Novel Vaccine Platforms and Combinations最新文献

{"title":"Abstract B107: Next generation of poxvirus-based immunotherapeutics","authors":"Laetitia Fend","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B107","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B107","url":null,"abstract":"Oncolytic virus (OV) therapy has emerged as a promising approach for cancer treatment with the potential to be less toxic and more efficient than classic cancer therapies. Various types of OVs in clinical development, including Vaccinia virus (VACV)-derived OVs, have shown good safety profiles. We report here that a VACV can induce immunogenic cell death and generate a systemic immune response. Effects on tumor growth and survival was largely driven by CD8 T-cells, and immune cell infiltrate in the tumor could be reprogrammed toward a higher ratio of effector CD8 T-cells to regulatory CD4 T-cells. We demonstrate also the successful vectorization of a monoclonal anti-mPD-1 antibody in our VACV. The vectorized anti-mPD-1 antibody was able to block the binding of mPD-1 ligand to mPD-1 in vitro. Moreover, mAb was detected in tumor and in serum of C57BL/6 mice when the recombinant VACV was injected intratumorally (i.t.) in B16F10 and MCA 205 tumors. The concentration of circulating mAb detected after i.t. injection was up to 1,900-fold higher than the level obtained after a subcutaneous (s.c.) injection (i.e., without tumor), confirming the virus tropism for tumoral cells. Moreover, the overall tumoral accumulation of the mAb was higher and lasted longer after i.t. injection of the recombinant VACV than after i.t. administration of 10 µg of anti-mPD1. Interestingly, in the MCA 205 tumor model, the antitumoral activity of the VACV expressing mPD-1 is similar to the therapeutic efficacy of the combination of the unarmed VACV combined with a systemically administration of an anti-mPD-1 antibody and superior to that obtained with the unarmed VACV alone. These results pave the way for next generation of OV armed with immunomodulatory therapeutic molecules. Citation Format: Laetitia Fend. Next generation of poxvirus-based immunotherapeutics [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 B107.","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"148 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73476855","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 B135: Novel immunotherapeutic strategy based on the immunopathologic properties of cancer stem cells","authors":"T. Torigoe, Y. Hirohashi","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B135","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B135","url":null,"abstract":"Cancer stem-like cells (CSCs) are small subpopulation of cancer cells that contribute to cancer initiation and progression. These cells have a huge impact in the field of cancer therapy since they are resistant to standard chemoradiotherapy and responsible for disease recurrence. We have studied immunopathologic properties of CSCs derived from colon, breast, and gynecologic cancers to develop a novel CSC-targeted immunotherapy. #1 CSC-specific antigens: CSCs express several germ cell-specific genes. Remarkably, some of them were involved in tumor initiation capacity of CSCs and highly immunogenic since specific cytotoxic T-cells (CTLs) were efficiently induced from peripheral blood lymphocytes. The CTLs exerted specific cytotoxicity against CSCs. Adoptive transfer of the CSC-specific CTLs efficiently protected tumor growth in mouse models. #2 Fibroblastic niche of CSCs: Cancer-associated fibroblasts (CAFs) have important roles in tumor microenvironment. CSCs recruited fibroblasts, which enhanced tumor initiation capacity and immune resistance of CSCs. Gene expression analysis revealed that fibroblast growth factor 4 (FGF4) and FGFR2, a receptor for FGF4 were involved in the fibroblastic niche of CSCs. #3 Innate PD-L1 expression of CSCs: Some CSCs constitutively expressed PD-L1 on the cell surface through activation of PI3K/AKT signaling. Based on these unique properties of CSCs, we propose immunotherapeutic and immunoprophylactic strategy targeting CSCs. Citation Format: Toshihiko Torigoe, Yoshihiko Hirohashi. Novel immunotherapeutic strategy based on the immunopathologic properties of cancer stem cells [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 B135.","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":"74992591","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 B102: Pre-existing citrulline-specific CD4 T-cells can be efficiently harnessed for tumor therapy","authors":"Victoria A Brentville, P. Symonds, K. Cook, I. Daniels, Suha Atabani, R. Choudhury, Poonam M Vaghela, R. Metheringham, Mohamed Gijon, W. Xue, L. Durrant","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B102","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B102","url":null,"abstract":"Citrullination is the post-translational modification of arginine to citrulline mediated by Peptidylarginine deiminases (PADs), which are a family of calcium dependent enzymes found in a variety of tissues. Citrullinated proteins are known to play a significant role in the pathogenesis of autoimmune diseases and are presented in complex with MHC class II. We have previously shown that citrullinated peptides from vimentin and α-enolase are presented on HLA-DR4 in tumor cells and mediate strong anti-tumor responses (Brentville et al., 2016; Cook et al., 2017). Here we show that responses to these peptides are also restricted through HLA-DP4. These responses can be detected within 2 days of vaccination and can mediate rapid regression of tumors within 4 days in mice suggesting evidence of a pre-existing repertoire of T-cells specific for these citrullinated peptides. Evidence of CD4 T-cells specific to citrullinated antigens have been identified in a number of autoimmune disease patients in particular rheumatoid arthritis patients. These patients show an increase in frequency and change in phenotype of citrulline specific CD4 T-cells compared to healthy individuals (James et al., 2014). In this report we also demonstrate that a repertoire of CD4 T-cell responses to citrullinated peptides exists in healthy individuals and that this can be uncovered/enhanced by removal of CD25+ T-cells thus suggesting the existence of a regulatory mechanism keeping these responses in check. The responding populations appear to be oligoclonal and show an increase in effector memory and Temra phenotype. This suggests that a repertoire of CD4 T-cells exists to citrullinated peptides that could be targeted for cancer therapy. Citation Format: Victoria A. Brentville, Peter Symonds, Katherine W. Cook, Ian Daniels, Suha Atabani, Ruhul Choudhury, Poonam Vaghela, Rachael L. Metheringham, Mohamed Gijon, Wei Xue, Lindy G. Durrant. Pre-existing citrulline-specific CD4 T-cells can be efficiently harnessed for tumor therapy [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 B102.","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"26 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78539324","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 B119: DC-recruiting biomaterial vaccine to enhance antitumor immunity","authors":"Aileen W. Li, Maxence O. Dellacherie, Miguel C. Sobral, Omr O. Ali, Jaeyun Kim, D. Mooney","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B119","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B119","url":null,"abstract":"Biomaterials have shown substantial potential to integrate synergistically with current cancer vaccine strategies and enhance their effectiveness. We recently developed an injectable biomaterial vaccine via spontaneous assembly of mesoporous silica (MPS) microparticles into a 3D scaffold in vivo. When formulated with GM-CSF and the TLR-9 agonist CpG, the MPS vaccine modulates host dendritic cell (DC) activation and trafficking. Here we demonstrate that a single injection of the MPS vaccine induced persistent germinal center B cell activity for over 30 days. Consequently, when immunized with a small linear Her2/neu peptide within the Trastuzumab binding domain, the MPS vaccine elicited over 2 orders of magnitude higher IgG1 and IgG2a antibody titer compared to a traditional bolus vaccine, and the antibody exhibited immunoreactivity on the native Her2 structure on breast cancer cells. To further enhance CTL responses against tumor antigens, we co-presented the antigen with polyethylenimine (PEI) in the MPS vaccine. PEI increased antigen cross-presentation in murine DCs, and TNF-a and IL-6 production in both murine and human DCs in vitro. Compared to the MPS vaccine, the MPS-PEI vaccine enhanced activated and antigen+ DCs in the vaccine and the vaccine draining lymph node by ~2 fold. Systemically, using both OVA and a HPV-E7 peptide as antigens, the MPS-PEI vaccine induced ~2.5 fold higher IFN-y producing antigen specific circulating CD8+ T-cells compared to the MPS vaccine. Impressively, using a HPV-E7 expressing tumor model, we demonstrated that a single injection of the MPS-PEI vaccine completely eradicated large established tumors in over 80% of mice. Finally, when immunized with a pool of recently sequenced B16 melanoma neoantigen peptides, the MPS-PEI vaccine induced potent therapeutic tumor growth control and synergy with anti-CTLA4 checkpoint blockade therapy. These findings suggest that the MPS vaccine may serve as a facile multifunctional and multi-epitope platform to modulate host immune cell function and augment personalized antitumor immunity. Citation Format: Aileen W. Li, Maxence O. Dellacherie, Miguel Sobral, Omr O. Ali, Jaeyun Kim, David J. Mooney. DC-recruiting biomaterial vaccine to enhance antitumor immunity [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 B119.","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79639860","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 B100: Development of fargeted multiple myeloma cancer vaccine and antigen-specific T-cell immunotherapy using novel Immunogenic-engineered heteroclitic BCMA peptides","authors":"J. Bae, T. Hideshima, Y. Tai, N. Munshi, K. Anderson","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B100","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B100","url":null,"abstract":"Background: Multiple myeloma (MM), the second most common hematologic malignancy in the US, is characterized by the proliferation and accumulation of clonal malignant plasma cells in the bone marrow, associated with hypercalcemia, renal dysfunction and bone disease. Despite recent advances in treatment including novel therapeutics in combination with transplantation, MM still remains incurable. We have recently developd a highly immunogenic HLA-A2-specific multipeptide cancer vaccine targeting XBP1 (X-box binding protein 1), CD138 (Syndecan-1) and CS1 (SLAMF7) antigens. In both pre-clinical studies and Phase 1/2a clinical trials in patients with smoldering multiple myeloma and triple negative breast cancer, vaccination with this multi-peptide based cancer vaccine induced antigen-specific and Th1-type anti-tumor immune responses, which were maintained for long-term within tetramer+/memory (CD45RO+) CD8 cytotoxic T lymphocytes (CTL). The immune responses were further enhanced in patients who received vaccination in combination with lenalidomide or checkpoint inhibitor. To allow for vaccination against additional tumor-associated antigens, we have recently investigated B Cell Maturation Antigen (BCMA), a cell surface antigen restricted to MM and normal plasma cells, as well as accessory dendritic cells. As the receptor for binding of B cell activating factor (BAFF) and of a proliferation-inducing ligand (APRIL), BCMA promotes MM cell growth, drug resistance, as well as survival of long lived plasma cells. Due to its restricted expression pattern, targeting of this antigen with antibodies, immunotoxins, and CAR T-cells is already ongoing in MM at present. Objective: We aimed to identify immunogenic BCMA peptides in order to generate antigen-specific CD8+ effector cytotoxic T lymphocytes against MM cells. Findings: We identified novel immunogenic HLA-A2 native and engineered heteroclitic BCMA peptides that induce tumor-specific CTL against MM. The engineered heteroclitic BCMA72-80 and BCMA54-62 peptides have improved HLA-A2 binding affinity and stability compared to their native BCMA72-80 and BCMA54-62 peptides. In preclinical studies, each of the heteroclitic BCMA peptide induced antigen specific CTL, which expressed increased T-cell activation (CD38, CD69) and co-stimulatory (CD40L, OX40, GITR) molecules. The engineered heteroclitic BCMA72-80 triggered a more robust immune response than BCMA54-62 peptide, associated with increased HLA-A2 binding affinity and stability. Importantly, the heteroclitic BCMA72-80 peptide-specific CTL induced selective and robust proliferative and cytolytic activities in response to MM patients’ tumor cells. Specifically, these tetramer+ CD8+ CTL demonstrated HLA-A2-restricted immune responses against MM, associated with CD107a degranulation, proliferation, Th-1 cytokine (IFN-γ/IL-2/TNF-α) cytokine production, perforin/granzyme B up-regulation, and increased 41BB expression. Furthermore, the heteroclitic BCMA72-80 peptide","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"76 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80729787","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 B099: Elucidating the mechanisms that underpin RAG chromatin scanning in V(D)J recombination at antigen receptor gene loci","authors":"Zhaoqing Ba, S. Jain, Jiazhi Hu, F. Alt","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B099","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B099","url":null,"abstract":"Immunoglobulin heavy (IgH) and light (IgL) chain variable region exons are assembled from V, D and J segments by V(D)J recombination, which is initiated by RAG1/RAG2 endonuclease (RAG) that introduces DNA double-stranded breaks (DSBs) between a pair of V, D, and J coding segments and flanking recombination signal sequences (RSSs). IgH V(D)J recombination is ordered, with D-JH joining occurring before appendage of a VH to a DJH intermediate in pro-B cells. In pre-B cells, a single-step VL-to-JL recombination event is invoked at IgL loci, with Ig kappa rearrangement usually preceding that of Ig lambda. The mechanisms of Ig V(D)J recombination, especially long-range VH-to-DJH and Vkappa-to-Jkappa recombination are still not fully understood. Recently, our work showed CTCF-binding elements (CBEs) immediately downstream of frequently rearranged VH-RSSs increase recombination potential of their associated VH far beyond that provided by RSS alone. This CBE activity becomes particularly striking upon the inactivation of IgH IGCR1 control element, which promotes DJH intermediate formation by insulting Ds, JHs, and recombination center (RC) from upstream VHs in a CBE-anchored chromatin loop. By developing and applying 3C-HTGTS, a new high-throughput chromosome conformation capture method that shows great advantages over classical 4C-seq in sensitivity and specificity, we found VH-associated CBEs promotes interaction with the RC. Based on these, we proposed a RAG chromatin scanning model for V(D)J recombination, in which VH CBEs stabilize interactions of D-proximal VHs first encountered by the DJH RC during linear RAG scanning on chromatin and thereby promote dominant rearrangement of these VHs by an unanticipated chromatin accessibility-enhancing CBE function. However, it is still not known if such chromatin scanning also happens on other antigen receptor loci and what the underlying mechanism is. Here, we will show our new findings on the roles of RAG chromatin scanning in Vkappa-to-Jkappa recombination at Ig kappa locus by multiple comprehensive approaches. Moreover, we will also discuss our most updated understanding of the mechanisms underlying RAG chromatin scanning using a novel and sophisticated approach. The potent mutagenic and oncogenic effects of aberrant RAG chromatin scanning at RAG “off-target” sites genome-wide will be also discussed. Citation Format: Zhaoqing Ba, Suvi Jain, Jiazhi Hu, Frederick Alt. Elucidating the mechanisms that underpin RAG chromatin scanning in V(D)J recombination at antigen receptor gene loci [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 B099.","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83728787","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 B130: Induced lymphangiogenesis enhances antigen-specific T-cell response in anticancer vaccination","authors":"M. Sasso, S. Hauert, P. Briquez, Yue Wang, J. Ishihara, J. Hubbell, M. Swartz","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B130","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B130","url":null,"abstract":"Tumor-associated lymphatic vessels play multiple and complex roles in the regulation of antitumor immunity. In both mouse and human melanomas, lymphatic markers correlate with increased tumor immune infiltrates and enhanced responsiveness to immunotherapy. Despite the immune-promoting functions of lymphatics in cancer immunotherapy, manipulation of lymphatic vessels directly within the tumor site appears controversial as a therapeutic strategy, due to the correlation of tumor lymphatic growth (lymphangiogenesis) with cancer cell dissemination and metastasis. Here, we sought to manipulate and exploit lymphatic vessels remotely from the tumor by developing and characterizing a lymphangiogenic cancer vaccine. Lymphangiogenic whole-cell vaccines were formulated using lethally irradiated tumor cells overexpressing the pro-lymphangiogenic growth factor VEGF-C in combination with topically retained immune adjuvants (VEGFC vax). In the B16F10 and B16F10-OVA mouse melanoma models, VEGFC vax induced extensive lymphatic growth at the cutaneous injection site, as assessed by both flow cytometry and histologic analysis. Induced lymphangiogenesis increased the rate of fluorescent microbead transport from the skin to the draining lymph nodes, suggesting an enhanced antigen trafficking. In addition, VEGF-C overexpression drove the recruitment in the vaccine injection site of naive T-cells (responsive to lymphatic-derived CCL21), which could be primed in situ. Compared to a control VEGF-C-free vaccine formulation, VEGFC vax induced a broader T-cell response targeting multiple mouse melanoma antigens (including tumor neoantigens), as assessed by IFNγ ELISPOT following antigen-specific stimulation. In a prophylactic setting, VEGFC vax provided complete protection against B16F10 melanoma challenge, outperforming both the control vaccine and a GM-CSF-secreting whole-cell vaccine (GVAX). Overall this study provides a proof of concept for the use of VEGF-C as an immunostimulatory agent in cancer vaccines, based on its ability to activate and expand lymphatic vessels and consequently promote local immune cell trafficking, antigen transport and T-cell activation. In addition, we here developed and characterized a whole-cell VEGF-C vaccine formulation with potential for clinical translation. Citation Format: Maria Stella Sasso, Sylvie Hauert, Priscilla Briquez, Yue Wang, Jun Ishihara, Jeffrey A. Hubbell, Melody A. Swartz. Induced lymphangiogenesis enhances antigen-specific T-cell response in anticancer vaccination [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 B130.","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84019001","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 B101: Novel oncolytic vaccinia virus platform for systemic delivery of immunotherapeutic payloads","authors":"J. Bell, A. Pelin, Mike Huh, Matthew Tang, F. Boeuf, B. Keller, Jessie Duong, K. Clark-Knowles, Julia Petryk, V. Jennings, A. Melcher, Mathieu J. F. Crupi, L. Pikor, C. Breitbach, S. Bernstein, F BurgessMichael","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B101","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B101","url":null,"abstract":"The treatment paradigm for patients with metastatic cancer has evolved rapidly with the approval of agents targeting CTLA-4 and the PD-1/L1 immune checkpoint axis. Despite the profound impact these agents have had, they are minimally effective in the majority of cancer patients. Rational combinations of complementary immune modulating agents have thus far not led to clear patient benefit, and newer technologies that are better able to safely combine multiple modes of action could well prove to be vital. Oncolytic viruses (OVs) have the capacity to be the ideal therapeutic partner for immune checkpoint therapeutics in several ways. First, on their own OVs can “heat-up” immunologically “cold” tumors by initiating a pro-inflammatory infection within the tumor microenvironment (TME). Second, some OVs can be engineered to strategically express one or more immune-modulating molecules. Finally, certain OVs have the capacity to be delivered systemically and thus enhance immune cell recruitment and activation in all metastatic sites. We have selected a novel vaccinia virus as our therapeutic OV platform and are using it to engineer multi-mechanistic cancer therapeutics. Previously it has been demonstrated that certain oncolytic vaccinia viruses can be delivered systemically and spread within metastatic lesions. These early clinical viruses, however, contain multiple potent immune suppressive genes and are not ideal for the generation of antitumor immune responses “in situ.” Furthermore, in clinical studies some of these therapeutics exhibited off-tumor infections (e.g., pox lesions), which may ultimately limit their ability to be used to deliver potent immune modulators. We used a combination of functional genomics and bio-selection strategies to optimize the vaccinia virus platform. Initially we developed a fitness assay to identify the vaccinia strain with the best ability to replicate in and kill both established cancer cell lines and cancer patient tumor explants. Next, we used a transposon insertion strategy and deep sequencing of viral populations to systematically examine the role of each vaccinia virus gene in its ability to be an anticancer therapeutic. Ultimately, we identified large regions (25Kb) of the vaccinia genome that when deleted, augment the oncolytic activity of a newly generated vaccinia backbone termed SKV. Our new best-in-class vaccinia, SKV, robustly stimulates anti-immune responses, rapidly spreads within and between tumors and has a substantially improved preclinical safety profile when compared to other vaccinia clinical candidates. As predicted, SKV synergizes well with immune checkpoint inhibitor antibodies and potently activates human immune cells. Due to the exquisite tumor selectivity of SKV, we have been able to engineer and express from the backbone a combination of very potent immune modulators that are safest and most effective when expressed within the TME. These include an immune checkpoint inhibitor, a membrane teth","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81388394","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 B133: Implantable synthetic immune hydrogel for spatiotemporal modulation of tumor-derived immunosuppression and systemic antitumor immunity","authors":"Chanyoung Song, Il Woo Shin, Long Ren, Y. Lim","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B133","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B133","url":null,"abstract":"The development of biomaterial-based immune niches that can shape tumor-induced immunosuppressive factors will play an important role to improve current cancer immunotherapy. Herein, we developed an engineered 3-dimensional porous scaffold for creating synergistic action between myeloid-derived suppressor cell (MDSC)-depleting drugs, which can revert an immunosuppressive tumor microenvironment to one supporting antitumor immunity, and cancer vaccines (whole tumor lysate-based antigens and nano-adjuvants carrying Toll-like receptor 3 agonists), which can induce tumor antigen-specific T-cell responses. The local implantation of the scaffold (called immuneCare-DISC, iCD) as a post-surgical treatment in large established 4T1 breast tumors induced systemic antitumor immunity and prevented relapse and metastasis, resulting in survival of 100%. These therapeutic results were obtained from the depletion of MDSCs by control releasing of gemcitabine and the recruitment/activation of dendritic cells, increased infiltrating of T-cells and enhanced level of IFN-γ production by sustained releasing of cancer vaccine from the iCD. This synthetic immune niche iCD as a spatiotemporal modulation of tumor-induced immunosuppression and cancer vaccine-induced immune stimulation is proposed to generate favorable environment to prevent recurrence and metastasis following the surgical resection. Citation Format: Chanyoung Song, Il Woo Shin, Long Ren, Yong Taik Lim. Implantable synthetic immune hydrogel for spatiotemporal modulation of tumor-derived immunosuppression and systemic antitumor immunity [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 B133.","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79112313","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 PR09: Intratumoral delivery of engineered modified vaccinia virus Ankara expressing Flt3L and OX40L for \"in situ\" therapeutic cancer vaccination","authors":"L. Deng, N. Yang, Yi Wang, Wei Yan, Jiahu Wang, John Choi, S. Shuman, T. Merghoub, J. Wolchok","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-PR09","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-PR09","url":null,"abstract":"Modified vaccinia virus Ankara (MVA) is a highly attenuated, effective, and safe vaccinia strain that is an important vaccine vector for infectious diseases and cancers. We have previously shown that intratumoral (IT) injection of inactivated MVA elicits stronger antitumor immunity compared with live MVA in murine B16-F10 melanoma and MC38 colon cancer models, indicating that viral immune inhibitory factors might be involved in attenuating antitumor effects. Here we provide evidence that vaccinia virulence factor C7 interacts with transcription factors IRF3 and STAT2, which attenuates both type I IFN production and IFN receptor signaling. Infection of conventional dendritic cells (cDCs) with MVAΔC7L in which C7L gene is deleted results in higher levels of IFNB gene induction and IRF3 phosphorylation compared with MVA. IT MVAΔC7L also induced stronger antitumor responses compared with MVA, which correlates with higher levels of tumor infiltrating activated CD4+ and CD8+ T-cells in both injected and noninjected tumors in a bilateral B16-F10 tumor implantation model. We engineered a recombinant MVA in which the C7L gene was replaced with human Flt3L (hFlt3L) and the J2R gene (a.k.a. TK gene) was replaced with murine OX40L (mOX40L) or human OX40L (hOX40L). Using B16-F10 and MC38 tumor models, we show that IT MVAΔC7L-hFlt3L-ΔJ2R-mOX40L is more effective than MVAΔC7L-hFlt3L, or MVAΔC7L, or heat-inactivated MVAΔC7L in eradicating injected tumors, delaying the growth of the noninjected tumors, and prolonging mice survival. ELISPOT analysis demonstrate that IT MVAΔC7L-hFlt3L-ΔJ2R-mOX40L generates the most tumor-specific CD8+ and CD4+ T-cells compared with the other viruses mentioned above. The combination of IT MVAΔC7L-hFlt3L-ΔJ2R-mOX40L with systemic delivery of anti-CTLA-4 or anti-PD-L1 antibodies results in more efficient eradication of injected tumors, higher survival rate compared with IT virus alone in both bilateral tumor implantation and unilateral large established tumor models. MVAΔC7L-hFlt3L-ΔJ2R-hOX40L has been generated and will be investigated in clinical trials for patients with metastatic cancers in the near future. Taken together, we provide proof-of-concept results for the development of immune activating recombinant MVA to alter tumor immunosuppressive microenvironment through the induction of type I IFN via the cytosolic DNA-sensing pathway, activation of CD103+ dendritic cells, as well as direct activation of both CD4 and CD8 T-cells. This approach enhances tumor antigen presentation and T-cell activation through \"in situ\" therapeutic vaccination effects, either used as monotherapy or in combination with anti-CTLA-4 or anti-PD-L1 antibody therapy. Citation Format: Liang Deng, Ning Yang, Yi Wang, Wei Yan, Jiahu Wang, John Choi, Stewart Shuman, Taha D. Merghoub, Jedd D. Wolchok. Intratumoral delivery of engineered modified vaccinia virus Ankara expressing Flt3L and OX40L for \"in situ\" therapeutic cancer vaccination [abstract]. In: Proce","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78987518","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}