Topical and intralesional immunotherapy for melanoma metastases

Author: Anoma Ranaweera, Medical Writer, Auckland, New Zealand, 2014.

Introduction

Melanoma is a potentially serious form of skin cancer. Some patients have advanced melanoma at high risk for recurrence, progression, and metastasis, despite surgery to remove the primary tumour.

Intralesional/topical therapy can be used to deliver therapy directly into a local recurrence or metastasis. The goals of intralesional therapy are to destroy the target lesion and to stimulate regression of other, untreated lesions by inducing an immune response to the melanoma.

A variety of agents have been investigated, including various cytokines (messenger proteins), small molecule immunomodulators and viral and plasmid vectors expressing immunologically active molecules.

Who are the best candidates for topical and/or intralesional therapy for melanoma?

Candidates for intralesional/topical melanoma therapy include:

Effective agents for intralesional /topical melanoma immunotherapy

Bacillus Calmette-Guerin (BCG) was the first intralesional treatment described.

Further research into intralesional/topical therapy has been conducted since the BCG trials, in conjunction with a variety of treatment methods, such as:

IL-2 has been noted to produce 70%–80% overall response rates and 62.5%–69% complete responses, but treatment is time-intensive, costly and has not demonstrated regression of noninjected lesions.

Interest has been heightened recently by three investigational agents that appear to destroy tumours at the site of injection and produce systemic effects:

OncoVEXGM-CSF (T-VEC)

Intralesional injection of granulocyte macrophage colony–stimulating factor (GM-CSF) into melanoma metastases results in infiltration of macrophages and lymphocytes into the tumour. GM-CSF has a high response rate, and offers hope of regional immune stimulation and regression of noninjected lesions.

OncoVEXGM-CSF, now called T-VEC (Talimogene laherparepvec), is an oncolytic HSV-1 virus genetically modified to secrete the cytokine GM-CSF. Researchers engineered T-VEC by taking herpes simplex virus type-1a (the cold sore virus) and introducing genetic mutations to knock out its herpes-causing capacity and transform it into a cancer-killing therapy.

Based on these preliminary results, an international prospective, randomised phase 3 clinical trial in patients with unresectable stage IIIB or IIIC or stage IV melanoma (OPTiM) is currently underway (2014).

Allovectin-7®

Major histocompatibility complex class I (MHC-I) expression is reduced in melanoma cells, which is thought to enable them to evade recognition by T-cells. Components of MHC-1 include HLA-B7 and ß2 microglobulin.

Allovectin-7® is an HLA-B7/beta2-microglobulin plasmid formulated with cationic lipids. It increases the ability of the immune system to recognize cancer cells and kill them. In 1999, the US FDA granted Allovectin-7 orphan drug designation for intralesional treatment of invasive and metastatic melanoma.

PV-10 (10% w/v Rose Bengal in saline)

Rose Bengal (RB) disodium is a small molecule fluorescein derivative that has been used in radiolabeled assay for impaired hepatic function (hepatic 131I radiolabeled RB). It is also used as a dye in eyedrops, as it stains damaged conjunctival cells.

Ten percent (w/v) RB in saline (PV-10) injections may also be used to destroy localised tumours such as metastatic melanoma. RB accumulates in the lysosomes of cancer cells, which undergo autophagy within 30-60 minutes. Tumour fragments are then exposed to antigen-presenting cells, resulting in an increase in T-cells in peripheral blood, including CD3+ and cytotoxic CD8+ cells, an immunological antitumour response.

Phase 1 study

Phase 2 study

Phase 3 study

Diphencyprone

Diphencyprone (DPCP) is a contact sensitiser with immunomodulatory effects, commonly used for alopecia areata and viral warts.

Recent reports indicate that topical diphencyprone (DPCP) can be effective for in-transit and cutaneous metastatic melanoma on its own and in combination with cimetidine or dacarbazine and radiation therapy. Diphencyprone is presumed to act by promoting lymphocyte-mediated tumour destruction, although its exact mechanism of action remains unknown.

The topical immune response modifier imiquimod may be added to DPCP in refractory cases. Imiquimod has antiviral and antitumour TH1 effects, mediated via activation of Toll-like receptor 7 and TLR 8 and secretion of various cytokines including interferon, IL-1, IL-6, IL-8, IL-10 and IL-12. It has previously been used off-license to treat melanoma in situ and cutaneous metastatic melanoma.

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