Topical and intralesional immunotherapy for melanoma metastases

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 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:

• Patients with unresectable, multiple or advanced locally/regionally metastatic Stage IIIb/c or Stage IV M1a melanoma, with or without distant disease
• Tumours that are accessible to direct injection
• Patients that cannot tolerate other aggressive therapies

Effective agents for intralesional/topical melanoma immunotherapy

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

• The initial use of BCG was reported to result in local control in 90% of injected intradermal metastases and induced systemic immune response to melanoma antigens.
• A 17% response rate for patients undergoing intralesional injection with BCG has been reported in another study.
• Interest in BCG receded when anaphylactic reactions and death due to disseminated BCG were reported.
• Subsequent randomised trials of BCG failed to confirm significant clinical benefit, and its use was discontinued.

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

• Carbon dioxide laser
• Cryotherapy
• Electroporation (ECT)
• Cytotoxic agents (intralesional cisplatin, topical 5-fluorouracil)
• Cytokines (intralesional interleukin [IL]-2 and interferon [IFN]-alpha and beta).

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
• Allovectin-7
• Rose Bengal (PV-10).

OncoVEX^GM-CSF (T-VEC)

Intralesional injection of granulocyte macrophage colony-stimulating factor (GM-CSF) into melanoma metastases results in the 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.

• A phase I clinical trial demonstrated a 26% objective response rate in both injected and noninjected lesions (including visceral deposits).
• In a phase 2 trial, 20 percent of patients achieved a complete response and 28 percent achieved some objective response rate (complete response + partial response). Ninety-two percent of the responses lasted at least 6 months. The median overall survival was 23.3 months in the T-VEC group and 19.0 months in the control group.

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).

• The phase 3 OPTim trial has enrolled 436 stage IIIB/IV melanoma patients randomised 2:1 to T-VEC versus subcutaneous GM-CSF alone.
• Interim results from the OPTiM study showed that the virus significantly improved the durable response rate compared with GM-CSF alone in patients with melanoma metastases (16.3% vs. 2.1%; p < 0.0001). A durable response was defined as a complete or partial response that began within 12 months of treatment initiation and lasted 6 months or more.

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.

• In a Phase 2 trial of 133 patients with melanoma, the overall response rate was 12% with no grade 3 or higher toxicities.
• A phase 3 trial of 2 mg intralesional Allovectin-7® in patients with stage III or IV melanoma did not demonstrate statistically significant improvement in objective response rate at ≥24 weeks or in overall survival, when compared with dacarbazine or temozolomide.

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 anti-tumour response.

Phase 1 study

• 11 patients with stage III metastatic melanoma were injected with PV-10 at a dose of 0.5 ml/cc lesion volume. Treatment was well tolerated and objective response was observed in 12/26 target lesions.
• An additional 28 untreated lesions were observed for potential bystander effect. These had a 27% objective response rate that increased to 44% in patients that had a positive response of target lesions.

Phase 2 study

• In a multicenter, international trial in 80 patients with measurable stage III-IV melanoma, up to 4 intralesional injections of PV-10 were administered at monthly intervals over a 16-week period, with a median dose of PV-10 per treatment of 1.6 mL.
• Twenty-four percent of patients had complete responses (CR) of target lesions and 25 percent had partial responses (PR).
• Among the 38 subjects with bystander lesions, CR of their untreated lesions was reported to be 24 percent. Regression of bystander lesions strongly correlated with a response in target lesions.
• In a further analysis of the first 40 patients, those with CRs achieved significantly longer progression-free survival (11.1 months) than those with stable disease or progressive disease (2.8 and 2.7 months, respectively).

Phase 3 study

• A phase 3 trial of PV-10 is ongoing (2014) and is expected to enrol up to 300 subjects with stage IIIB-IIIC melanoma.
• In this trial, PV-10 will be compared with a control arm of chemotherapy with either dacarbazine (DTIC) or temozolomide, with progression-free survival as a primary endpoint.

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.

• In an Australian study, 50 melanoma patients were treated with DPCP alone for at least 1 month. DPCP diluted in aqueous cream was applied to melanoma lesions at weekly intervals, 10–14 days after sensitization.
• Complete clearance of cutaneous disease was noted in 46% and partial response in a further 38% of patients. The mean DPCP treatment duration to clearance of all cutaneous lesions was 8 months. The mean duration of complete response was 17 months.

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.