–994. doi:10.1038/mt.2008.32

    CAS  PubMed  Google Scholar 

  48. Gupta P, Su ZZ, Lebedeva IV et al (2006) mda-7/IL-24: multifunctional cancer-specific apoptosis-inducing cytokine. Pharmacol Ther 111:596–628. doi:10.1016/j.pharmthera.2005.11.005

    CAS  PubMed Central  PubMed  Google Scholar 

  49. Ning J, Wakimoto H (2014) Oncolytic herpes simplex virus-based strategies: toward a breakthrough in glioblastoma therapy. Front Microbiol 5:303. doi:10.3389/fmicb.2014.00303

    PubMed Central  PubMed  Google Scholar 

  50. Amos SM, Pegram HJ, Westwood JA et al (2011) Adoptive immunotherapy combined with intratumoral TLR agonist delivery eradicates established melanoma in mice. Cancer Immunol Immunother 60:671–683. doi:10.1007/s00262-011-0984-8

    CAS  PubMed Central  PubMed  Google Scholar 

  51. Lou Y, Liu C, Lizee G et al (2011) Antitumor activity mediated by CpG: the route of administration is critical. J Immunother 34:279–288. doi:10.1097/CJI.0b013e31820d2a05

    CAS  PubMed  Google Scholar 

  52. Nierkens S, den Brok MH, Roelofsen T, Wagenaars JA, Figdor CG, Ruers TJ, Adema GJ (2009) Route of administration of the TLR9 agonist CpG critically determines the efficacy of cancer immunotherapy in mice. PLoS ONE 4:e8368. doi:10.1371/journal.pone.0008368

    PubMed Central  PubMed  Google Scholar 

  53. Nierkens S, den Brok MH, Garcia Z et al (2011) Immune adjuvant efficacy of CpG oligonucleotide in cancer treatment is founded specifically upon TLR9 function in plasmacytoid dendritic cells. Cancer Res 71:6428–6437. doi:10.1158/0008-5472.CAN-11-2154

    CAS  PubMed Central  PubMed  Google Scholar 

  54. Marabelle A, Kohrt H, Sagiv-Barfi I et al (2013) Depleting tumor-specific Tregs at a single site eradicates disseminated tumors. J Clin Invest 123:2447–2463. doi:10.1172/JCI64859

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Shirota Y, Shirota H, Klinman DM (2012) Intratumoral injection of CpG oligonucleotides induces the differentiation and reduces the immunosuppressive activity of myeloid-derived suppressor cells. J Immunol 188:1592–1599. doi:10.4049/jimmunol.1101304

    CAS  PubMed Central  PubMed  Google Scholar 

  56. Kobayashi N, Hong C, Klinman DM, Shirota H (2013) Oligodeoxynucleotides expressing polyguanosine motifs promote antitumor activity through the upregulation of IL-2. J Immunol 190:1882–1889. doi:10.4049/jimmunol.1201063

    CAS  PubMed Central  PubMed  Google Scholar 

  57. Stone GW, Barzee S, Snarsky V, Santucci C, Tran B, Langer R, Zugates GT, Anderson DG, Kornbluth RS (2009) Nanoparticle-delivered multimeric soluble CD40L DNA combined with Toll-Like Receptor agonists as a treatment for melanoma. PLoS ONE 4:e7334. doi:10.1371/journal.pone.0007334

    PubMed Central  PubMed  Google Scholar 

  58. Davis MB, Vasquez-Dunddel D, Fu J, Albesiano E, Pardoll D, Kim YJ (2011) Intratumoral administration of TLR4 agonist absorbed into a cellular vector improves antitumor responses. Clin Cancer Res 17:3984–3992. doi:10.1158/1078-0432.CCR-10-3262

    CAS  PubMed Central  PubMed  Google Scholar 

  59. Oldford SA, Haidl ID, Howatt MA, Leiva CA, Johnston B, Marshall JS (2010) A critical role for mast cells and mast cell-derived IL-6 in TLR2-mediated inhibition of tumor growth. J Immunol 185:7067–7076. doi:10.4049/jimmunol.1001137

    CAS  PubMed  Google Scholar 

  60. Craft N, Bruhn KW, Nguyen BD, Prins R, Lin JW, Liau LM, Miller JF (2005) The TLR7 agonist imiquimod enhances the anti-melanoma effects of a recombinant Listeria monocytogenes vaccine. J Immunol 175:1983–1990

    CAS  PubMed  Google Scholar 

  61. Hayashi T, Chan M, Norton JT et al (2011) Additive melanoma suppression with intralesional phospholipid-conjugated TLR7 agonists and systemic IL-2. Melanoma Res 21:66–75. doi:10.1097/CMR.0b013e328340ce6c

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Kalb ML, Glaser A, Stary G, Koszik F, Stingl G (2012) TRAIL(+) human plasmacytoid dendritic cells kill tumor cells in vitro: mechanisms of imiquimod- and IFN-alpha-mediated antitumor reactivity. J Immunol 188:1583–1591. doi:10.4049/jimmunol.1102437

    CAS  PubMed  Google Scholar 

  63. Drobits B, Holcmann M, Amberg N, Swiecki M, Grundtner R, Hammer M, Colonna M, Sibilia M (2012) Imiquimod clears tumors in mice independent of adaptive immunity by converting pDCs into tumor-killing effector cells. J Clin Invest 122:575–585. doi:10.1172/JCI61034

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Tamada K, Chen L (2006) Renewed interest in cancer immunotherapy with the tumor necrosis factor superfamily molecules. Cancer Immunol Immunother 55:355–362. doi:10.1007/s00262-005-0081-y

    CAS  PubMed  Google Scholar 

  65. Kwong B, Gai SA, Elkhader J, Wittrup KD, Irvine DJ (2013) Localized immunotherapy via liposome-anchored Anti-CD137+ IL-2 prevents lethal toxicity and elicits local and systemic antitumor immunity. Cancer Res 73:1547–1558. doi:10.1158/0008-5472.CAN-12-3343

    CAS  PubMed Central  PubMed  Google Scholar 

  66. Quetglas JI, Dubrot J, Bezunartea J, Sanmamed MF, Hervas-Stubbs S, Smerdou C, Melero I (2012) Immunotherapeutic synergy between anti-CD137 mAb and intratumoral administration of a cytopathic Semliki Forest virus encoding IL-12. Mol Ther 20:1664–1675. doi:10.1038/mt.2012.56

    CAS  PubMed Central  PubMed  Google Scholar 

  67. Marabelle A, Kohrt H, Caux C, Levy R (2014) Intratumoral immunization: a new paradigm for cancer therapy. Clin Cancer Res 20:1747–1756. doi:10.1158/1078-0432.CCR-13-2116

    CAS  PubMed Central  PubMed  Google Scholar 

  68. Marabelle A, Kohrt H, Levy R (2013) Intratumoral anti-CTLA-4 therapy: enhancing efficacy while avoiding toxicity. Clin Cancer Res 19:5261–5263. doi:10.1158/1078-0432.CCR-13-1923

    CAS  PubMed  Google Scholar 

  69. Fransen MF, Ossendorp F, Arens R, Melief CJ (2013) Local immunomodulation for cancer therapy: providing treatment where needed. Oncoimmunology 2:e26493. doi:10.4161/onci.26493

    PubMed Central  PubMed  Google Scholar 

  70. Ishikawa H, Barber GN (2008) STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455:674–678. doi:10.1038/nature07317

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Gajewski TF, Corrales L (2015) New perspectives on type I IFNs in cancer. Cytokine Growth Factor Rev 26:175–178. doi:10.1016/j.cytogfr.2015.01.001

    CAS  PubMed  Google Scholar 

  72. Nakhaei P, Hiscott J, Lin R (2010) STING-ing the antiviral pathway. J Mol Cell Biol 2:110–112. doi:10.1093/jmcb/mjp048

    CAS  PubMed  Google Scholar 

  73. Burdette DL, Vance RE (2013) STING and the innate immune response to nucleic acids in the cytosol. Nat Immunol 14:19–26. doi:10.1038/ni.2491

    CAS  PubMed  Google Scholar 

  74. Fuertes MB, Kacha AK, Kline J, Woo SR, Kranz DM, Murphy KM, Gajewski TF (2011) Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8{alpha} + dendritic cells. J Exp Med 208:2005–2016. doi:10.1084/jem.20101159

    CAS  PubMed Central  PubMed  Google Scholar 

  75. Ishikawa H, Ma Z, Barber GN (2009) STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461:788–792. doi:10.1038/nature08476

    CAS  PubMed  Google Scholar 

  76. Woo SR, Fuertes MB, Corrales L et al (2014) STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 41:830–842. doi:10.1016/j.immuni.2014.10.017

    CAS  PubMed  Google Scholar 

  77. Woo SR, Corrales L, Gajewski TF (2015) The STING pathway and the T cell-inflamed tumor microenvironment. Trends Immunol 36:250–256. doi:10.1016/j.it.2015.02.003

    CAS  PubMed  Google Scholar 

  78. Ohkuri T, Ghosh A, Kosaka A, Zhu J, Ikeura M, David M, Watkins SC, Sarkar SN, Okada H (2014) STING contributes to antiglioma immunity via triggering type I IFN signals in the tumor microenvironment. Cancer Immunol Res 2:1199–1208. doi:10.1158/2326-6066.CIR-14-0099

    CAS  PubMed  Google Scholar 

  79. Woodmansee C, Pillow J, Skinner RB Jr (2006) The role of topical immune response modifiers in skin cancer. Drugs 66:1657–1664

    CAS  PubMed  Google Scholar 

  80. Alessi SS, Sanches JA, Oliveira WR, Messina MC, Pimentel ER, Festa Neto C (2009) Treatment of cutaneous tumors with topical 5% imiquimod cream. Clinics (Sao Paulo) 64:961–966. doi:10.1590/S1807-59322009001000005

    Google Scholar 

  81. Garland SM, Sellors JW, Wikstrom A, Petersen CS, Aranda C, Aractingi S, Maw RD, Imiquimod Study G (2001) Imiquimod 5% cream is a safe and effective self-applied treatment for anogenital warts–results of an open-label, multicentre Phase IIIB trial. Int J STD AIDS 12:722–729

    CAS  PubMed  Google Scholar 

  82. Ooi T, Barnetson RS, Zhuang L, McKane S, Lee JH, Slade HB, Halliday GM (2006) Imiquimod-induced regression of actinic keratosis is associated with infiltration by T lymphocytes and dendritic cells: a randomized controlled trial. Br J Dermatol 154:72–78. doi:10.1111/j.1365-2133.2005.06932.x

    CAS  PubMed  Google Scholar 

  83. Stockfleth E, Trefzer U, Garcia-Bartels C, Wegner T, Schmook T, Sterry W (2003) The use of Toll-like receptor-7 agonist in the treatment of basal cell carcinoma: an overview. Br J Dermatol 149(Suppl 66):53–56

    CAS  PubMed  Google Scholar 

  84. Smirnov D, Schmidt JJ, Capecchi JT, Wightman PD (2011) Vaccine adjuvant activity of 3M-052: an imidazoquinoline designed for local activity without systemic cytokine induction. Vaccine 29:5434–5442. doi:10.1016/j.vaccine.2011.05.061

    CAS  PubMed  Google Scholar 

  85. Hofmann MA, Kors C, Audring H, Walden P, Sterry W, Trefzer U (2008) Phase 1 evaluation of intralesionally injected TLR9-agonist PF-3512676 in patients with basal cell carcinoma or metastatic melanoma. J Immunother 31:520–527. doi:10.1097/CJI.0b013e318174a4df

    CAS  PubMed  Google Scholar 

  86. Carpentier A, Metellus P, Ursu R et al (2010) Intracerebral administration of CpG oligonucleotide for patients with recurrent glioblastoma: a phase II study. Neuro Oncol 12:401–408. doi:10.1093/neuonc/nop047

    CAS  PubMed Central  PubMed  Google Scholar 

  87. Salazar AM, Erlich RB, Mark A, Bhardwaj N, Herberman RB (2014) Therapeutic in situ autovaccination against solid cancers with intratumoral poly-ICLC: case report, hypothesis, and clinical trial. Cancer Immunol Res 2:720–724. doi:10.1158/2326-6066.CIR-14-0024

    PubMed  Google Scholar 

  88. Vom Berg J, Vrohlings M, Haller S, Haimovici A, Kulig P, Sledzinska A, Weller M, Becher B (2013) Intratumoral IL-12 combined with CTLA-4 blockade elicits T cell-mediated glioma rejection. J Exp Med 210:2803–2811. doi:10.1084/jem.20130678

    CAS  PubMed Central  PubMed  Google Scholar 

  89. Sondergaard H, Galsgaard ED, Bartholomaeussen M, Straten PT, Odum N, Skak K (2010) Intratumoral interleukin-21 increases antitumor immunity, tumor-infiltrating CD8+ T-cell density and activity, and enlarges draining lymph nodes. J Immunother 33:236–249. doi:10.1097/CJI.0b013e3181c0c1cb

    PubMed  Google Scholar 

  90. Cha E, Daud A (2012) Plasmid IL-12 electroporation in melanoma. Hum Vaccin Immunother 8:1734–1738. doi:10.4161/hv.22573

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Chinnasamy D, Yu Z, Kerkar SP, Zhang L, Morgan RA, Restifo NP, Rosenberg SA (2012) Local delivery of interleukin-12 using T cells targeting VEGF receptor-2 eradicates multiple vascularized tumors in mice. Clin Cancer Res 18:1672–1683. doi:10.1158/1078-0432.CCR-11-3050

    CAS  PubMed  Google Scholar 

  92. Yang RK, Kalogriopoulos NA, Rakhmilevich AL et al (2012) 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 189:2656–2664. doi:10.4049/jimmunol.1200934

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Pan J, Zhang M, Wang J, Wang Q, Xia D, Sun W, Zhang L, Yu H, Cao X (2005) 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 131:468–478. doi:10.1007/s00432-004-0651-y

    CAS  PubMed  Google Scholar 

  94. Van der Jeught K, Joe PT, Bialkowski L, Heirman C, Daszkiewicz L, Liechtenstein T, Escors D, Thielemans K, Breckpot K (2014) Intratumoral administration of mRNA encoding a fusokine consisting of IFN-beta and the ectodomain of the TGF-beta receptor II potentiates antitumor immunity. Oncotarget 5:10100–10113

    PubMed Central  PubMed  Google Scholar 

  95. Heinzerling L, Burg G, Dummer R, Maier T, Oberholzer PA, Schultz J, Elzaouk L, Pavlovic J, Moelling K (2005) Intratumoral injection of DNA encoding human interleukin 12 into patients with metastatic melanoma: clinical efficacy. Hum Gene Ther 16:35–48. doi:10.1089/hum.2005.16.35

    CAS  PubMed  Google Scholar 

  96. Weide B, Eigentler TK, Pflugfelder A et al (2014) Intralesional treatment of stage III metastatic melanoma patients with L19-IL2 results in sustained clinical and systemic immunologic responses. Cancer Immunol Res 2:668–678. doi:10.1158/2326-6066.CIR-13-0206

    CAS  PubMed  Google Scholar 

  97. Okano S, Kondoh H, Toshima T et al (2013) Fas-deficient fully allogeneic dendritic cells administered via an intratumoral injection route show efficient antitumor effects in murine models. Fukuoka Igaku Zasshi 104:15–26

    CAS  PubMed  Google Scholar 

  98. Liu C, Lou Y, Lizee G et al (2008) Plasmacytoid dendritic cells induce NK cell-dependent, tumor antigen-specific T cell cross-priming and tumor regression in mice. J Clin Invest 118:1165–1175. doi:10.1172/JCI33583

    CAS  PubMed Central  PubMed  Google Scholar 

  99. Mito K, Sugiura K, Ueda K et al (2010) IFN{gamma} markedly cooperates with intratumoral dendritic cell vaccine in dog tumor models. Cancer Res 70:7093–7101. doi:10.1158/0008-5472.CAN-10-0600

    CAS  PubMed  Google Scholar 

  100. Fujimura T, Nakagawa S, Ohtani T, Ito Y, Aiba S (2006) Inhibitory effect of the polyinosinic-polycytidylic acid/cationic liposome on the progression of murine B16F10 melanoma. Eur J Immunol 36:3371–3380. doi:10.1002/eji.200636053

    CAS  PubMed  Google Scholar 

  101. Shevtsov MA, Kim AV, Samochernych KA, Romanova IV, Margulis BA, Guzhova IV, Yakovenko IV, Ischenko AM, Khachatryan WA (2014) Pilot study of intratumoral injection of recombinant heat shock protein 70 in the treatment of malignant brain tumors in children. Onco Targets Ther 7:1071–1081. doi:10.2147/OTT.S62764

    PubMed Central  PubMed  Google Scholar 

  102. Galili U (2011) Conversion of tumors into autologous vaccines by intratumoral injection of alpha-Gal glycolipids that induce anti-Gal/alpha-Gal epitope interaction. Clin Dev Immunol. doi:10.1155/2011/134020

    PubMed Central  PubMed  Google Scholar 

  103. Doukas J, Rolland A (2012) Mechanisms of action underlying the immunotherapeutic activity of Allovectin in advanced melanoma. Cancer Gene Ther 19:811–817. doi:10.1038/cgt.2012.69

    CAS  PubMed Central  PubMed  Google Scholar 

  104. Sandin LC, Eriksson F, Ellmark P, Loskog AS, Totterman TH, Mangsbo SM (2014) Local CTLA4 blockade effectively restrains experimental pancreatic adenocarcinoma growth in vivo. Oncoimmunology 3:e27614. doi:10.4161/onci.27614

    PubMed Central  PubMed  Google Scholar 

  105. Mahvi DM, Henry MB, Albertini MR, Weber S, Meredith K, Schalch H, Rakhmilevich A, Hank J, Sondel P (2007) Intratumoral injection of IL-12 plasmid DNA-results of a phase I/IB clinical trial. Cancer Gene Ther 14:717–723. doi:10.1038/sj.cgt.7701064

    CAS  PubMed  Google Scholar 

  106. Hofbauer GF, Baur T, Bonnet MC, Tartour E, Burg G, Berinstein NL, Dummer R (2008) Clinical phase I intratumoral administration of two recombinant ALVAC canarypox viruses expressing human granulocyte-macrophage colony-stimulating factor or interleukin-2: the transgene determines the composition of the inflammatory infiltrate. Melanoma Res 18:104–111. doi:10.1097/CMR.0b013e3282f702cf

    CAS  PubMed  Google Scholar 

  107. Kaufman HL, Kim DW, DeRaffele G, Mitcham J, Coffin RS, Kim-Schulze S (2010) 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. doi:10.1245/s10434-009-0809-6

    PubMed  Google Scholar 

  108. Khorana AA, Rosenblatt JD, Sahasrabudhe DM et al (2003) A phase I trial of immunotherapy with intratumoral adenovirus-interferon-gamma (TG1041) in patients with malignant melanoma. Cancer Gene Ther 10:251–259. doi:10.1038/sj.cgt.7700568

    CAS  PubMed  Google Scholar 

  109. Rochlitz C, Dreno B, Jantscheff P et al (2002) Immunotherapy of metastatic melanoma by intratumoral injections of Vero cells producing human IL-2: phase II randomized study comparing two dose levels. Cancer Gene Ther 9:289–295. doi:10.1038/sj.cgt.7700441

    CAS  PubMed  Google Scholar 

  110. Triozzi PL, Khurram R, Aldrich WA, Walker MJ, Kim JA, Jaynes S (2000) Intratumoral injection of dendritic cells derived in vitro in patients with metastatic cancer. Cancer 89:2646–2654

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Institutes of Health (NIH) Grants R01 1CA143077 (Willem W. Overwijk), P01 CA128913 (Patrick Hwu/Willem W. Overwijk).

Conflict of interest

The authors disclose no potential conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 7455 Fannin St., Unit 0904, Houston, TX, 77030, USA

    Manisha Singh & Willem W. Overwijk

  2. The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA

    Willem W. Overwijk

Authors
  1. Manisha Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Willem W. Overwijk
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Willem W. Overwijk.

Additional information

This paper is a Focussed Research Review based on a presentation given at the Twelfth Annual Meeting of the Association for Cancer Immunotherapy (CIMT), held in Mainz, Germany, 6th–8th May, 2014. It is part of a CII series of Focussed Research Reviews and meeting report.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Singh, M., Overwijk, W.W. Intratumoral immunotherapy for melanoma. Cancer Immunol Immunother 64, 911–921 (2015). https://doi.org/10.1007/s00262-015-1727-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-015-1727-z

Keywords

Search

Navigation