Cancer Immunology, Immunotherapy

, Volume 66, Issue 5, pp 647–656 | Cite as

Intralesional treatment of metastatic melanoma: a review of therapeutic options

Focussed Research Review

Abstract

Intralesional therapy of melanoma patients with locally advanced metastatic disease is attracting increasing interest, not least due to its ability to lead to both direct tumor cell killing and the stimulation of both a local and a systemic immune response. An obvious pre-requisite for this type of approach is the presence of accessible metastases that are amenable to direct injection with the therapeutic agent of interest. Patients who present with these characteristics belong to stages IIIB/C or IV of the disease. Surgical resection with intention to cure is the standard of care for patients with limited tumor burden and confined spread of disease (resectable patients). However, this category of patients is at a high risk of further recurrences until the disease becomes inoperable (unresectable) or progresses to a more advanced stage with visceral organ involvement, after which the prognosis is particularly grim. Most of the intralesional treatments tested so far, including the recently approved oncolytic virus talimogene laherparepvec, target the subpopulation of patients with unresectable disease, but the possibility to use the intralesional treatment in a neoadjuvant setting for fully resectable patients is attracting considerable interest. The present article reviews approved products and advanced stage pharmaceutical agents in development for the intralesional treatment of melanoma patients.

Keywords

Intralesional Immunocytokine Neoadjuvant Stage III B/C melanoma Phase 3 CIMT 2016 

Abbreviations

AEs

Adverse events

CR

Complete responses

CTLA-4

Cytotoxic T lymphocyte antigen 4

DLT

Dose-limiting toxicity

DPCP

Diphencyprone

ECOG

Eastern Cooperative Oncology Group

EMA

European medicine agency

FDA

Food and drug administration

IFNa

Interferon α

IFNb

Interferon β

IL2

Interleukin-2

ILP

Isolated limb perfusion

irRC

Immune-related response criteria

ITT

Intention-to-treat

OR

Objective response

ORR

Objective response rate

PFS

Progression-free survival

PR

Partial response

PV-10

Rose Bengal (Provectus)

RFS

Recurrence-free survival

TLR7

Toll-like receptor 7

TNF

Tumor necrosis factor α

T-Vec

Talimogene laherparepvec, Imlygic™ (Amgen)

References

  1. 1.
    Geller AC, Annas GD (2003) Epidemiology of melanoma and nonmelanoma skin cancer. Semin Oncol Nurs 19(1):2–11CrossRefPubMedGoogle Scholar
  2. 2.
    Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, Forman D, Bray F (2013) Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer 49(6):1374–1403. doi:10.1016/j.ejca.2012.12.027 CrossRefPubMedGoogle Scholar
  3. 3.
    Balch CM, Gershenwald JE, Soong SJ et al (2009) Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 27(36):6199–6206. doi:10.1200/JCO.2009.23.4799 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Essner R, Lee JH, Wanek LA, Itakura H, Morton DL (2004) Contemporary surgical treatment of advanced-stage melanoma. Arch Surg 139(9):961–966. doi:10.1001/archsurg.139.9.961 (discussion 966–967)CrossRefPubMedGoogle Scholar
  5. 5.
    Lee CC, Faries MB, Wanek LA, Morton DL (2009) Improved survival for stage IV melanoma from an unknown primary site. J Clin Oncol 27(21):3489–3495. doi:10.1200/JCO.2008.18.9845 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Meier F, Will S, Ellwanger U, Schlagenhauff B, Schittek B, Rassner G, Garbe C (2002) Metastatic pathways and time courses in the orderly progression of cutaneous melanoma. Br J Dermatol 147(1):62–70CrossRefPubMedGoogle Scholar
  7. 7.
    Abbott AM, Zager JS (2014) Locoregional therapies in melanoma. Surg Clin North Am 94(5):1003–1015, viii. doi:10.1016/j.suc.2014.07.004 Google Scholar
  8. 8.
    Andtbacka RH, Kaufman HL, Collichio F et al (2015) Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol 33(25):2780–2788. doi:10.1200/JCO.2014.58.3377 CrossRefPubMedGoogle Scholar
  9. 9.
    Weide B, Derhovanessian E, Pflugfelder A, Eigentler TK, Radny P, Zelba H, Pfohler C, Pawelec G, Garbe C (2010) High response rate after intratumoral treatment with interleukin-2: results from a phase 2 study in 51 patients with metastasized melanoma. Cancer 116(17):4139–4146. doi:10.1002/cncr.25156 CrossRefPubMedGoogle Scholar
  10. 10.
    Mastrangelo MJ, Bellet RE, Berkelhammer J, Clark WH Jr (1975) Regression of pulmonary metastatic disease associated with intralesional BCG therapy of intracutaneous melanoma metastases. Cancer 36(4):1305–1308CrossRefPubMedGoogle Scholar
  11. 11.
    Boyd KU, Wehrli BM, Temple CL (2011) Intra-lesional interleukin-2 for the treatment of in-transit melanoma. J Surg Oncol 104(7):711–717. doi:10.1002/jso.21968 CrossRefPubMedGoogle Scholar
  12. 12.
    Dehesa LA, Vilar-Alejo J, Valeron-Almazan P, Carretero G (2009) [Experience in the treatment of cutaneous in-transit melanoma metastases and satellitosis with intralesional interleukin-2]. Actas Dermosifiliogr 100(7):571–585CrossRefPubMedGoogle Scholar
  13. 13.
    Gutwald JG, Groth W, Mahrle G (1994) Peritumoral injections of interleukin 2 induce tumour regression in metastatic malignant melanoma. Br J Dermatol 130(4):541–542CrossRefPubMedGoogle Scholar
  14. 14.
    Radny P, Caroli UM, Bauer J, Paul T, Schlegel C, Eigentler TK, Weide B, Schwarz M, Garbe C (2003) Phase II trial of intralesional therapy with interleukin-2 in soft-tissue melanoma metastases. Br J Cancer 89(9):1620–1626. doi:10.1038/sj.bjc.6601320 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    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(7):668–678. doi:10.1158/2326-6066.CIR-13-0206 CrossRefPubMedGoogle Scholar
  16. 16.
    Pretto F, Elia G, Castioni N, Neri D (2014) Preclinical evaluation of IL2-based immunocytokines supports their use in combination with dacarbazine, paclitaxel and TNF-based immunotherapy. Cancer Immunol Immunother 63(9):901–910. doi:10.1007/s00262-014-1562-7 CrossRefPubMedGoogle Scholar
  17. 17.
    Marabelle A, Kohrt H, Caux C, Levy R (2014) Intratumoral immunization: a new paradigm for cancer therapy. Clin Cancer Res 20(7):1747–1756. doi:10.1158/1078-0432.CCR-13-2116 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Temizoz B, Kuroda E, Ishii KJ (2016) Vaccine adjuvants as potential cancer immunotherapeutics. Int Immunol 28(7):329–338. doi:10.1093/intimm/dxw015 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Kaufman HL, Kohlhapp FJ, Zloza A (2015) Oncolytic viruses: a new class of immunotherapy drugs. Nat Rev Drug Discov 14(9):642–662. doi:10.1038/nrd4663 CrossRefPubMedGoogle Scholar
  20. 20.
    Karakousis CP, Douglass HO Jr, Yeracaris PM, Holyoke ED (1976) BCG immunotherapy in patients with malignant melanoma. Arch Surg 111(6):716–718CrossRefPubMedGoogle Scholar
  21. 21.
    Robinson JC (1977) Risks of BCG intralesional therapy: an experience with melanoma. J Surg Oncol 9(6):587–593CrossRefPubMedGoogle Scholar
  22. 22.
    Barth A, Morton DL (1995) The role of adjuvant therapy in melanoma management. Cancer 75(2 Suppl):726–734CrossRefPubMedGoogle Scholar
  23. 23.
    Seigler HF, Shingleton WW, Pickrell KL (1975) Intralesional BCG, intravenous immune lymphocytes, and immunization with neuraminidase-treated tumor cells to manage melanoma; a clinical assessment. Plast Reconstr Surg 55(3):294–298CrossRefPubMedGoogle Scholar
  24. 24.
    Agarwala SS, Neuberg D, Park Y, Kirkwood JM (2004) Mature results of a phase III randomized trial of bacillus Calmette-Guerin (BCG) versus observation and BCG plus dacarbazine versus BCG in the adjuvant therapy of American Joint Committee on Cancer Stage I-III melanoma (E1673): a trial of the Eastern Oncology Group. Cancer 100(8):1692–1698. doi:10.1002/cncr.20166 CrossRefPubMedGoogle Scholar
  25. 25.
    Damian DL, Shannon KF, Saw RP, Thompson JF (2009) Topical diphencyprone immunotherapy for cutaneous metastatic melanoma. Australas J Dermatol 50(4):266–271. doi:10.1111/j.1440-0960.2009.00556.x CrossRefPubMedGoogle Scholar
  26. 26.
    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(9):716–720. doi:10.1097/CJI.0b013e31827457bd CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Hemmi H, Kaisho T, Takeuchi O et al (2002) Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol 3(2):196–200. doi:10.1038/ni758 CrossRefPubMedGoogle Scholar
  28. 28.
    Walter A, Schafer M, Cecconi V et al (2013) Aldara activates TLR7-independent immune defence. Nat Commun 4:1560. doi:10.1038/ncomms2566 CrossRefPubMedGoogle Scholar
  29. 29.
    Miller RL, Gerster JF, Owens ML, Slade HB, Tomai MA (1999) Imiquimod applied topically: a novel immune response modifier and new class of drug. Int J Immunopharmacol 21(1):1–14CrossRefPubMedGoogle Scholar
  30. 30.
    Bilu D, Sauder DN (2003) Imiquimod: modes of action. Br J Dermatol 149(Suppl 66):5–8PubMedGoogle Scholar
  31. 31.
    Sisti A, Sisti G, Oranges CM (2015) Topical treatment of melanoma skin metastases with Imiquimod: a review. Dermatol Online J 21(2)Google Scholar
  32. 32.
    Florin V, Desmedt E, Vercambre-Darras S, Mortier L (2012) Topical treatment of cutaneous metastases of malignant melanoma using combined imiquimod and 5-fluorouracil. Invest New Drugs 30(4):1641–1645. doi:10.1007/s10637-011-9717-2 CrossRefPubMedGoogle Scholar
  33. 33.
    Buckley DA, Du Vivier AW (2001) The therapeutic use of topical contact sensitizers in benign dermatoses. Br J Dermatol 145(3):385–405CrossRefPubMedGoogle Scholar
  34. 34.
    van der Steen PH, Happle R (1993) Topical immunotherapy of alopecia areata. Dermatol Clin 11(3):619–622PubMedGoogle Scholar
  35. 35.
    Damian DL, Saw RP, Thompson JF (2014) Topical immunotherapy with diphencyprone for in transit and cutaneously metastatic melanoma. J Surg Oncol 109(4):308–313. doi:10.1002/jso.23506 CrossRefPubMedGoogle Scholar
  36. 36.
    He B, Chou J, Brandimarti R, Mohr I, Gluzman Y, Roizman B (1997) Suppression of the phenotype of gamma(1)34.5-herpes simplex virus 1: failure of activated RNA-dependent protein kinase to shut off protein synthesis is associated with a deletion in the domain of the alpha47 gene. J Virol 71(8):6049–6054PubMedPubMedCentralGoogle Scholar
  37. 37.
    Liu BL, Robinson M, Han ZQ et al (2003) ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties. Gene Ther 10(4):292–303. doi:10.1038/sj.gt.3301885 CrossRefPubMedGoogle Scholar
  38. 38.
    Hu JC, Coffin RS, Davis CJ et al (2006) A phase I study of OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor. Clin Cancer Res 12(22):6737–6747. doi:10.1158/1078-0432.CCR-06-0759 CrossRefPubMedGoogle Scholar
  39. 39.
    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(34):5763–5771. doi:10.1200/JCO.2009.24.3675 CrossRefPubMedGoogle Scholar
  40. 40.
    Chen L, Daud A (2016) A review of novel intralesional therapies for melanoma, with an emphasis on a potential combination approach. Oncology (Williston Park) 30(5):442–443Google Scholar
  41. 41.
    Agarwala SS (2015) Intralesional therapy for advanced melanoma: promise and limitation. Curr Opin Oncol 27(2):151–156. doi:10.1097/CCO.0000000000000158 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Engeland CE, Grossardt C, Veinalde R et al (2014) CTLA-4 and PD-L1 checkpoint blockade enhances oncolytic measles virus therapy. Mol Ther 22(11):1949–1959. doi:10.1038/mt.2014.160 CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Puzanov I, Milhem MM, Minor D et al (2016) Talimogene laherparepvec in combination with ipilimumab in previously untreated, unresectable stage IIIb-IV melanoma. J Clin Oncol 34(22):2619–2626. doi:10.1200/JCO.2016.67.1529 CrossRefPubMedGoogle Scholar
  44. 44.
    Long GV, Dummer R, Ribas A et al (2016) Efficacy analysis of MASTERKEY-265 phase 1b study of talimogene laherparepvec (T-VEC) and pembrolizumab (pembro) for unresectable stage IIIB-IV melanoma. J Clin Oncol 34, (suppl; abstr TPS9598)Google Scholar
  45. 45.
    Mousavi H, Zhang X, Gillespie S, Wachter E, Hersey P (2006) Rose Bengal induces dual modes of cell death in melanoma cells and has clinical activity against melanoma. Melanoma Res 16:S8CrossRefGoogle Scholar
  46. 46.
    Thompson JF, Hersey P, Wachter E (2008) Chemoablation of metastatic melanoma using intralesional Rose Bengal. Melanoma Res 18(6):405–411. doi:10.1097/CMR.0b013e32831328c7 CrossRefPubMedGoogle Scholar
  47. 47.
    Wiener M, Damian DL, Thompson JF (2008) Systemic phototoxicity following intralesional rose bengal for subcutaneous melanoma metastases. Dermatology 216(4):361–362. doi:10.1159/000117707 CrossRefPubMedGoogle Scholar
  48. 48.
    Thompson JF, Agarwala SS, Smithers BM et al (2015) Phase 2 study of intralesional pv-10 in refractory metastatic melanoma. Ann Surg Oncol 22(7):2135–2142. doi:10.1245/s10434-014-4169-5 CrossRefPubMedGoogle Scholar
  49. 49.
    Schrama D, Reisfeld RA, Becker JC (2006) Antibody targeted drugs as cancer therapeutics. Nat Rev Drug Discov 5(2):147–159. doi:10.1038/nrd1957 CrossRefPubMedGoogle Scholar
  50. 50.
    Johannsen M, Spitaleri G, Curigliano G et al (2010) The tumour-targeting human L19-IL2 immunocytokine: preclinical safety studies, phase I clinical trial in patients with solid tumours and expansion into patients with advanced renal cell carcinoma. Eur J Cancer 46(16):2926–2935. doi:10.1016/j.ejca.2010.07.033 CrossRefPubMedGoogle Scholar
  51. 51.
    Eigentler TK, Weide B, de Braud F et al (2011) A dose-escalation and signal-generating study of the immunocytokine L19-IL2 in combination with dacarbazine for the therapy of patients with metastatic melanoma. Clin Cancer Res 17(24):7732–7742. doi:10.1158/1078-0432.CCR-11-1203 CrossRefPubMedGoogle Scholar
  52. 52.
    Spitaleri G, Berardi R, Pierantoni C et al (2013) Phase I/II study of the tumour-targeting human monoclonal antibody-cytokine fusion protein L19-TNF in patients with advanced solid tumours. J Cancer Res Clin Oncol 139(3):447–455. doi:10.1007/s00432-012-1327-7 CrossRefPubMedGoogle Scholar
  53. 53.
    Papadia F, Basso V, Patuzzo R et al (2013) Isolated limb perfusion with the tumor-targeting human monoclonal antibody-cytokine fusion protein L19-TNF plus melphalan and mild hyperthermia in patients with locally advanced extremity melanoma. J Surg Oncol 107(2):173–179. doi:10.1002/jso.23168 CrossRefPubMedGoogle Scholar
  54. 54.
    Schwager K, Hemmerle T, Aebischer D, Neri D (2013) The immunocytokine L19-IL2 eradicates cancer when used in combination with CTLA-4 blockade or with L19-TNF. J Invest Dermatol 133(3):751–758. doi:10.1038/jid.2012.376 CrossRefPubMedGoogle Scholar
  55. 55.
    Danielli R, Patuzzo R, Di Giacomo AM et al (2015) Intralesional administration of L19-IL2/L19-TNF in stage III or stage IVM1a melanoma patients: results of a phase II study. Cancer Immunol Immunother 64(8):999–1009. doi:10.1007/s00262-015-1704-6 CrossRefPubMedGoogle Scholar
  56. 56.
    Johnson DB, Sosman JA (2015) Therapeutic advances and treatment options in metastatic melanoma. JAMA Oncol 1(3):380–386. doi:10.1001/jamaoncol.2015.0565 CrossRefPubMedGoogle Scholar
  57. 57.
    Hauschild A, Gogas H, Tarhini A, Middleton MR, Testori A, Dreno B, Kirkwood JM (2008) Practical guidelines for the management of interferon-alpha-2b side effects in patients receiving adjuvant treatment for melanoma: expert opinion. Cancer 112(5):982–994. doi:10.1002/cncr.23251 CrossRefPubMedGoogle Scholar
  58. 58.
    Lotze MT (1995) Biologic therapy with interleukin-2: Preclinical studies. In: DeVita VTJ, Hellman S, Rosenberg SA (eds) Biologic therapy of cancer. Lippincott, Philadelphia, pp 207–233Google Scholar
  59. 59.
    Rosenberg SA, Lotze MT, Yang JC et al (1989) Combination therapy with interleukin-2 and alpha-interferon for the treatment of patients with advanced cancer. J Clin Oncol 7(12):1863–1874CrossRefPubMedGoogle Scholar
  60. 60.
    van Horssen R, Ten Hagen TL, Eggermont AM (2006) TNF-alpha in cancer treatment: molecular insights, antitumor effects, and clinical utility. Oncologist 11(4):397–408. doi:10.1634/theoncologist.11-4-397 CrossRefPubMedGoogle Scholar
  61. 61.
    Teulings HE, Limpens J, Jansen SN, Zwinderman AH, Reitsma JB, Spuls PI, Luiten RM (2015) Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis. J Clin Oncol 33(7):773–781. doi:10.1200/JCO.2014.57.4756 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  1. 1.Department of DermatologyUniversity Medical Center TübingenTübingenGermany
  2. 2.Department of Chemistry and Applied BiosciencesSwiss Federal Institute of Technology ZurichZurichSwitzerland
  3. 3.Philochem AGOtelfingenSwitzerland

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