Immunotoxins: a promising treatment modality for metastatic melanoma?

Abstract

The incidence of melanoma is rising in the Western population, and melanoma is the most aggressive form of skin cancer with a very poor prognosis once it has progressed to metastatic stages. Patients with stage IV melanoma (metastases to distant lymph nodes and other areas of the body) are treated with the chemotherapeutic drug dacarbazine (DTIC). However, fewer than 5% of the patients treated with DTIC sustain long-term complete responses; hence, DTIC is administered with palliative purposes. New therapy is urgently needed. We are developing another therapeutic strategy, specifically targeting melanoma cells with the 9.2.27PE immunotoxin (IT). ITs bind to antigens overexpressed on cancer cells and are therefore tumor selective. This targeted approach may potentially cause fewer side effects in a clinical situation compared to conventional approaches like chemotherapy and radiotherapy.

Keywords: 9.2.27PE; Cell death; dacarbazine; immunotoxin; melanoma.

Figure 1

Schematic illustration of Pseudomonas exotoxin A (PE)–based immunotoxin (IT) targeting antigens overexpressed on cancer cells. The IT is subsequently taken up by endocytosis. The catalytic part of the toxin (PE) is cleaved off and transported from the acidic compartments via the Golgi and endoplasmic reticulum (ER) to the cytosol where it inhibits protein synthesis by adenosine diphosphate (ADP)–ribosylating elongation factor (EF)-2. The catalytic part has also been shown to induce apoptosis, involving depolarization of the mitochondrial membrane, resulting in release of cytochrome c, activation of caspase-9 and caspase-3, and inactivation of poly (ADP-ribose) polymerase (PARP).

Figure 2

A panel of early passage melanoma cells was established from lymph node metastases. These Melmet cell lines were treated with increasing concentrations of dacarbazine (DTIC) and 9.2.27PE for 72 hours. The Melmet cell lines showed varied response to dacarbazine. These cell lines were also treated with increasing doses of 9.2.27PE, and the 9.2.27PE was effective in killing the Melmet cells, as cell viability was close to 0 for all cell lines. All data represent the mean ± SD of 3 independent experiments, each plated in triplicate. Melmet-1 (♦), Melmet-5 (•), Melmet-28 (x), Melmet-30 (▴), Melmet-44 (-). (The figure [slightly modified] was first published in Risberg K, et al. J Immunother. 2010;33(3):272–278.53)