Intralesional Therapy for Metastatic Melanoma

Intralesional Therapy Revisited

Further research into intralesional therapy^[3] has been conducted since the BCG trials, in conjunction with a variety of treatment methods, such as carbon dioxide lasers, cryotherapy, electroporation (ECT), and cytokines (IL-2 and IFN-alpha and beta). Interest has especially been heightened recently by three investigational agents that appear to ablate tumors locally and produce systemic "bystander" effects: Allovectin-7, OncoVEX^GM-CSF and PV-10. Given that melanoma is considered to become a systemic disease early in its course, the potential systemic effects of these newer agents could prove important.

Allovectin-7 is a plasmid/lipid complex with the DNA sequences encoding HLA-B7 and ß2 microglobulin, both components of major histocompatibility complex class I (MHC-I). The reduced expression of MHC-I in melanoma cells is thought to enable them to evade recognition by T-cells. Researchers believe that Allovectin-7 will increase the immune system's ability to recognize and target melanoma cells. The drug induces a fivefold increase in the frequency of HLA-B27 cytotoxic T cells, upregulates/restores MHC-I molecules, and induces a proinflammatory response. In a phase 2 trial of Allovectin-7^[4] including 133 patients with stage IIIB/C and stage IV M1a/b injectable cutaneous, subcutaneous or nodal melanoma lesions, the objective response rate (ORR) was 12 percent. There were no grade 3 or higher toxicities. A phase 3 trial of Allovectin-7 versus dacarbazine (DTIC)/temozolomide in recurrent stage III or IV melanoma with ORR (Complete Response + Partial Response, or CR + PR) at or >24 weeks as the primary endpoint is fully enrolled and awaiting analysis.

OncoVEX^GM-CSF is a 2nd generation oncolytic herpes simplex virus encoding GM-CSF. It is thought to replicate only in tumor cells with subsequent lysing of injected tumors. Lysed cells are then taken up by antigen-presenting cells (APCs). There may also be an adaptive antimelanoma response enhanced by local expression of GM-CSF. In a phase 2 trial^[5] of OncoVEX^GM-CSF, 20 percent of patients ultimately achieved a CR and 28 percent achieved an ORR. Ninety-two percent of the responses were durable (lasting at least 6 months), and the majority are ongoing, with a range of 18 to 40 months. Responses, observed in patients with all stages of disease, included complete resolution of visceral deposits.

The phase 3^[6] OPTim trial of OncoVEX^GM-CSF has enrolled 360 stage IIIB/IV melanoma patients randomized 2:1 to OncoVEX^GM-CSF versus subcutaneous GM-CSF alone. The endpoints are durable response at 6 months and overall survival.

PV-10 contains a small molecule fluorescein derivative. It is a non-pyrogenic solution of Rose Bengal disodium (10% RB) which is not metabolized, has about a 30-minute circulatory half-life and is excreted via bile. While PV-10 is excluded from normal cells, it transits through the plasmalemma (cell membrane) of cancer cells (including liver, breast, and other cancers in addition to melanoma) and accumulates in the lysosomes,^[7] triggering lysosomal release. It enters cancer cells and not normal cells because the cancer cells have a much higher fluidity (higher lipid content) in their cell membranes than normal cells do; even so, it requires a significant amount of PV-10 to ablate even the cancer cells, which helps explain why no hair loss or stomach lining problems have been observed to date in clinical studies. Autolysis is complete within 30–60 minutes. Acute exposure of antigenic tumor fragments to APCs is believed to produce the "bystander" effect in uninjected tumors. This mechanism is unique in that it leads to immediate reduction in tumor burden concomitant with immunologic activation.

The Melanoma Letter. 2012;30(1):5-7. © 2012  The Skin Cancer Foundation