Novel Vaccine Platforms and Combinations最新文献

{"title":"Abstract B116: Nano-neo-mRNA vaccine: A novel platform technology for cancer-immunotherapy","authors":"Manzoor Koyakutty, Navyashree Ramesh, A. Nambiar, Najuma Nujum Ambili Anna, M. Abraham, M. Anoop, A. Ramkumar, N. Shanti, V. Harish, A. Ashokan","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B116","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B116","url":null,"abstract":"Nanoparticle-based immunotherapeutic platforms are emerging as radically different, biocompatible alternatives for viral-vectors. Liposomal nanoplexes already showed potential for clinical translation of mutanome specific personalized cancer-vaccines in human. Here, we report a novel nanoparticle platform technology for neoantigen specific mRNA (neo-mRNA) vaccine delivery and demonstrated its potential for evoking T-cell mediated immune response against drug/radiation resistant glioma cells. Glioblastoma multiforme (GBM) is one of the most aggressive type primary brain tumors with high rate of recurrence and poor prognosis. Temozolomide (TMZ) chemotherapy in concurrence with radiation is less effective for patients with over-expression of DNA repair protein, O6-methyl guanine-DNA methyltransferase (MGMT) or epidermal growth factor receptor variant III (EGFRvIII) mutation. Here, we developed a unique pathogen mimicking nanoparticle platform that can effectively encapsulate and transfect dendritic cells with mRNA vaccine specific to MGMT or EGFRvIII. MGMT/EGFRvIII mRNA was synthesized by in vitro transcription (IVT) from respective cDNA plasmid and 100-150nm sized nanoplex was formed with mRNA at the core with >90% encapsulation efficiency. This Nano-neo-mRNA vaccineTM platform was successfully delivered to human monocyte derived DCs with a transfection efficiency of 35-50% compared to 3-5% in the case of naked mRNA. The transfected DCs showed significant phenotypic expression of MGMT-GFP with MHC I/II and CD80/86 co-activation compared to the naked mRNA or vehicle control. The efficiency of vaccinated DCs to prime cytotoxic T-cells was demonstrated in co-cultures where the nanoplex showed efficient activation of T-cell-mediated cytotoxicity on MGMT or EGFRvIII expressing, TMZ/radiation resistant glioblastoma cells . Biocompatibility of the nano-carrier was demonstrated in primary human cells and animal models. Thus, we present a new, biocompatible nanoparticle platform technology for IVT-mRNA based cancer-immunotherapy. Citation Format: Manzoor Koyakutty, Navyashree A. Ramesh, Ashwathy Nambiar, Najuma Nujum Ambili Anna, Manju C. Abraham, Minu Anoop, Anjana Ramkumar, Nair Shanti, Vijay Harish Harish, Anusha Ashokan. Nano-neo-mRNA vaccine: A novel platform technology for cancer-immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B116.","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85133713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B103: Altering the mevalonate pathway to enhance CD8+ T-cell responses","authors":"Olivia K. Burn, A. Authier-Hall, C. Brooks, R. Anderson, Andrew J Marshall, G. Painter, R. Weinkove, I. Hermans","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B103","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B103","url":null,"abstract":"Inhibitors of the mevalonate pathway have been found to induce inflammatory reactions and delay the progression of cancer. Emerging evidence suggests these inhibitors sensitise immune cells to signalling from the myeloid differentiation primary response gene 88 (MyD88) and in turn enhance NF-κB dependent activation of antigen presenting cells (APCs), an essential element in inducing an immune response. To further explore the adjuvant effect of these inhibitors, we designed a vaccine comprising an inhibitor of the mevalonate pathway conjugated to a tumor-specific peptide. We hypothesized that immunisation with these vaccines would elicit functional peptide-specific CD8+ T-cells. Using an in vivo mouse model, we found the vaccine generates greater peptide-specific cytotoxicity against targeT-cells bearing a human papillomavirus antigen than its unconjugated components, a chemical control vaccine or peptide alone. Moreover, the vaccine delayed outgrowth of an antigen-expressing tumor. Using human PBMCs, we obtained preliminary evidence that a similar vaccine can promote greater in vitro activation of CD8+ T-cells specific for a cytomegalovirus antigen than peptide alone. These results suggest that inhibitors of the mevalonate pathway can act as adjuvants in eliciting cytotoxic T-cell responses, and may have utility for the treatment or prevention of viral infections or neoplasia. Citation Format: Olivia K. Burn, Astrid Authier-Hall, Collin Brooks, Regan Anderson, Andrew Marshall, Gavin Painter, Robert Weinkove, Ian Hermans. Altering the mevalonate pathway to enhance CD8+ T-cell responses [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B103.","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"07 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86182006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B129: Human endogenous retroviruses as a potential reservoir for T-cell mediated cancer immunotherapy","authors":"S. Saini, Anne-Mette Bjerregaard, A. D. Ørskov, Ashwin Unnikrishnan, S. Holmberg, Govardhan Anande, A. Bentzen, Z. Szallasi, A. Eklund, K. Grønbæk, S. Hadrup","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B129","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B129","url":null,"abstract":"Epigenetic modulation using DNA methyltransferase inhibitors (DNMTis), such as 5-azacytidine (5-aza-CR), have been shown to affect the cellular immunogenicity in vitro through upregulations of human endogenous retroviruses (HERV) leading to activation of the INFγ response pathway. HERVs comprise up to 8% of the human genome, and may hold a large reservoir of potential tumor antigens.We examined the in vivo efficacy of 5-aza-CR in terms of upregulations of HERV expression during standard treatment regimen, as well as the ability of such HERV transcripts to form T-cell antigens leading to measurable T-cell recognition upon treatment. We have studied 66 HERV genes that have been shown to be transcribed in human tissues. To identify HERV derived immune recognition, we generated a library of 1169 HERV derived potential antigenic peptides restricted to most abundant MHC class I molecules in the Caucasian population. Peripheral blood mononuclear cells (PBMCs) from a cohort of 19 patients and bone marrow samples from a cohort of 11 patients, treated with DNMTis for different hematological malignancies (MDS, AML, and CMML) were used to detect CD8+ T-cells reactive to ERV-derived peptides. We detected CD8+ T-cells specific to several HERV-derived peptides both in healthy and diseased individuals. Further, in an additional cohort of patients we examined expression level of these HERVs by RNA seq analysis and compared with healthy individuals demonstrating a disease associated upregulation of HERVs in hematological malignancies. Presence of T-cells reactive to HERV antigens and enhanced expression of HERVs in these malignancies suggest that HERVs may indeed provide a pool of shared tumor associated antigens. These antigens could potentially be enhanced through DNMTi treatment and may provide a target for T-cell mediated immunotherapy. Citation Format: Sunil Kumar Saini, Anne-Mette Bjerregaard, Andreas D. Orskov, Ashwin Unnikrishnan, Staffan Holmberg, Govardhan Anande, Amalie Kai Bentzen, Zoltan Szallasi, Aron C. Eklund, Kirsten Gronbaek, Sine Reker Hadrup. Human endogenous retroviruses as a potential reservoir for T-cell mediated cancer immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B129.","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84216604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B127: NT219, a novel dual inhibitor of STAT3 and IRS1/2, converts immuno-oncology resistant tumors to responders","authors":"H. Reuveni, I. Haviv, L. Kupershmidt","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B127","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B127","url":null,"abstract":"Feedback activation of STAT3 and IGF1R/IRS plays a prominent role in mediating drug resistance to a broad spectrum of targeted cancer therapies and chemotherapies. Both the IRS1/2 and STAT3 are major signaling junctions regulated by various oncogenes, and altered during EMT and drug resistance. STAT3 has also been known to play an active role in immune-evasion of tumors and inhibition of STAT3, both in the tumor, as well as in the tumor’s microenvironment, may therefore potentiate immune attack on the tumor. NT219 is a dual inhibitor of STAT3 and IRS1/2 developed by TyrNovo Ltd. to overcome cancer drug resistance. NT219 inhibits STAT3 phosphorylation and eliminates IRS1/2 in a unique 3-step mechanism: dissociation of IRS1/2 from the IGF1 receptor, induction of IRS1/2 serine phosphorylation, and subsequent degradation by the proteasome. We recently demonstrated that the inhibition of both IRS and STAT3 are required and essential for overcoming drug resistance. NT219 efficacy was demonstrated in patient-derived tumor xenograft (PDX) models of multiple cancer types: melanoma, sarcoma, pancreatic, colon, lung, and head and neck when added on to the approved therapies. In these models, NT219 overcame acquired resistance to several oncology drug families: inhibitors of EGFR (Tarceva®, Erbitux®, Tagrisso®), MEK (Mekinist®), mutated-BRAF (Zelboraf®), mTOR (Afinitor®) as well as with chemotherapy agents (Gemzar®, 5FU, oxaliplatin). We recently demonstrated that NT219 works in synergy also with immune-oncology therapies. By using double autologous PDX models we demonstrated that NT219 converted non-responding tumors to responders to Keytruda®. It also enhanced the immunotherapeutic potential of cetuximab. FACS analysis showed increased tumor infiltrated lymphocyte population following treatment with NT219 and the combination of NT219 and the immuno-oncology drug.The unique mode of action of NT219 may open a new avenue of combined targeted therapies in a wide range of malignancies, and has the potential to expand response duration and target patient population to the applicable drugs. Citation Format: Hadas Reuveni, Izhak Haviv, Lana Kupershmidt. NT219, a novel dual inhibitor of STAT3 and IRS1/2, converts immuno-oncology resistant tumors to responders [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B127.","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"129 2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84284783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B114: Cancer immunotherapy combining oral vaccination of recombinant Bifidobacterium longum displaying human Wilms’ tumor 1 protein and anti-PD-1 checkpoint blockade for solid tumors in mice experimental model","authors":"K. Kitagawa, M. Tatsumi, Mako Kato, Shota Komai, Y. Hashii, T. Katayama, T. Shirakawa","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B114","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B114","url":null,"abstract":"Nowadays, cancer immunotherapies such as immune-checkpoint inhibitors, chimeric antigen receptor T-cells and cancer vaccines have achieved great success in cancer therapy. Nevertheless, increasing cancer antigen-specific immune responses is necessary to obtain significant therapeutic effect. Recently, we had developed an oral cancer vaccine utilizing recombinant Bifidobacterium longum displaying murine Wilms’ tumor 1 antigen ( B. longum 420) and had showed significant antitumor effect against WT1-positive leukemic cells by induction of WT1-specifc cytotoxic T-cell (CTL)-mediated immunity via activation of gut mucosal immune system in mice. In this study, we constructed B. longum displaying modified-human WT1 ( B. longum 440) and investigated the antitumor effect against solid tumors in mice experimental model. Wild-type B. longum 105-A strain was transformed by electroporation by E. coli-B. longum shuttle vector and recombinant B. longum 440 was constructed. B. longum 440 was displaying human WT1 protein that had modified human WT1-CTL epitope to increase the affinity for MHC-class I. 1×106 of TRAMP-C2, a murine prostate cancer, MBT-2, a murine bladder cancer, and 3LL, a murine lung cancer cell lines were subcutaneously inoculated into mice respectively. All the cell lines were endogenously expressing WT1 protein. After tumor formation, 1×109 of B. longum 440, B. longum 2012 (negative control), or PBS were orally administered 5 times a week for following weeks. PD1-antibody therapy was combined with B. longum 440 therapy to investigate synergistic antitumor effect of immune checkpoint inhibitor against MBT-2. We also performed in vitro co-culture experiments by using B. longum 440, human dendritic cells (DCs) and CTLs derived from human peripheral blood mononuclear cells (PBMCs) to investigate the immune-interaction between B. longum 440 and human immune cells responsible for WT1-spcific immunity. As the results, oral vaccination of B. longum 440 induced significantly higher antitumor effect against TRAMP-C2 and 3LL compared with other therapies, and significantly prolonged overall survival (p B. longum 440 and anti-PD-1 induced substantially higher antitumor effect against MBT-2 tumor than B. longum 440 or PD-1 single therapy, and 40% of the mice completely suppressed the tumor growth. Significantly higher WT1-CTL-epitope, Db126 and mp235-specific IFN-γ and IL-2 production in CD4 and CD8 T-cells were seen in spleen cells isolated from B. longum 440-immunized mice, suggesting that human B. longum 440 could induce WT1-specific T-cell responses in mice as well as murine B. longum 420 as previously reported. Regarding in vitro assay, after co-culturing of B. longum 440 and human DCs, matured DCs that ingested WT1 protein were successfully induced. Then, WT1-specific CTLs were induced by co-culturing of the matured DCs and suspended PBMCs in vitro. As the results, those WT1-specific CTLs elicited significantly higher cell cytotoxicity against A549, a","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"86 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89734654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}