Novel Vaccine Platforms and Combinations最新文献

{"title":"Abstract IA28: Nanodisc platform technology for cancer vaccination","authors":"J. Moon","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-IA28","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-IA28","url":null,"abstract":"Recent innovations in DNA/RNA sequencing have allowed for the identification of patient-specific tumor neo-antigens, ushering in the new era of personalized cancer vaccines. Peptide vaccines in general may serve as an ideal platform for neo-antigen vaccines, but the therapeutic efficacy of peptide vaccines have been limited in clinical trials. Here we present an alternative strategy where preformed nanodiscs based on synthetic high density lipoproteins, with an established clinical manufacturing procedure and excellent safety profiles in humans, are readily formulated with adjuvants and antigen peptides. We show that these nanodiscs can efficiently deliver immunostimulatory molecules and antigens, including neo-antigens to draining lymph nodes. Notably, nanodiscs elicited up to 47-fold greater frequency of tumor neoantigen-specific CD8+ T lymphocytes (CTLs) than soluble vaccines in mice and even 31-fold greater than the standard adjuvant in clinical trials (i.e. CpG in Montanide). When nanodisc vaccination was combined with anti-PD-1 immune checkpoint inhibitor, ~88% complete response was observed in MC-38 tumor-bearing mice, compared with 25% response rate in the control group that received soluble vaccine plus anti-PD-1 therapy. In more aggressive B16F10 melanoma model, nanodiscs delivering multiple MHC class I and class II neo-epitopes were combined with α-PD-1/α-CTLA-4 therapy, leading ~90% complete response in B16F10 tumor-bearing mice, compared with ~38% response rate in the control group with soluble vaccine plus α-PD-1/α-CTLA-4 therapy. Furthermore, we have demonstrated the efficacy of nanodisc technology using shared tumor antigens in murine models of HPV+ mucosal tumors. The reproductive tract tumor model was established in C57BL/6 mice by intravaginal administration of luciferase-expressing TC-1 cells, a surrogate for HPV-induced human tumors, such as cervical carcinoma. The lung metastasis model was established by intravenous injection of luciferase-expressing TC-1 tumor cells. In mice bearing intravaginal or lung TC-1 tumors, two nanodisc vaccinations with HPV16 E7 antigen generated the peak frequency of ~35% tetramer+ CTLs in peripheral blood and eliminated established TC-1 tumors in the majority of animals (without immune checkpoint blockade). Owning to the facile production process, robust therapeutic efficacy, and good safety profiles, our nano-vaccine technology offers a powerful and convenient platform for vaccination using personalized as well as shared tumor antigens. Citation Format: James J. Moon. Nanodisc platform technology for cancer 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 IA28.","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78200345","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 B137: Preclinical evaluation of a Wilms’ tumor protein 1-targeted interleukin-15 dendritic cell vaccine: T-cell activity and batch production","authors":"Maarten Versteven, D. Damoiseaux, D. Campillo-Davo, H. V. Acker, H. D. Reu, S. Anguille, Z. Berneman, E. Smits, V. Tendeloo, E. Lion","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B137","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B137","url":null,"abstract":"Encouraging results from clinical trials demonstrate that dendritic cell (DC) vaccination is a valuable tool in cancer immunotherapy. Empowering DC vaccine immunogenicity to improve clinical outcome is at center stage in the rapidly evolving immunotherapeutic landscape. Developing a unique type of DC vaccine, so-called interleukin (IL)-15 DCs generated with IL-15 and strong immune stimulating maturation signals, we could demonstrate superior in vitro activities at both adaptive as well as innate immunity as compared to gold-standard IL-4 DCs. In this light, IL-15 DCs are capable of activating NK cells and gamma-delta T-cells, whereas IL-4 DCs are not. Designed to induce durable antitumor T-cell immunity, this pre-clinical research focuses on the improvement of Wilms’ Tumor protein 1 (WT1)-targeted T-cell activity. The WT1 antigen is overexpressed in a wide variety of human cancers and thus appears to fulfill the criteria of a universal tumor-associated antigen. The capacity of our novel IL-15 DCs to induce WT1-specific immunity is assessed using two in-house developed tumor antigen-specific T-cell assays. The first series of experiments demonstrate in a head-to-head comparison that WT1 mRNA-electroporated IL-15 DCs perform at least as well as IL-4 DCs in triggering a WT1 T-cell receptor (TCR)-transfected T-cell line. Using an autologous primary TCR-engineered CD8+ T-cell approach, we are now comparing their WT1-specific antitumor function. With its unique characteristics, including IL-15-transpresentation and interferon-gamma secretion, IL-15 DCs are expected to significantly promote WT1-specific T-cell-mediated tumor cell killing. Enabling its clinical application, we also evaluated the upscaled IL 15 DC vaccine production and cryopreservation processes. We were able to employ the three-day culture protocol in clinically suitable culture flasks. In addition, the use of an optimized cryopreservation medium results in a pre- to-post cryopreservation yield of 81.3 ± 7.4 % with a preserved phenotype and functionality. High-scale production and cryopreservation allows for the implementation of DC vaccination in multimodal treatment schedules. Underscoring the tumor antigen-specific T-cell-stimulating capacity among previously described superior characteristics and warranting batch production of patient-specific DC vaccines, further strengthens the impetus to bring WT1-loaded IL-15 DCs to the clinic. Citation Format: Maarten Versteven, David Damoiseaux, Diana Campillo-Davo, Heleen Van Acker, Hans De Reu, Sebastien Anguille, Zwi N Berneman, Evelien L Smits, Viggo F Van Tendeloo, Eva Lion. Preclinical evaluation of a Wilms’ tumor protein 1-targeted interleukin-15 dendritic cell vaccine: T-cell activity and batch production [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 Sup","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"69 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74427475","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 B132: A new concept of cancer immunotherapy by targeting pancreatic ductal adenocarcinoma through a childhood recall antigen","authors":"B. Selvanesan, D. Chandra, W. Quispe, Ankur Patel, K. Meena, S. Libutti, Ziqiang Yuan, J. Chuy, C. Gravekamp","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B132","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B132","url":null,"abstract":"Patients with pancreatic ductal adenocarcinoma (PDAC) have a five-year survival of only 6%. Cancer immunotherapy has shown promising results for metastatic cancer but only in 20% of the patients. Our lab has developed a new concept of immunotherapy using an attenuated non-pathogenic bacterium Listeria monocytogenes for the selective delivery of a highly immunogenic recall antigen tetanus toxoid (TT) into tumor cells of pancreatic tumors and metastases. Most individuals have been exposed to TT during childhood vaccinations and memory T-cells to TT circulate in blood for live. These memory T-cells to TT can be reactivated by Listeria-TT at any time in life and will now destroy the infected tumor cells. Low doses of gemcitabine (GEM) were added to further improve T-cell responses. Panc-02 and KPC mice were immunized with the “human TT vaccine” to generate memory T-cells before development of the pancreatic cancer. After cancer development, mice were treated with Listeria-TT and GEM, and tumors (weight) and metastases (number) were analyzed by eye in the Panc-02 mice, and by SUVmax (measurement of tumor growth) in the KPC mice. T-cell responses in the spleen were analyzed by flow cytometry and ELISPOT, and KPC tumors were analyzed by RNAseq. Listeria-TT and GEM nearly completely eliminated both early and advanced pancreatic cancer in Panc-02 and KPC mice, in correlation with abundant CD4 and CD8 T-cell responses producing perforin, granzyme B, or IFNγ, in vivo or in vitro, respectively. RNAseq analysis of “treated” KPC tumors showed a strong influx of CD4 and CD8 T-cells, upregulation of multiple granzymes, perforin, co-stimulatory molecules, and cell death pathways. These results suggest the multiple synergistic effects of Listeria-TT and GEM on pancreatic cancer. This novel treatment modality of Listeria-TT and GEM warrants further investigation in a clinical setting. Citation Format: Benson C. Selvanesan, Dinesh Chandra, Wilber Quispe, Ankur Patel, Kiran Meena, Steven K. Libutti, Ziqiang Yuan, Jennifer Chuy, Claudia Gravekamp. A new concept of cancer immunotherapy by targeting pancreatic ductal adenocarcinoma through a childhood recall antigen [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 B132.","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":"81298603","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 B139: Plant viral particle vaccine induces a potent antitumor response through induction of antigen-specific T-cells and overcoming an immunosuppressive tumor microenvironment","authors":"Chuan Wang, Yidao Wang, A. Allen, Jantipa Jobsri, G. Thomas, C. Ottensmeier, N. Savelyeva","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B139","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B139","url":null,"abstract":"In order to develop an effective vaccination strategy for cancer, it is necessary to induce robust T-cell responses and to overcome the immunosuppressive tumor microenvironment (TME). To induce anticancer immunity, we focused on a plant viral particle (PVP) that contains-single strand RNA (ssRNA) as a flexible and economical platform to deliver cancer antigens. Initially using PVP loaded with SIINFEKL, we demonstrated the induction of a rapid CD8 T-cell response leading to a significant therapeutic effect in the B16 tumor model. The induction of high levels of CD8 T-cells was also achieved when clinically relevant cancer antigens were used with lysis of human cancer cells expressing these antigens. Further, PVP loaded with whole protein antigen induced CD8 and CD4 T-cell responses against the epitopes delivered through the whole antigen and these cleared established tumors. The mechanisms behind the high immunogenicity of the PVP vaccine revealed that this ssRNA containing vaccine activated the immune mechanisms closely resembling the natural antiviral defence. In a murine model, the immune induction was through the activation of TLR7, leading to release of type I IFN by plasmacytoid dendritic cells and activation of conventional DCs (cDCs) followed with the priming of Th1 immunity. These findings were further supported by experiments using human monocytes derived DCs (moDCs) stimulated in vitro with PVP. The stimulated moDCs released Th1-polarizing cytokines and chemokines, and upregulated CD40 and B7 family surface molecules. Further investigation of the TME demonstrated that cDCs, MHC-II high tumor associated macrophages (TAMs) and tumor-infiltrating neutrophils were recruited into the tumor bed 24 hours after vaccination. While MHC-II low TAMs and myeloid-derived suppressor cells were down-regulated in response to vaccination. This was followed by the increase of tumor-infiltrating lymphocytes (TILs) specific for endogenous tumor antigens. In conclusion, the PVP vaccine is an effective platform to induce T-cells specific to the delivered cancer antigens, and furthermore benefit from its ability to convert an immunosuppressive TME towards an immunostimulatory environment, facilitating the endogenous T-cell epitopes spread. Citation Format: Chuan Wang, Yidao Wang, Alex J. Allen, Jantipa Jobsri, Gareth J. Thomas, Christian H. Ottensmeier, Natalia Savelyeva. Plant viral particle vaccine induces a potent antitumor response through induction of antigen-specific T-cells and overcoming an immunosuppressive tumor microenvironment [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 B139.","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79916731","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 B124: Personalized peptide vaccination based on patient-individual tumor-specific variants induces T-cell responses in pediatric patients","authors":"A. Rabsteyn, C. Kyzirakos, C. Schroeder, M. Sturm, C. Mohr, Jakob Matthes, M. Feldhahn, Nicolas Casadei, M. Ebinger, S. Stevanović, P. Bauer, O. Kohlbacher, C. Gouttefangeas, J. Schaefer, H. Rammensee, R. Handgretinger, P. Lang","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B124","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B124","url":null,"abstract":"Background: We established a platform for the design of patient-individual peptide vaccination cocktails by combination of whole exome sequencing of tumor and normal tissue with in silico epitope prediction algorithms for individual patient HLA types. Accumulation of somatic mutations is one characteristic feature of malignanT-cells. These single-nucleotide variants (SNVs) can lead to altered amino acid sequences of the translated proteins, which in turn can be presented by malignant cells as antigenic peptides on HLA molecules. A peptide vaccination to induce neoantigen-specific T-cell responses, therefore, is a promising and versatile immunotherapeutic approach for the treatment of malignant diseases. Such approaches were predominantly applied in malignancies with high mutational load in adult patients until now. We developed a vaccine design platform based on sequencing data generated from a cohort of acute lymphoblastic leukemia (ALL) patients and tested individualized peptide vaccines in pediatric patients suffering from a variety of tumors with low mutational profiles. Methods: Nonsynonymous mutations were identified by whole-exome and transcriptome sequencing of patient leukemic blasts and healthy reference tissue. HLA binding peptides harboring the altered amino acids were subsequently predicted in silico by algorithms SYFPEITHI, NetMHC and NetMHCpan for the patients’ individual HLA type. Individual peptides for treatment attempts were produced by chemical synthesis and vaccination cocktails were formulated. The vaccination schedule was 16 vaccinations over 33 weeks using GM-CSF and Imiquimod as adjuvants. Some patients received simultaneous checkpoint blockade treatment with pembrolizumab or nivolumab. Response to the vaccination was monitored by detection of T-cells recognizing the vaccinated peptides occurring over time in peripheral blood of the patients. Monitoring was performed for each vaccination time point by pre-stimulation with the peptides and subsequent intracellular cytokine staining (ICS) of T-cells and FACS analysis. Results: Whole-exome sequencing was performed for 25 patients to identify ALL-specific SNVs using a comparative bioinformatics pipeline. We found an average of 39.2 mutations per patient on DNA level, with an average validation rate of 47% by RNA sequencing. Based on these data, an average of 35.1 HLA binders could be predicted per patient. We applied our platform for 6 patients with various malignancies based on compassionate need and designed individual peptide vaccines. In all cases validated mutations could be identified and epitope prediction was performed for HLA Class I and II binders. In 6/6 patients a de novo induced T-cell response against the vaccinated mutated HLA-binding peptides was detectable. Combination therapy with PD-1 blockade and peptide vaccination was well tolerated. T-cell responses were predominantly, but not exclusively, CD4+-restricted. Encouraged by these findings, we started a phas","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87694597","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 B126: Degradation-regulatable architectured implantable macroporous scaffold for the spatiotemporal modulation of immunosuppressive microenvironment and enhanced combination cancer immunotherapy","authors":"Long Ren, Il Woo Shin, Chanyoung Song, Y. Lim","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B126","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B126","url":null,"abstract":"The presence of immunosuppressive cells such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) in residual tumors after surgery is known to be related to high recurrence of tumors which are more resistant to therapeutic interventions compared with the primary ones. Herein, a degradation-regulatable architectured implantable macroporous scaffold (Dr-AIMS) is designed to act as a local drug delivery reservoir, modulating the immunosuppressive tumor microenvironment (TME) and activating T-cell-based antitumor immunity as well. The Dr-AIMS is fabricated by the crosslink of methacrylate-modified hyauronic acid under frozen state to form the interconnected macroprorous architacture with pore size of 252.36 ± 59.57 μm. By combining stable “bulk” material (methacrylate-modified hyaluronic acid) and hydrolytic-labile “sacrificing” component (methacrylate-modified oxidized hyaluronic acid) with varied blending ratios, the degradation can be regulated with 10-28 days after implantation in mice. In vitro results indicated that PTX could induce immunogenic 4T1 cell death and deplete TAMs, and R837 could activate antigen presenting cells and inhibit MDSCs functions. After loading PTX, R837 and combined immune checkpoint blockade molecules (anti-CTLA-4 and anti-OX40 mAbs, invigorating T-cells function), Dr-AIMS was implanted as postsurgical treatment (~10% remaining) in 4T1 breast tumor model. In vivo results suggested that the generation of systemic anti-tumor immunity required continuous drug supplies for at least two weeks. The sustained and localized supply of immunomodulatory drugs from Dr-AIMS facilitated the depletion of MDSCs and M2-like macrophages simultaneously within the tumor tissues, converting immunosuppressive TME into antitumor immunity niches. Also, enhanced infiltration of DCs and effector T-cells into tumor was observed, and systemic antitumor immunity was generated with 10-fold reduced doses, resulting in the prolonged survival of mice after surgery of incompletely removed tumor. Citation Format: Long Ren, Il Woo Shin, Chanyoung Song, Yong Taik Lim. Degradation-regulatable architectured implantable macroporous scaffold for the spatiotemporal modulation of immunosuppressive microenvironment and enhanced combination 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 B126.","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":"79549141","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 B121: Checkpoint inhibitor vaccine stimulates antitumor T-cells that block tumor growth","authors":"Takuya Tada, N. Landau, T. Norton","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B121","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B121","url":null,"abstract":"Checkpoint inhibitor therapy augments pre-existing T-cell responses to tumor antigens, resulting in tumor control in 20-40% of patients with melanoma and other cancers. As a means to increase the effectiveness of this approach, we developed a dendritic cell (DC)-based vaccine strategy that specifically induces anti-tumor T-cell responses and prevents checkpoint activation. The approach is based on lentiviral vectors that express checkpoint inhibitor and tumor antigen and transduce DCs at high efficiency as a result of virion-packaging of the lentiviral accessory protein Vpx. In addition, the vectors express CD40 ligand (CD40L), a cell surface protein that strongly activates DCs, causing the cells to mature and secrete immunostimulatory cytokines, including TNFα, IL-6, and IL-12, that potentiate T-cell responses. The therapy harnesses the ability of DCs to prime T-cell responses against tumors, resulting in long-term antigen expression and continuous, localized release of checkpoint inhibitor during antigen-presentation. In the lymphocytic choriomeningitis virus (LCMV) mouse model, immunization with DCs transduced with lentiviral vectors that express soluble programmed cell death protein 1 (PD-1), CD40L and LCMV epitopes induced a 10-fold expansion of LCMV-specific CD8 T-cells and protected the mice against high-titer LCMV and a lethal intracranial LCMV challenge. Protection was 100-fold greater than that achieved by vaccination with LCMV peptide epitope-pulsed DCs. The strategy also appeared to cure mice infected with clone 13 LCMV, a chronic form of disease that results from T-cell exhaustion induced by checkpoint activation. In the B16-OVA mouse melanoma model, immunization with DCs transduced with vectors that express soluble PD-1, CD40L and OVA epitopes or a tumor antigen epitope from tyrosinase-related protein (TRP-1) protected mice from tumor formation. DC vaccination post-B16 challenge reduced tumor growth and prolonged survival. Mice immunized four days after intravenous injection of B16 cells showed no evidence of lung melanoma nodules three weeks later. Remarkably, immunization by direct injection of lentiviral vector, a method that obviates the need to harvest patient DCs, proved equally effective as ex vivo DC transduction in suppressing tumor growth. In addition, direct injection resulted in a much longer half-life of transduced cells. These studies demonstrate the ability of this approach to induce antigen-specific responses and overcome CTL exhaustion. Moreover, the lentiviral vector approach provides a means to express tumor neoantigens for the development of personalized immunotherapies that stimulate tumor-specific T-cell responses by clones present at low level or to antigens that the host has not responded. Citation Format: Takuya Tada, Nathaniel R. Landau, Thomas David Norton. Checkpoint inhibitor vaccine stimulates antitumor T-cells that block tumor growth [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR Internat","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"59 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75711181","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 B131: Live-attenuated LCMV-based vector for active immunotherapy of HPV16+ cancer","authors":"S. Schmidt, A. El-Gazzar, Weldy V. Bonilla, Mindaugas Paužuolis, A. Reiter, T. Kleissner, Daniel Oeler, Felix Stemeseder, U. Berka, Bettina Kiefmann, Sophie Schulha, I. Matushansky, D. Merkler, D. Pinschewer, K. Orlinger","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B131","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B131","url":null,"abstract":"Active immunization against cancer requires the induction of exquisitely potent tumor-specific CD8+ T-cell (CTL) responses, which can be repeatedly boosted and reactivated. Hookipa Pharma engineered a replication-attenuated viral vector platform (TheraT®) based on the arenavirus lymphocytic choriomeningitis virus (LCMV), which meets these aforementioned criteria. Here, we present a preclinical data package of Hookipa´s lead immunotherapy product HB-201, targeting HPV16-driven head and neck cancer. It encodes a non-oncogenic version of the human papilloma virus 16 (HPV16) oncoproteins E7 and E6 (TheraT®-E7E6). Attenuation and safety of TheraT®-E7E6 were demonstrated by i) rapid viral clearance after systemic administration of the vector and ii) reduced neurovirulence in mice. TheraT®-E7E6 treatment was shown to induce substantial CD8+ T-cell expansion and high frequencies of E7- and E6-specific CTL responses with a balanced effector / central memory profile. These responses were boosted and reactivated upon TheraT®-E7E6 re-administration. TheraT®-E7E6 eradicated palpable TC-1 tumors, a syngeneic mouse tumor model of HPV-driven cancer. Even in mice with large tumors (~300mm3), TheraT®-E7E6 afforded significant tumor control and improved survival, with high frequencies of E7-specific CTLs persisting for several weeks. Furthermore, the efficacy of TheraT®-E7E6 can be potentiated in combination therapies, e.g., with PD-1 checkpoint inhibitors. In conclusion, replication-attenuated TheraT®-E7E6 is safe, highly immunogenic and shows excellent therapeutic efficacy as mono- or combination therapy in a preclinical model of HPV-induced cancer. Clinical trials for the treatment of HPV16+ cancers will be initiated in 2019. Citation Format: Sarah Schmidt, Ahmed ElGazzar, Weldy V. Bonilla, Mindaugas Pauzuolis, Andrea Reiter, Theresa Kleissner, Daniel Oeler, Felix Stemeseder, Ursula Berka, Bettina Kiefmann, Sophie Schulha, Igor Matushansky, Doron Merkler, Daniel Pinschewer, Klaus Orlinger. Live-attenuated LCMV-based vector for active immunotherapy of HPV16+ cancer [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 B131.","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75224809","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 B136: Optimized messenger RNA immunolipoplexes for cancer immunotherapy: Balancing immunogenicity and adjuvancy","authors":"Rein Verbeke, I. Lentacker, K. Breckpot, S. V. Calenbergh, S. Smedt, H. Dewitte","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B136","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B136","url":null,"abstract":"Messenger RNA has garnered a lot of attention as a new therapeutic drug class for vaccination (1). Particularly for cancer immunotherapy, mRNA encoding tumor antigens has the potential to design personalized and effective cancer vaccines (2). However, the major challenge remains to directly deliver the mRNA to (professional) antigen presenting cells (APCs), evoking safe and effective antitumor immunity. The mRNA vaccines that are currently being evaluated in first-in-human clinical trials depend on the self-adjuvant effect of mRNA and subsequent signaling via type I IFN (3-4). We and others have reported that type I IFNs have the downside of inducing anti-mRNA (anti-viral) innate responses, which makes it challenging to strike a balance between evoking innate immunity and obtaining adequate levels of mRNA expression (5-6). In addition, high levels of IFN-α are known to cause adverse effects (e.g., flu-like symptoms and autoimmune sequelae) (7).To overcome these issues, we developed a nanoparticle platform which protects mRNA against degradation while successfully delivering mRNA to APCs in vivo (6). In this platform, we choose to minimize the mRNA-based immune recognition using a nucleoside-modified (“immune-silent”) mRNA construct, but instead to co-package clinically-approved immune adjuvants (e.g., MPLA) to achieve strong and controllable immunogenicity. The vaccine potential of mRNA lipid nanoparticles with different immune adjuvants was evaluated by performing biodistribution and immunogenicity studies after systemic delivery in mice. The preclinical antitumor efficacy was assessed in an EG7-OVA lymphoma and B16-OVA melanoma model. In addition to evaluating overall survival, experiments were performed where tumors were isolated after immunization and screened for effector responses (e.g., antigen-specific CD8+ T-cells and NK cells) and suppressive mechanisms that could impact the therapeutic outcome (e.g., immune checkpoints, myeloid derived suppressor cells [MDSCs] and tumor-associated macrophages [TAMs]). To tackle adaptive resistance to activated T-cells, we evaluated a combinatory therapy of the mRNA vaccine with anti-PDL1 antibodies (8). Upon i.v. injection in mice, these particles are mainly detected within APCs (macrophages and dendritic cells) in lungs and spleen. Importantly, this resulted in high mRNA expression as well as functional activation of the particle-loaded immune cells, marked by cytokine production of IL-12p70 and IFN-γ. We were able to optimize a formulation of adjuvanted-nanoparticles with modified mRNA, which resulted in 6 to 7 times higher numbers of tumor-infiltrating antigen-specific T-cells compared to unmodified mRNA particles. In addition to CD8+ T-cell responses, we also observed a 2- to 3-fold increase in intratumoral NK cells, compared to untreated mice. Furthermore, these mice exhibited reduced immune suppression at the tumor site: low numbers of MDSCs whereas TAMs displayed proinflammatory M1-like changes ","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"145 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80482385","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 IA27: Oncolytic viruses: Potential for in situ anti-tumor vaccination and combination with checkpoint blockade","authors":"A. Melcher","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-IA27","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-IA27","url":null,"abstract":"Oncolytic virotherapy (OV) is increasingly recognised as a form of immunotherapy, with the lead agent, a herpes simplex virus (HSV) encoding GM-CSF, talimogene laherparepvec (T-Vec), now licensed for clinical use by intratumoural injection in advanced melanoma. Although early clinical data is showing promise for OV/immune checkpoint blockade combinations, the underlying mechanisms by which such strategies may be optimised for the widest possible clinical application, remain poorly understood. We have focused on intravenous delivery of OV as a more practical clinical approach than intratumoural injection, and shown that the dsRNA, non-genetically modified OV reovirus, can access tumours in patients in the brain or liver following systemic injection, despite the presence of anti-viral neutralising antibodies (NAB) in the blood prior to treatment. The ability of reovirus (but not necessarily all OV) to evade antibody-mediated neutralisation appears to be via protective cell carriage (or \"hitchhiking\") of virus or virus/NAB complexes by monocytes in the circulation. Once systemically delivered reovirus has accessed the brain tumour microenvironment we showed, consistent with clinical data using intratumoural T-Vec in melanoma, that the virus converted an immunologically ‘cold’ tumour milieu to ‘hot’, which effectively primed for combination oncolytic immunovirotherapy with immune checkpoint blockade, when tested back in an immunocompetent murine glioma model. To complement murine data and translational clinical trial sample analysis, we have developed human in vitro pre-clinical models of innate and adaptive anti-tumour immune priming by OV. OV innately activated human peripheral blood mononuclear cells (PBMC), including differentiation of monocytes towards a more antigen presenting cell (APC)-like phenotype. Hence OV-hitchhiking monocytes in the blood, after delivering virus to tumour, may pick up infected tumour cells undergoing immunogenic cell death and act as APC to initiate adaptive anti-tumour immune priming. In support of this paradigm, we showed that human monocytes, antigen loaded by phagocytosis of OV-infected dying tumour cells, supported greater priming of a specific anti-tumour CD8+ cytotoxic T cell (CTL) response than uninfected controls, when co-cultured with responder PBMC. This OV-mediated enhanced anti-tumour CTL priming response included expansion of T cells specific for multiple, non-mutated tumour associated antigens (TAA) expressed by the original, antigen loading tumour cell, as demonstrated using a CTL re-stimulation readout assay. In this assay, autologous monocytes were first pulsed with long, 15mer overlapping peptides, spanning the length of 3 melanoma TAAs, gp100, TRP-2 or MART-1. MHC class I epitopes processed from these long peptides pools, and presented by the monocytes, could then stimulate their specific, responder T cells on co-culture with primed CTL, and the TAA-specific, non-HLA restricted T cell response quanti","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"47 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78385105","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}