Novel Vaccine Platforms and Combinations最新文献

{"title":"Abstract B140: Positron emission tomography-guided photodynamic therapy with biodegradable silica nanoparticles for personalized cancer immunotherapy","authors":"Cheng Xu, J. Moon","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B140","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B140","url":null,"abstract":"Recent clinical trials with neoantigen-based vaccines have shown the feasibility and potential of personalized cancer immunotherapy. Photodynamic therapy (PDT), which utilizes photosensitizer and laser irradiation to produce reactive oxygen species, has been widely explored for local cancer treatment. In addition, positron emission tomography (PET) is a highly sensitive and noninvasive imaging method that can visualize solid tumors while allowing for quantitative analysis of drug biodistribution. In this work, we aimed to combine vaccination and PET imaging-guided PDT as an effective combination platform for personalized cancer immunotherapy. We have synthesized biodegradable silica nanoparticles (bMSN) loaded with neoantigen, CpG oligodeoxynucleotide (a potent Toll-like recetor-9 agonist) and chlorin e6 (a widely used photosensitizer). Using PET imaging, we have shown that bMSN effectively accumulates in MC-38 colon carcinoma tumors after intravenous administration in vivo. Subsequent PDT with 660 nm laser irradiation eliminated tumors, resulting in the release of tumor antigens and danger signals that promoted recruitment of dendritic cells to PDT-treated sites. The bMSN nanoplatform sustain-released neoantigen and CpG oligodeoxynucleotide, while activating DCs and enhancing neoantigen-specific cytotoxic CD8+ T-cell responses and their infiltration into tumors. In mice bearing two contralateral MC-38 tumors, the combination of vaccination and PDT completely eradicated locally treated, large MC-38 tumors while significantly delaying the growth of distant, untreated tumors. Our findings suggest that bMSN is a promising immunotherapeutic platform for combining imaging, vaccination, and PDT for treatment of advanced cancer. Citation Format: Cheng Xu, James Moon. Positron emission tomography-guided photodynamic therapy with biodegradable silica nanoparticles for personalized 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 B140.","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"85 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74932485","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 B113: Protective serum responses by CRISPR/Cas9-edited primary B cells expressing antibodies of choice","authors":"H. Hartweger, M. Jankovic, M. Nussenzweig","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B113","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B113","url":null,"abstract":"Attempts to create an effective, traditional vaccine against several pathogens such as HIV have so far failed and current research suggests that in the case of HIV protective serum responses mediated by broadly-neutralizing antibodies (bNAbs) will only be achieved by multiple, sequential immunizations. Identifying, producing and implementing a regimen consisting of a series of immunogens that lead to a relatively consistent, protective immune response in a heterogeneous population will be highly challenging. We are developing an alternative approach in which autologous primary B cells are edited to express an antibody of choice, in this case a bNAb against HIV. Following adoptive transfer the individual is immunized with a cognate antigen to activate the edited B cells and generate a protective, humoral immune response to HIV. This method can be adapted for any combination of high-affinity antibody and antigen. We have developed a CRISPR/Cas9-based method to target the endogenous IgH and IgK loci in mice. Both loci must be targeted in order to avoid producing B cells with chimeric and potentially self-reactive receptors. In addition, both of the bNAb encoding chains must be coordinately expressed. To do so we assemble an RNP consisting of Cas9 and single stranded DNA (ssDNA) encoding IgK followed by a P2A self-cleaving oligopeptide and the VDJ exon. A separate Cas9/guide complex is included to ablate the endogenous IgK locus. Since the heavy chain variable region is knocked into the endogenous locus in between the VDJ and constant regions normal isotype switching can occur and only on-target integrations can express the full BCR of choice. B cell survival is dependent on Ig expression and therefore all of the B cells that have lost Igk expression and do not properly integrate the bNAb will die. Using this approach, we have created cells carrying a synthetic intermediate of the anti-HIV bNAb 3BNC60. Transfer of 3BNC60 synthetic intermediate-edited cells into congenically marked wild-type mice followed by immunization with a cognate Env-derived antigen showed that the edited cells were able to start an immune response and create 3BNC60 synthetic intermediate serum antibody with the predicted epitope specificity of different isotypes. One of the potential benefits to this approach is that it would not be limited to a single monoclonal. B cells could be edited to express different antibodies and then be transferred together. Our initial experiments show that the approach is feasible but the process must be optimized to become practical; particularly, the number of correctly edited B cells needs to be increased for efficient transfer. We are also working on translating these experiments from mice to macaques in order to do protection experiments.We believe the approach presented here would have wide-ranging implications for both research and public health. It boasts several advantages compared to traditional vaccination, particularly in the context of","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"304 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75454123","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 B138: Cancer immunotherapy with APOBEC3B-induced heteroclitic library tumor cell vaccines and immune checkpoint blockade","authors":"R. Vile, Laura Evgin, T. Kottke, M. Schuelke, C. Driscoll, Amanda L. Huff, Jill Thompson, Amy M. Molan, R. Harris, J. Pulido, Phonphimon Wongthida","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B138","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B138","url":null,"abstract":"We have previously shown that a vesicular stomatitis virus-based cDNA library expressing xenogeneic altered self-epitopes led to T-cell mediated rejection of prostate cancer, glioma and melanoma. The use of a library of altered self-peptides which reflects the transcriptome of the tumor circumvents the necessity for a priori knowledge of which antigens may be immunogenic in a patient, and primes a polyclonal T-cell response that provides strong cumulative antitumor selective pressure. We have expanded this concept of altered-self library vaccination using tumor vaccines modified by the overexpression of APOBEC3B, a cytosine deaminase that generates C to T transition mutations. A freeze-thawed whole tumor cell vaccine prepared from B16 melanoma cells stably overexpressing human APOBEC3B treated established subcutaneous parental B16 tumors and, when combined with PD-1 checkpoint blockade, cured between 75%-100% of mice. T-cells from mice treated with the vaccine and anti-PD1 produced high levels of IFN-γ when restimulated with parental unmodified B16 melanoma cells in vitro. Whole-genome sequencing of B16APOBEC3B overexpressing cells identified 301 C to T or G to A missense mutations unique to the APOBEC3B line. Using an in silico MHC binding affinity algorithm, we identified and experimentally validated a short list of 10 APOBEC3B- induced heteroclitic peptides. We have also shown that this approach can be extended to an orthotopic brainstem model of high grade glioma. GL261 tumors stereotactically implanted into the brainstem were significantly responsive to treatment with an APOBEC3B- modified GL261 vaccine in combination with anti-PD-1 checkpoint blockade. In summary, when overexpressed in tumor cells, APOBEC3B generates a library of heteroclitic sequences that primes both CD4 and CD8 T-cells that have escaped central tolerance and that recognize both newly mutated antigens from the vaccine, and the corresponding unaltered self epitopes expressed on the tumor cells. Citation Format: Richard Vile, Laura Evgin, Timothy Kottke, Matthew Schuelke, Christopher B. Driscoll, Amanda L. Huff, Jill Thompson, Amy Molan, Reuben S. Harris, Jose S. Pulido, Phonphimon Wongthida. Cancer immunotherapy with APOBEC3B-induced heteroclitic library tumor cell vaccines and immune checkpoint blockade [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 B138.","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"43 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76328998","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 B143: Lace molecular vaccine with adjuvant booster to enhance immunogenicity","authors":"Chunsong Yu, Haipeng Liu","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B143","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B143","url":null,"abstract":"Manipulation of vaccine adjuvants, including bioconjugation and particle formulation, is a prevailing approach to achieve efficient delivery and improve therapeutic efficacy. However, these approaches may compromise bioactivity or may not be desirable when these compounds are chemically or physically unmanipulable. Here, we report an “adjuvant booster” strategy to markedly promote immunogenicity by simply lacing molecular vaccines with an adjuvant booster. We created an adjuvant booster, lipid modified 20-mer thymidine oligodeoxynucleotide (lipo T20), which could significantly increase the potency of Toll-like receptor 7 (TLR7) ligands in both murine and human TLR7 HEK 293 cells and substantially target draining lymph nodes where unmodified adjuvant rarely accumulated. Subcutaneous administration of “imiquimod/protein antigen” vaccine laced with lipo T20 in mice resulted in a five-fold increase in T-cell priming and enhanced antibody response in comparison to booster-free vaccine. “Adjuvant booster” strategy provides an alternative and simple methodology to further enhance immunogenicity of molecular vaccines. Citation Format: Chunson Yu, Haipeng Liu. Lace molecular vaccine with adjuvant booster to enhance immunogenicity [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 B143.","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"58 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91297277","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 B108: Molecular and cellular properties of neoantigen-specific CD8+ T-cells on interaction with B16F10 melanoma in situ","authors":"J. Finnigan, A. Ishizuka, G. Lynn, A. Rubinsteyn, R. Seder, N. Bhardwaj","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B108","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B108","url":null,"abstract":"Mutation-derived tumor antigens (MTA)—alternatively known as “neoantigens”—are a class of tumor antigens generated by tumor cell-intrinsic somatic DNA alterations. MTA are thought to be the predominant target of spontaneous and treatment-induced anti-tumor immunity. Direct targeting of MTA with therapeutic vaccination or other approaches is thus an active area of clinical research. However, pre-clinical studies of MTA-specific immunity have been limited in part due to a lack of reproducible targets. Furthermore, properties distinguishing effective MTA-specific immune responses, from less effective responses targeting other types of non-mutated tumor antigens have not been identified. To address this deficit, we previously reported the development of a system wherein MTA-specific CD8+ T-cell-mediated immunity could be systematically characterized. Briefly, we performed exome (WES) and RNASeq on the B16F1 and B16F10 melanoma cell lines, as well as matched normal tissue. We identified somatic single-nucleotide substitutions, insertion and deletion (INDEL), as well as larger INDEL and gene translocation events. The sequence identity and expression of somatic variants was validated by RNASeq. Standard in silico protocols were used to predict MHC-I binding affinity, which we subsequently validated via cell-free fluorescent peptide:MHC-I stability assay. Using a nanoparticle-based vaccination protocol, we identified and characterized multiple MHC-I restricted MTA in the B16F10 model system. We report an initial characterization of the vaccine-induced MTA-specific CD8+ T-cell response and demonstrate activity of vaccine monotherapy following subcutaneous tumor challenge. We extend prior observations were expanded upon in the following manner: First, the sensitivity and specificity of MTA-specific CD8+ T-cells was determined by in vitro stimulation with target MTA peptide and matched wildtype-sequence peptide followed by intracellular flow cytometry. Vaccine-induced CD8+ T-cells exhibit selectivity to MTA peptide targets ranging perfect specificity to moderate selectivity. A cell-based MHC-I binding assay was used to measure the relative affinity of MTA and matched wildtype peptides. The selectivity of vaccine-induced CD8+ T-cells to MTA peptides was observed to depend both on peptide:MHC-I as well as TCR:pMHC interactions. With respect to sensitivity of CD8+ T-cells towards target antigen, CD8+ T-cells targeting MTA were found to be more sensitive than those targeting nonmutated tumor antigens. We assessed direct recognition of target antigen endogenously presented by autologous tumor cells and describe tumor cell-intrinsic, as antigen-specific features affecting lymphocyte recognition and effector function. Second, we longitudinally profiled the surface receptor phenotype, and transcription factor usage of MTA-specific CD8+ T-cells by single-cell mass cytometry (CyTOF). We describe the phenotype of peripheral, as well as tumor-infiltrating MTA-specific ","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"105 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79252021","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 B110: Proinflammatory allogeneic dendritic cells promote activation of bystander immune cells and indirectly license antigen-specific T-cells","authors":"G. Fotaki, Chuan Jin, I. Kerzeli, Mohanraj Ramachandran, A. Karlsson-Parra, Di Yu, M. Essand","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B110","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B110","url":null,"abstract":"Autologous patient-derived dendritic cells (DCs) modified ex vivo to present tumor-associated antigens have frequently been utilized as cancer vaccines. However, apart from the stringent logistics in producing DCs on a patient basis, accumulating evidences indicate that such DCs are poor in migration and in fact do not directly interact with naive T-cells in vivo. Instead, it is the bystander host-DCs taking up material from apoptotic vaccine DCs and subsequently initiate antitumor T-cell responses. We examine the possibility of harnessing allogeneic pro-inflammatory DCs (alloDCs) as immune enhancers which may affect the activation of bystander immune cells and promote antigen-specific T-cell responses. We have verified the inflammatory state of DCs matured with a maturation cocktail in combination with an infection-enhanced adenovirus. Such proinflammatory alloDCs expressed co-stimulatory and activation molecules and secreted Th-1 type cytokines in vitro. T and NK cells up-regulated activation markers after co-culture with such alloDCs and created an immunostimulatory environment which was found to promote maturation of antigen-loaded DCs and the subsequent activation of antigen-specific T-cells by cross-presentation. Our findings were evaluated as a therapeutic strategy in murine models with success. We are proposing that vaccination with proinflammatory alloDCs in combination with the use of Ad5M as possible antigen delivery vehicle can be a cost-effective strategy to induce antitumor immune responses. Citation Format: Grammatiki Fotaki, Chuan Jin, Iliana Kyriaki Kerzeli, Mohanraj Ramachandran, Alex Karlsson-Parra, Di Yu, Magnus Essand. Proinflammatory allogeneic dendritic cells promote activation of bystander immune cells and indirectly license antigen-specific T-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 B110.","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"92 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80432081","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 B134: Use of p19Arf/interferon-β immunotherapy in association with chemotherapy permits reduced drug dosage and avoids cardiotoxicity associated with doxorubicin","authors":"B. Strauss, R. F. Medrano, R. E. Tamura, S. Mendonça, V. Feitosa, R. Dariolli, T. Salles, Aline Hunger, J. P. Catani, E. G. Rodrigues","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B134","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B134","url":null,"abstract":"Background: A variety of methods have been shown to induce immunogenic cell death (ICD) and overcome the immunosuppressive tumor microenvironment, thus generating an effective immunotherapy. In our previous work, we have shown that non-replicating adenovirus mediated gene transfer of p19Arf and interferon-β (IFNβ) forms a strategic alliance between gene function and the vector, resulting in a multi-modal mechanism of cell death consistent with necroptosis and with the liberation of ICD molecules HMGB1, ATP and calreticulin in B16F10 mouse melanoma cells. We have performed vaccine and immunotherapy assays as well as in situ vaccination in order to show that our gene transfer approach contributes to an antitumor immune response that involves neutrophils, NK, CD4+ and CD8+ T-cells and cytokine production that is consistent with a Th1 profile. While promising so far, we strive to boost tumor cell killing while preserving the well-being of the study subject. Objective: To use our gene transfer approach in association with doxorubicin (Dox), a well-known inducer of ICD, in order to promote cell killing while permitting the use of reduced drug dosages, thus ameliorating collateral effects, including cardiopathy, and possibly benefitting the antitumor immune response. Materials and Methods: MCA205 and B16F10 cells were used in this study. The AdRGDPG vectors are non-replicating recombinant Ad5 viruses containing the RGD tripeptide modification of the virus fiber protein and which utilize a p53-responsive promoter (termed PG) to control transgene expression. The AdRGDPG-GFP, AdRGDPG-p19, and AdRGDPG-IFNβ vectors encode enhanced green fluorescent protein (GFP), the mouse cDNAs for p19Arf (a functional partner of p53) and IFNβ, respectively. Using flow cytometry (Attune, Thermo Fisher), accumulation of hypodiploid cells was revealed upon fixation and propidium iodide staining while caspase 3/7 activity was visualized using Cell Event Caspase 3/7 (Thermo Fisher). Alternatively, BLI (IVIS Spectrum, Perkin Elmer) was used to detect a DEVD-dependent luciferase reporter construct in vivo. Cardiac function was monitored using echocardiography (VisualSonics Vevo 2100 Imaging System) and data analyzed using VevoCQ LV analysis software (VisualSonics). All animal assays were performed according to and with the approval of the Committee for the Ethical Use of Animals, FM-USP. Results: Association of p19Arf/IFNβ gene transfer with Dox treatment in vitro improved cell killing and central composite rotational design analysis revealed that indeed, the association permits the application of less drug and/or virus while preserving high levels of death in either cell line. In vitro, caspase 3/7 activity was additive upon exposure of MCA205 cells to the associated treatments, yet Dox was sufficient in B16F10. In vivo, Dox (20 mg/kg) alone or in combination with in situ gene therapy was correlated with inhibition of MCA205 tumor progression, increased caspase 3/7 activity and ","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75448968","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 B104: Post-translationally modified homocitrulline induced by MDSCs can be an effective antitumor target for CD4 T-cells","authors":"K. Cook, W. Xue, P. Symonds, Mohamed Gijon, Sabaria Shah, Suha Atabani, Poonam M Vaghela, R. Choudhury, R. Metheringham, I. Daniels, Victoria A Brentville, L. Durrant","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B104","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B104","url":null,"abstract":"Post-translational modifications such as citrullination and phosphorylation have been shown to provide novel target for cancer vaccines. Epitopes from modified proteins allow the generation of cytotoxic CD4 cells capable of targeting tumor. In this study we show that homocitrulline, an amino acid produced when lysine is post translationally modified by the process of carbamylation, can be a target for effective tumor immunity. Homocitrullinated epitopes from the cytoskeletal protein vimentin and the glycolytic enzyme aldolase were selected based upon MHC-II binding algorithms. Immunization of HLA transgenic mice with three homocitrullinated peptides, one from vimentin and two from aldolase A, induced potent IFNγ responses restricted via HLA-DR4, DR1 or DP4. Responses are specific to the homocitrullinated peptides and did not cross react with unmodified peptides. The responses have been characterized as CD4-mediated, Th1-type responses with minimal IL-10 or IL-17 production. In humans, we have also shown that healthy donors and cancer patients both have a CD4 T-cell repertoire recognizing these homocitrullinated peptides. In B16 melanoma tumor models, vaccination with homocitrullinated peptides increases survival in transgenic HLA-DR4 (survival 70%, p=0.0042), HHDII/DR1 (survival 50%, p Citation Format: Katherine W. Cook, Wei Xue, Peter Symonds, Mohamed Gijon, Sabaria Shah, Suha Atabani, Poonam Vaghela, Ruhul Choudhury, Rachael L. Metheringham, Ian Daniels, Victoria Brentville, Lindy Durrant. Post-translationally modified homocitrulline induced by MDSCs can be an effective antitumor target for CD4 T-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 B104.","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":"87553982","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 IA29: Peptide-TLR-7/8 agonist conjugate vaccines chemically programmed for nanoparticle self-assembly to enhance the magnitude and breadth of anticancer neoantigen CD8 T cell immunity","authors":"G. Lynn, Faezzah Baharom, Yaling Zhu, Vincent L. Coble, A. Ramirez-Valdez, H. Yamane, Kennedy K. S. Tobin, Brennan Decker, A. Ishizuka, R. Seder","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-IA29","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-IA29","url":null,"abstract":"T cells recognizing tumor-specific neoantigens can mediate effective anti-tumor immunity and provide the rationale for personalized cancer vaccines (PCVs). Current approaches for PCVs include synthetic long peptides given with adjuvants or RNA vaccines. Such approaches induce de novo CD8 T cell responses in ~10% or less of predicted neoantigens. Here, we focused on how peptide based neoantigen vaccines could be altered to enhance the magnitude and breadth of CD8 T cells. A key finding was that particulate peptide antigens, unlike soluble peptide antigens, are more efficiently taken up by dendritic cells in draining lymphoid tissue for increasing CD8 T cell expansion. However, due to the broad range of neoantigen physicochemical properties, ensuring consistent particle vaccine formulations with neoantigen peptides is a major challenge. Therefore, we developed a new PCV platform based on charge-modified peptide-TLR-7/8 agonist conjugates that are chemically programmed for self-assembling into nanoparticles (“SNP-7/8a”) of a defined size (20–50 nm) irrespective of the underlying neoantigen peptide composition. Bioinformatics analysis of 72 million human genome-derived neoantigens shows that SNP-7/8a ensures consistent nanoparticle formation with neoantigens at extremes of charge and hydropathy. Vaccination of mice with SNP-7/8a using predicted neoantigens (n = 179) from three tumor models induced CD8 T cells in ~50% of those with high predicted MHC-I binding affinity (IEDB consensus score Citation Format: Geoffrey M. Lynn, Faezzah Baharom, Yaling Zhu, Vincent Coble, Andrei Ramirez-Valdez, Hide Yamane, Kennedy Tobin, Brennan Decker, Andrew Ishizuka, Robert Seder. Peptide-TLR-7/8 agonist conjugate vaccines chemically programmed for nanoparticle self-assembly to enhance the magnitude and breadth of anticancer neoantigen CD8 T cell 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 IA29.","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76664080","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 B120: TIPE2 regulates apoptosis and autophagy to inhibit tumorigenesis in colon cancer","authors":"Jun Li, X. Xia","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B120","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B120","url":null,"abstract":"TIPE2 is an important immune negative regulator which regulates innate immunity and adaptive immunity to maintain immune homeostasis. Abnormal expression of TIPE2 is related to many acute and chronic inflammatory diseases, as well as the tumorigenesis. Here, we identified that overexpression of TIPE2 in colon cancer cell line inhibited cell growth. Recombinant adenovirus-expression TIPE2 effectively inhibited the proliferation of several kinds of cancer cell. Using protein biochip ananlysis, we found that in the TIPE2-overexpressing colon cancer cell, the expression levels of phosphorylated p38-MAPK/JNK, pro-apoptotic survivin were downregulated. These results suggest TIPE2 regulates tumor cell growth though p38-MAPK/JNK pathway. Western blot analysis showed that the proliferation level of AKT and the expression level of Bad were also changed in the TIPE2-overexpressing colon cancer cell, suggesting that TIPE2 may inhibit tumor cell proliferation through inducing cell death. Using flow cytometry analysis, we found that the overexpression of TIPE2 could promote apoptosis of tumor cell while knockdown of TIPE2 expression by shRNA could inhibit apoptosis. Previous studies have demonstrated that p38-MAPK/JNK and Akt pathway play important roles in autophagy. In this study, with the accumulation of LC3-II by stimulating TIPE2, tumor autophagy was increased in vitro. Thus, the function of TIPE2 in the inhibition of tumorigenesis may have broad implications in cancer gene therapy. Citation Format: Jun Li, Xiaoli Xia. TIPE2 regulates apoptosis and autophagy to inhibit tumorigenesis in colon 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 B120.","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":"89356345","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}