Our current preclinical research in cancer vaccine development includes the following accomplishments: [] We have continued our preclinical and clinical investigations of two diverse recombinant (rec.) vaccine platforms (each with demonstrated unique properties): (a) rec. poxviral vectors employing a rec. vaccinia prime followed by multiple rec. fowlpox booster vaccinations;each vector contains the transgenes for one or more tumor-associated antigens (TAAs) and three T-cell costimulatory molecules (designated TRICOM);and (b) heat-killed rec. Saccharomyces cerevisiae (yeast) containing TAA protein via the insertion of a yeast plasmid. [] We have further interrogated the transcription factor brachyury, which is a major driver of the epithelial-to-mesenchymal transition (EMT) process in human carcinoma cells, as a novel vaccine target. These studies were conducted in collaboration with Dr. Palena. A rec. yeast-brachyury vaccine has been developed and a first-in-human clinical trial is underway. We have demonstrated both CD8+ and CD4+ brachyury-specific T-cell responses. A Phase II trial in chordoma patients is planned. [] We have analyzed biopsies of human lung and breast carcinomas and have found overexpression of brachyury mRNA and protein in carcinomas vs. normal adult tissues with the exception of testes and staining in some thyroids. Expression of brachyury has been shown to be increased in higher grade tumors and metastases. [] In collaboration with investigators at Duke, we have shown that brachyury expression is significantly and independently associated with a high risk of recurrence (P=0.0027) and distal metastasis (P=0.005) in breast cancer patients treated with tamoxifen. [] We have shown that while brachyury is overexpressed in human carcinomas, it is not overexpressed in murine carcinomas. The transcription factor Twist was shown by others to be a driver of the metastatic process in a murine breast carcinoma model. In collaboration with Drs. Hodge and Palena we have demonstrated in murine models that rec. Twist vaccines are capable of mediating anti-tumor therapy directed against an endogenous transcription factor driving the metastatic process. [] The C-terminus of MUC1 (MUC1-C) has been shown by others to be an oncogene and is associated with drug resistance and poor prognosis for a range of human tumors. We have now identified 9 novel CD8 T-cell epitopes of MUC1;most importantly, 7 are in the C-terminus. We have identified and characterized enhancer agonist epitopes for each of the 9 epitopes. A rec. yeast-MUC1(agonist) vector has been developed that efficiently processes the agonist epitopes for T-cell activation. [] We have characterized a tumor-targeting immunocytokine. NHS-IL12 is a fully human MAb that binds DNA/histone in necrotic tumor, which is fused to human IL-12 heterodimers. The agent was designed to reduce the toxicity of rec. IL-12 protein while maintaining its immuno-enhancing properties at the tumor site. We have shown that the immunocytokine has anti-tumor activity in a range of tumor models and is extremely effective when used in combination therapies in several models. We have recently initiated a first-in-human clinical trial with NHS-IL12. [] We have characterized an anti-PDL1 MAb that, unlike other anti-PDL1 MAbs, is capable of mediating ADCC of human carcinomas cells. This MAb also binds murine PDL1 and we have demonstrated anti-tumor activity in murine models. In preclinical studies we have also demonstrated a synergy in anti-tumor activity combining anti-PDL1 with the immunocytokine NHS-IL12. We have initiated a first-in-human clinical trial with this anti-PDL1.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Knudson, Karin M; Hicks, Kristin C; Luo, Xiaoling et al. (2018) M7824, a novel bifunctional anti-PD-L1/TGF? Trap fusion protein, promotes anti-tumor efficacy as monotherapy and in combination with vaccine. Oncoimmunology 7:e1426519
Fujii, Rika; Schlom, Jeffrey; Hodge, James W (2018) A potential therapy for chordoma via antibody-dependent cell-mediated cytotoxicity employing NK or high-affinity NK cells in combination with cetuximab. J Neurosurg 128:1419-1427
McGee, Heather M; Daly, Megan E; Azghadi, Sohelia et al. (2018) Stereotactic Ablative Radiation Therapy Induces Systemic Differences in Peripheral Blood Immunophenotype Dependent on Irradiated Site. Int J Radiat Oncol Biol Phys 101:1259-1270
Friedman, Jay; Morisada, Megan; Sun, Lillian et al. (2018) Inhibition of WEE1 kinase and cell cycle checkpoint activation sensitizes head and neck cancers to natural killer cell therapies. J Immunother Cancer 6:59
Grenga, Italia; Donahue, Renee N; Gargulak, Morgan L et al. (2018) Anti-PD-L1/TGF?R2 (M7824) fusion protein induces immunogenic modulation of human urothelial carcinoma cell lines, rendering them more susceptible to immune-mediated recognition and lysis. Urol Oncol 36:93.e1-93.e11
Fujii, Rika; Jochems, Caroline; Tritsch, Sarah R et al. (2018) An IL-15 superagonist/IL-15R? fusion complex protects and rescues NK cell-cytotoxic function from TGF-?1-mediated immunosuppression. Cancer Immunol Immunother 67:675-689
Malamas, Anthony S; Hammond, Scott A; Schlom, Jeffrey et al. (2017) Combination therapy with an OX40L fusion protein and a vaccine targeting the transcription factor twist inhibits metastasis in a murine model of breast cancer. Oncotarget 8:90825-90841
Jochems, Caroline; Tritsch, Sarah R; Pellom, Samuel Troy et al. (2017) Analyses of functions of an anti-PD-L1/TGF?R2 bispecific fusion protein (M7824). Oncotarget 8:75217-75231
Morillon 2nd, Y Maurice; Hammond, Scott A; Durham, Nicholas M et al. (2017) Enhanced immunotherapy by combining a vaccine with a novel murine GITR ligand fusion protein. Oncotarget 8:73469-73482
Fallon, Jonathan K; Vandeveer, Amanda J; Schlom, Jeffrey et al. (2017) Enhanced antitumor effects by combining an IL-12/anti-DNA fusion protein with avelumab, an anti-PD-L1 antibody. Oncotarget 8:20558-20571

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