The long-standing field of cancer immunotherapy clearly needs well-substantiated pre-clinical evidences on the fine modality of action of the different strategies utilized for cancer treatment. In fact, a variety of therapeutic tools, including C-activating mAb have been extensively utilized in the clinic [
2‐
4], in the absence of accompanying studies designed to fully explore their biologic, functional and clinical potential. As a direct consequence of this partially "blind" therapeutic approach, several potentially useful immunotherapeutic agents and approaches have been rapidly dismissed, due to their limited clinical efficacy. Indeed, opposite to chemotherapy, a much broader number of variables must be taken into account to maximize the clinical accomplishment of immunobiologic agents used as therapeutic tools in cancer patients.
As far as the clinical efficacy of passive immunotherapy of cancer patients with therapeutic mAb that mediate the activation of the C cascade, a major limitation is certainly represented by the presence of a functional form of the C-regulatory protein CD59 on the cell membrane of neoplastic cells, as well as in the tumor microenvironment [
7,
8]. Among solid tumors, the expression and functional role of CD59 has been well investigated in melanoma. CD59 is broadly expressed on normal and neoplastic tissues of melanocytic origin, with few non-CD59 expressing melanomas, has a limited intra- and inter-lesional heterogeneity and, among known C-regulatory proteins, it represents the main restriction factor of C-susceptibility of human melanomas [
9,
10]. Furthermore, a statistically significant (
r = 0.914;
p < 0.001) inverse correlation was identified between absolute levels of CD59 molecules expressed on melanoma cells and their susceptibility to C-mediated cytotoxicity induced by anti-GD3 mAb R24 [
11]. Thus, melanomas from distinct patients were highly susceptible to C-mediated cytotoxicity, while neoplastic cells from other individuals were completely resistant to C-cytotoxicity, even in the presence of elevated amounts of C-sensitizing mAb R24 [
11]. Conversely, no significant correlation was found between levels of cell membrane GD3 expressed on melanoma cells and their C-susceptibility [
11]. Thus, in spite of the efficient and rapid tumor targeting potential of therapeutic mAb, these findings strongly caution that their therapeutic efficacy may be greatly implemented through the treatment of patients bearing melanoma lesions that express weak to intermediate levels of CD59 and, thus, are more susceptible to the cytolytic effect of autologous C activated by therapeutic mAb. This notion is clearly not restricted to human melanomas but rather represents a more general phenomenon; in fact, resistance to rituximab (anti-CD20)-mediated C cytotoxicity is associated with high levels of CD59 expression on neoplastic cells of non-Hodgkin's lymphoma and multiple myeloma patients [
12].
A soluble form of CD59 (sCD59) has been identified in body fluids and in the culture supernatants of normal and neoplastic cells [
8,
13,
14]. Concerning melanoma, it was demonstrated that the amounts of sCD59 released from CD59-positive melanoma cells correlate with the levels of CD59 expressed on the cell surface [
8]. Noteworthy, sCD59 released from melanoma cells blocks the binding of anti-CD59 mAb to cell surface CD59 neutralizing their functional activity [
8]. In light of these evidences, the recent observation that CD59 acts as a triggering co-receptor for Natural Killer (NK) cell-mediated cytotoxicity [
15] identifies an additional protective role for CD59 in natural immunity. In fact, high amounts of circulating sCD59 detectable in sera of cancer patients may bind to NK cells affecting CD59-mediated functional activation.