CM101 treatment overrides tumor-induced immunoprivilege leading to apoptosis

CM101, a bacterial polysaccharide exotoxin produced by group B Streptococcu s (GBS), also referred to as GBS toxin, has been shown to target pathologic al neovasculature and activate complement (C3), thereby inducing neovascula ritis, infiltration of inflammatory cells, inhibition of tumor growth, and apoptosis in murine tumor models. Data from refractory cancer patients in a Phase I clinical trial with CM101 indicated a similar mechanism of tumor-t argeted inflammation. To further our understanding of the mechanism of acti on of CM101 as an antitumor agent, we examined the role of the inflammatory response in inducing tumor apoptosis in a normal mouse and tumor-bearing m ouse model. The i.v, infusion of CM101 into B16BL-6 melanoma tumor-bearing mice elevated p53 mRNA in circulating leukocytes as measured by reverse tra nscription-PCR, and immunohistochemistry demonstrated infiltration and sequ estration of leukocytes. Whole tumor lysates from excised tumors exhibited an increase in binding to the murine p(21Wafl/Cip1)-derived p53 DNA binding sequence compared with control whole tumor lysates, in which minimal or no DNA binding was observed. CM101 infusion led to elevated levels of Fas pro tein within the tumors as well as a decrease in the expression of fas ligan d (fasL), Furthermore, tumors were apoptotic as determined by terminal deox ynucleotidyl transferase-mediated nick end labeling and DNA fragmentation a ssays, Collectively, these data suggest that CM101 up-regulates p53 in tumo r-infiltrating leukocytes, initiating a loss of tumor immunoprivilege and c onsequently rendering the tumor sensitive to Fas/fasL-mediated apoptosis. C M101 induced loss of tumor immunoprivilege through changes in the expressio n of leukocyte p53, tumor Fas and fasL coupled with neovascularitis and leu kocyte infiltration, constitutes a plausible molecular pathway for tumor re duction observed in cancer patients.