Annias Immunotherapeutics, Inc. — Department of Health and Human Services STTR Phase II: NCI

Description

DESCRIPTION provided by applicant Malignant primary brain tumors represent the most frequent cause of cancer death in children and young adults and account for more deaths than cancer of the kidney or melanoma Glioblastoma GBM is uniformly lethal and current therapy is non specific and produces a median overall survival of andlt months In contrast immunotherapeutic approaches are exquisitely precise and can eradicate large well established tumors in mice and humans even when tumors reside within the andquot immunologically privilegedandquot brain However immunotherapy is limited by the lack of frequent and homogeneously expressed tumor specific antigens We have previously demonstrated that a peptide vaccine targeting the tumor specific EGFRvIII mutation PEPvIII induces immune responses sufficient to eliminate all EGFRvIII expressing tumor cells in mice and humans without toxicity Unfortunately EGFRvIII is heterogeneously expressed and tumors recur as a result of outgrowth of the EGFRvIII negative tumor cells However the nearly universal presence and homogeneous expression of cytomegalovirus CMV antigens in GBM but not normal brain has now been well established and provides an unparalleled opportunity to subvert these immunogenic viral proteins as tumor specific targets In two consecutive clinical trials from our laboratory using dendritic cells DCs targeting CMV pp in patients with GBM specific immunologic responses were induced along with remarkably enhanced progression free survival and overall survival However DC vaccination is expensive time consuming and commercialization is challenging In contrast peptide vaccines are cost effective easier to produce and easier to commercialize Leveraging our experience with PEPvIII we have developed a CMV specific multi epitope peptide cocktail PEP CMV PEP CMV vaccination is immunogenic in HLA A transgenic mice and peripheral blood mononuclear cells from CMV seropositive patients with GBM respond to stimulation with PEP CMV indicating PEP CMV is broadly immunogenic in our patient population We have already shown with PEPvIII that lymphopenia induced by both standard of care temozolomide TMZ and dose intensified TMZ can be leveraged to augment immunogenicity and the impact these regimens have on PEP CMV immunogenicity will be compared in our proposed trial Additionally we will examine a novel immunostimulant tetanus Td as an adjuvant to PEP CMV In a recent pilot trial from our laboratory patients randomized to receive Td as vaccine site pre conditioning prior to CMV pp loaded DC immunization experienced significantly enhanced PFS and OS in comparison to the control arm A Td booster was included for site pre conditioning during PEP CMV immunogenicity analysis and was demonstrated to significantly enhance IFN secretion of CMV targeted T cells in HLA A transgenics Therefore in this proposal we will test the HYPOTHESIS that vaccination with PEP CMV after Td skin conditioning will be a feasible safe and immunogenic tumor specific therapy in patients with newly diagnosed GBM during TMZ chemotherapy without antigen escape or toxicity PUBLIC HEALTH RELEVANCE Glioblastoma GBM is uniformly lethal It is also the most common malignant primary brain tumor and these tumors now represent the most frequent cause of cancer death in children and young adults and account for more deaths than cancer of the kidney or melanoma Current therapy is incapacitating and produces a median overall survival of andlt months because of limits defined by non specific toxicity We have developed a peptide vaccine that specifically targets patient GBM and redirects patientsandapos own immune cells to recognize and destroy tumors