Electrochemotherapy
Electrochemotherapy (ECT) is used as an intralesional therapy that delivers agents into the treated lesion. ECT applies high-intensity, pulsed electrical current to the treated lesion that renders the tumor cells permissive for the uptake of drugs, viruses, or genetic material.31,46 By contrast, electroporation delivers the current to the lesion without the need of additional agents. Therefore, ECT can be used to deliver therapeutic agents. Of all the agents used in combination with ECT, bleomycin is the most commonly reported (0.025 units delivered with ECT at 1250 V/cm).32 ORRs up to 98% have been reported and CR in more than 50%; however, case series have been small and limited by short follow-up periods.33 No significant adverse events have been noted.22,35 Marty et al33 conducted the European Standard Operating Procedures of Electrochemotherapy study, based on the experience of leading European cancer centers, that has been a landmark trial in the field.33 Prior to the report by Marty et al,33 which was published in 2006, different study groups used a variety of protocols with different pulse parameters, pulse generators, electrode types, and dosages of chemotherapy. Marty et al33 generated standard operating procedures in a prospective study with 2 years of follow-up using bleomycin or cisplatin. For bleomycin, they used either intravenous 15,000 IU/m2 in a bolus lasting 30 to 45 seconds or various intratumoral doses, depending on the tumor size. Cisplatin was administered based on tumor size.33 Depending on the number of nodules treated, study participants either received local anesthesia or general anesthesia.33 Procedures were performed on an outpatient basis or during a 1-day admission.33 Using 5000 Hz electric pulses was more effective than using 1 Hz.33 Melanoma nodules showed a lesional response of 80% and a CR rate of 66.3%.33
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Subsequently, a meta-analysis of 44 studies analyzed intralesional treatment with ECT on 1,894 lesions.46 Results were reported for both bleomycin and cisplatin.46 When the clinical responses in all histological diagnoses were evaluated, the CR rate was 59.4% and the ORR was 84.1%.46 When the melanoma results were evaluated, the rate of CR and ORR of treated melanoma tumors were 56.8% and 80.6%, respectively.46 No adverse events were reported.29 Although these results are encouraging, the data are limited due to their small size and lack of long-term follow-up. Therefore, further studies are required to determine which patients may benefit from ECT.
Granulocyte Macrophage Colony-Stimulating Factor
Use of granulocyte macrophage colony-stimulating factor (GMCSF) for intralesional therapy against metastatic melanoma is based on 2 mechanisms.47 GMCSF stimulates dendritic cells that then induce antitumor immune responsiveness.47 The result is twofold: direct destruction of the injected lesion and enhanced antigen presentation, leading to an immune response against metastatic melanoma. T cells treated with GMCSF have demonstrated increased antitumor responsiveness.47 Reported adverse events have generally been tolerable and typically constitute flulike symptoms.9,34,47
In addition to increasing the antitumor responsiveness of T cells, GMCSF also appears to reduce the immune-inhibitory effects of metastatic melanoma by having an effect on the cells implicated as mediators of decreasing the immune response against cancer.9,47 GMCSF has been shown to decrease T-regulator, suppressor, and myeloid-derived suppressor cells, which are all mediators of decreased T-cell antitumor activity.9,47 Patients with a higher T-cell composition of the tumor infiltrate with higher interleukin 2 (IL-2) receptor expression are more likely to demonstrate a clinical response to therapy.9,47 Phase 1 data showed increased CD4, CD8, lymphocyte, histiocyte, and eosinophil tumor infiltrate in the injected lesions and a higher likelihood of clinical response in patients with a higher T-cell composition of the tumor infiltrate with a higher IL-2 receptor expression.48 Phase 1/2 studies showed ORRs up to 26%.34,35,48 Efforts are underway to further evaluate mechanisms to enhance the immune response against melanoma.
Interleukin 2
IL-2 is a naturally occurring glycoprotein secreted by T cells to augment the immune response and was first used in clinical cancer studies in the early 1980s.49 This glycoprotein promotes T-lymphocyte proliferation and stimulates cytotoxic T cells and natural killer cells.50 IL-2 has been used as immunotherapy for nearly 40 years, although it has mostly been employed as an intravenous agent.50 Its use for intralesional therapy is limited due to logistical problems because patients require multiple injections per lesion and IL-2 is costly.50
The immune-stimulating mechanism of IL-2 has already been applied to melanoma and other solid tumors as a systemic therapy.50-52 It produces a relatively high rate of morbidity when considering its relatively low response rates, which range from 10% to 15%.52 Because IL-2 has the potential to induce durable responses, high-dose systemic IL-2 was the mainstay for the treatment of tumors like melanoma and renal cell carcinoma up until the 2000s.51,52 Although its usage has recently tapered off as more effective drugs are now available, IL-2 is still considered a treatment option for unresectable melanoma.51,52 Treatment of tumors has been reported using intralesional and perilesional injections of IL-2, whereby an IL-2 injection into the tumor has been shown to be effective.53 Intralesional IL-2 has been studied in many forms, including use as viral vectors, xenogeneic monkey fibroblasts, and IL-2 cultured lymphocytes harvested from patients with melanoma, as well as adjunctive therapy with other systemic therapy and topical agents.17,49,54-57 Response rates were low and erratic until human recombinant IL-2 was developed, which has provided consistent and promising results.
