Checkpoints and Immunomodulation最新文献

{"title":"Abstract A23: Anti-PD-1 antibody scFv producing recombinant Bifidobacterium exerts antitumor effect in a larger fraction of the treated mice compared to full-length anti-PD-1 antibody","authors":"Koichiro Shioya, Li Wang, T. Matsumura, Hitomi Shimizu, Y. Kanari, Y. Seki, Yuko Shimatani, S. Taniguchi, S. Kataoka","doi":"10.1158/2326-6074.TUMIMM17-A23","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-A23","url":null,"abstract":"Anti-PD-1 therapy has improved therapeutic outcomes of patients in multiple cancer types. However, the therapy has demonstrated clinical benefits in only a small fraction of patients. The reason of the limited response in clinical practice is not fully understood. In an aim to improve anti-cancer drug delivery and potency, we have been developing in situ delivery and production system (i-DPS) by modifying a non-pathogenic anaerobic bacterium, Bifidobacterium, which localizes and proliferates only in the hypoxic environment like solid tumors after intravenous administration, produces anticancer proteins, enzymes or other pharmacologically active molecules selectively at the tumor site. Here we present anti-human PD-1 antibody scFv producing i-DPS in cancer immunotherapy, which could be specifically delivered to and amplified only at the hypoxic sites of solid tumors. A series of in vitro assays has been performed to confirm the stable expression and secretion of anti-human PD-1 scFv by recombinant Bifidobacterium, the binding inhibition of PD-1/PD-L1 interaction and elevated IFN gamma production in mixed lymphocyte culture by anti-human PD-1 scFv secreted from recombinant Bifidobacterium. Anti-murine PD-1 scFv producing Bifidobacterium as surrogate systemically administered to the syngeneic mice model demonstrated significant tumor growth inhibition. Of particular interest, the suppression of tumor growth was observed in a larger fraction of the treated mice while the control anti-PD-1 antibody showed the effect on only a few mice. The analysis of tumor infiltrating lymphocytes and myeloid cells will be presented as well. Taken together, i-DPS for anti-PD-1 antibody provides a new promising immune-therapeutic modality to target hypoxic solid tumors and also provides a unique insight for antibody drug delivery in cancer immunotherapy. Citation Format: Koichiro Shioya, Li Wang, Tomio Matsumura, Hitomi Shimizu, Yasuyoshi Kanari, Yuji Seki, Yuko Shimatani, Shun’ichiro Taniguchi, Shiro Kataoka. Anti-PD-1 antibody scFv producing recombinant Bifidobacterium exerts antitumor effect in a larger fraction of the treated mice compared to full-length anti-PD-1 antibody [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A23.","PeriodicalId":9948,"journal":{"name":"Checkpoints and Immunomodulation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80785409","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 A14: Surgical removal of metastatic lesions increases T-cell reactivity to tumor-associated antigens in stage III melanoma patients","authors":"Y. Coaña, Fríða Björk Gunnarsdóttir, Maria Wolodarski, S. E. Brage, G. Masucci, J. Hansson, R. Kiessling","doi":"10.1158/2326-6074.TUMIMM17-A14","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-A14","url":null,"abstract":"Currently, there are hardly any peripheral blood biomarkers that allow for identification of patients’ prognosis or survival in advanced melanoma patients. Our main objective was to compare the reactivity of peripheral blood T cells of patients with stage III or IV metastatic melanoma to Tumor-Associated Antigens, before and after surgery where metastatic lesions were removed. Peripheral blood mononuclear cells were isolated from blood samples taken before and after surgery and were stimulated over the course of two weeks with overlapping peptide pools of three known melanoma antigens: MelanA, NY-ESO-1, and Cripto-1. After 12 days, cells were re-stimulated and analyzed using multicolor flow cytometry. CD4 and CD8 positive cells were analyzed for cytokine production. McNemar’s test was used to analyze changes before and after surgery, and correlation between cell reactivity and cytokine production with progression free survival was determined by Kaplan Meier analysis. Surgical removal of metastatic lesions changed reactivity of T cells to MelanA, NY-ESO-1 and Cripto-1. The presence of CD4 T cells that produced IL-17 and/or TNF-a after stimulation was correlated with a worse progression-free survival (PFS). We show here that surgical removal of metastases increases T-cell reactivity in melanoma patients and that certain cytokine profiles may be associated to PFS. This could provide insight into the complexity of the correlation between a specific T-cell response and a favorable immune response to metastatic melanoma. Citation Format: Yago Pico de Coana, Friða Bjork Gunnarsdottir, Maria Wolodarski, Suzanne Egyhazi Brage, Giuseppe Masucci, Johan Hansson, Rolf Kiessling. Surgical removal of metastatic lesions increases T-cell reactivity to tumor-associated antigens in stage III melanoma patients [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A14.","PeriodicalId":9948,"journal":{"name":"Checkpoints and Immunomodulation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83085461","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 A15: Immune-related changes in breast cancer tumor evolution","authors":"C. R. G. D. Alcazar, S. Huh, Muhammad B Ekram, A. Trinh, Lin L. Liu, F. Beca, Zi Xiaoyuan, M. Kwak, Helga Bergholtz, Ying Su, L. Ding, H. Russnes, A. Richardson, Kirsten Babski, E. M. Kim, C. H. McDonnell, Jon Wagner, Ron Rowberry, G. Freeman, D. Dillon, T. Sørlie, L. Coussens, J. Garber, R. Fan, Kristie A. Bobolis, Joon Jeong, S. Y. Park, F. Michor, K. Polyak","doi":"10.1158/2326-6074.TUMIMM17-A15","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-A15","url":null,"abstract":"Immunotherapy is a highly promising therapeutic option in metastatic disease albeit only in a subset of patients possibly due to heterogeneity in the mechanisms by which tumors escape immune surveillance. Immune cells shape tumor evolution directly (e.g., anti-tumor immune response) and indirectly (e.g., changing the microenvironment) by selecting for cancer cells with certain properties. We hypothesized that the in situ (DCIS) to invasive ductal carcinoma (IDC) transition is a critical tumor progression step for immune escape in breast cancer that defines subsequent tumor evolution. In DCIS, cancer cells are physically separated from the stroma by the basement membrane and myoepithelial cell layer, and tumor-infiltrating leukocytes are rarely detected in direct contact with cancer cells. In contrast, in IDC, cancer cells and leukocytes are intermingled, thus, only cancer cells that can survive in this environment will play a role in disease progression. To dissect mechanisms of immune escape in breast cancer, we first analyzed the composition of leukocytes in normal breast tissues, DCIS, and IDC by polychromatic FACS. We found that DCIS and IDC contained significantly higher numbers of leukocytes, compared to normal breast, whereas in normal tissues more leukocytes were in the stromal than in the epithelial fraction. We also observed significant differences in the relative frequencies of several CD45+ cell types including increased neutrophils and decreased CD8+/CD4+ T cell ratios in tumors compared to normal stroma. Next, we analyzed the gene expression profiles of CD45+CD3+ T cells and found gene set enrichment of cytotoxic cells in DCIS including CD8+ T cells and NKT cells when compared to IDC. Conversely, we found enrichment for gene sets corresponding to regulatory T cells in IDC when compared to DCIS. Overall this suggested that DCIS had a more activated immune environment and IDC a more suppressed immune environment. We further explored this result by immunofluorescence (IF) and found fewer activated GZMB+CD8+ T cells in IDC than in DCIS, including a set of matched DCIS and locally recurrent IDC tissues. We also found that the TCR clonotype was more diverse in DCIS than in normal breast and IDCs. Interestingly we detected a few relatively frequent clones that were shared among different DCIS, one of which was previously shown to recognize a protein from the Epstein-Bar virus. To elucidate mechanisms of immune evasion in IDC, we performed IF analysis of immune checkpoint proteins PD-L1 and TIGIT and found significant differences between DCIS and IDC. TIGIT-expressing T cells were more slightly frequent in DCIS than in IDC. PD-L1 expression was higher in the epithelial cancer cells in triple negative IDC compared to DCIS, and amplification of CD274 (encoding PD-L1) was only detected in triple negative IDCs. Given the close proximity of ERBB2 (encoding HER2) to a cluster of genes encoding several chemokines, we analyzed the HER2+ samples fro","PeriodicalId":9948,"journal":{"name":"Checkpoints and Immunomodulation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88926361","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 A38: Blood-based T cell biomarkers and soluble PD-L1 predict responses and immune-related toxicity to PD-1 blockade in melanoma and lung cancer","authors":"R. Dronca, A. Mansfield, Xin Liu, S. Harrington, E. Enninga, S. Markovic, L. Kottschade, R. McWilliams, M. Block, W. Nevala, M. Thompson, Haidong Dong","doi":"10.1158/2326-6074.TUMIMM17-A38","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-A38","url":null,"abstract":"Despite unprecedented successes with immune checkpoint blockade in advanced cancers, these agents provide durable clinical benefit in only a subset of patients. In addition, the clinical management of patients receiving immune checkpoint blockade remains quite challenging due to the unpredictable and kinetically heterogeneous responses which can manifest as late responses, pseudoprogression, or hyperprogression in subsets of patients. The dynamics and heterogeneity of programmed cell death protein ligand 1 (PD-L1, aka B7-H1) expression confound its use as a predictive biomarker in cancer immunotherapy, but blood-based biomarkers have the potential to predict responders and detect mechanisms of resistance to immunotherapy. We previously reported that Bim (BH3-only protein) is a downstream signaling molecule of the PD-1 pathway, and that Bim levels in circulating tumor-reactive T-cells reflected patient responses to anti-PD-1 therapy in melanoma. We also discovered the existence of soluble PD-L1 (sPD-L1) in the plasma of cancer patients and showed a correlation of sPD-L1 with cancer stages in renal cell carcinoma and with prognosis in metastatic melanoma. Here we evaluated the frequency of tumor-reactive T cells with Bim expression along with effector memory profile and sPD-L1 as biomarkers of response in a new cohort of patients with metastatic melanoma and lung cancer undergoing anti-PD-1 therapy. We recruited 100 cancer patients treated with anti-PD-1 therapy who had peripheral blood collected at baseline and at each subsequent radiographic tumor evaluation. Frequencies of Bim+ and effector memory CD8+ T cells were measured by flow cytometry in gated tumor-reactive CD11a high PD1+ CD8+ T cells. We also measured levels of sPD-L1 in plasma at baseline and serially during treatment with ELISA. Baseline T cell markers and sPD-L1 levels and their percent changes in patients who had a radiographic response were compared to those who had progressive disease (PD). We found that patients with objective response after 4 cycles of anti-PD-1 therapy had higher frequency of Bim+ CD8+ T cells at baseline compared to patients with PD (mean 43% vs. 30%, P=0.0484). The frequencies of Bim+ T cells decreased significantly after the first 3 months of treatment in responders compared with progressors (mean -16% vs. + 40% P=0.0111). The frequency of effector memory CD8+ T cells also dramatically increased in responders in 3-6 months after anti-PD-1 therapy (mean 89% vs. 9.56%, p=0.002). High baseline sPD-L1 was associated with progression on anti-PD-1 therapy (mean 2.8 ng/mL vs. 0.7 ng/mL, p=0.07) or development of immune-related toxicities and the levels increased by 12 weeks in patients progressing on therapy. Conclusion: Measurements of T cell biomarkers (Bim and effector memory) and sPD-L1 levels provide a new noninvasive way to predict and monitor patient responses to anti-PD-1 monotherapy in melanoma and lung cancers. Note: This abstract was not presented at th","PeriodicalId":9948,"journal":{"name":"Checkpoints and Immunomodulation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90353204","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 A33: Tumor derived T cell clones for evaluation of check point inhibitor therapeutics","authors":"R. Shields, S. Saux, Sophie Li, M. Sathe, T. Mcclanahan, R. D. Malefyt","doi":"10.1158/2326-6074.TUMIMM17-A33","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-A33","url":null,"abstract":"Improving clinical outcomes using immunotherapeutics in cancer treatments will depend on a variety of factors including the composition and phenotype of effector T cell in tumors, the inhibitory factors from myeloid, tumor and stromal compartments of the tumor and selection of efficacious combination of therapeutic immunomodulatory agents that either neutralize immune checkpoint inhibitors or activate T cell costimulatory pathways. To address the issue of selecting optimal combinations of immune modulating agents we developed an in-vitro culture system for allo-stimulating and expanding tumor infiltrating lymphocytes (TILS) from tumor digests with an MHC Class II alloantigen expressing cell line. We selected allo-specific CD4 and CD8 clones from expanded TILS with an exhausted phenotype confirmed by cell surface expression of PD-1, LAG3 and TIGIT. T cell clones were incubated with the alloantigen expressing cell lines transduced with different combinations of immodulatory ligands and compared the effect of single agent versus combinations of checkpoint inhibitory monoclonal antibodies on T cell proliferation and cytokine production. Taqman and flow cytometry analysis was performed on several clones following allo-stimulation. A decrease in TIL clonality with repeated allo-stimulation was confirmed by TcR beta chain sequencing. In-vitro IFN gamma and Granzyme B production was enhanced with anti-PD-1 antibodies in combination with either anti-LAG3 or anti-TIGIT antibodies. This in-vitro system has the potential of screening combinations of immodulatory antibodies in a variety of TILS from different tumor types and can improve our understanding of new checkpoint inhibitor combinations. Citation Format: Robert L. Shields, Sabine Le Saux, Sophie Li, Manjiri Sathe, Terri McClanahan, Rene De Waal Malefyt. Tumor derived T cell clones for evaluation of check point inhibitor therapeutics [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A33.","PeriodicalId":9948,"journal":{"name":"Checkpoints and Immunomodulation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75656517","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 A34: Understanding mechanisms of checkpoint blockade in EGFR-driven glioblastoma","authors":"Alan T Yeo, A. Charest","doi":"10.1158/2326-6074.TUMIMM17-A34","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-A34","url":null,"abstract":"Background and Rationale: Glioblastoma multiforme (GBM) is the most common type of malignant glioma and has a poor prognosis, which calls for the exploration of alternative therapeutic approaches. Checkpoint blockade immunotherapies have produced significant clinical responses among a spectrum of malignancies. There are ongoing clinical trials for treatment of GBM with checkpoints inhibitors; however, it is anticipated that responses will be varied. With a preclinical GBM mouse model, we systematically evaluated the antitumor efficacy of antibodies targeting PD-1 and CTLA-4 administered as single agent monotherapy or combination in an EGFR genetically driven immunocompetent mouse model of GBM. In addition, we performed comprehensive immunophenotyping in EGFR-driven GBM. Methods: Transgenic EGFR, CDKN2A null, PTEN floxed mice with a floxed luciferase reporter were stereotactically injected intracranially with a TGFa- iCre lentivirus. Cohorts of mice were imaged with bioluminescence to detect growing tumors and were treated with murine monoclonal antibodies against PD-1, CTLA-4 and combination every 3 days for 3 doses beginning post tumor detection. Treated mice and controls were followed for overall survival and analysis of tumor infiltrating immune cells. Another cohort of mice was sacrificed 3 days post completion of treatment and immunophenotyping was performed by flow cytometry. Results: We observe that only mice treated with combination blockade of PD-1 and CTLA-4 had improved survival compared to untreated controls. Single agent monotherapies were ineffective as measured in no improvement in survival compared to controls. A small subset of mice treated with combination blockade of PD-1 and CTLA-4 displayed long term survival up to 100 days post tumor detection. Bioluminescence imaging revealed cytostatic effects in mice treated with combination blockade of PD-1 and CTLA-4 and in a smaller subset, sustained regression. Monotherapy treatment displayed continuing tumor growth similar to untreated controls. Characterization of tumor infiltrating immune cells displayed evidence that only combination treatment of PD-1 and CTLA-4 correlates with an increase in the number of CD8 T cell infiltrate and a decrease in the number of granulocytic MDSC (G-MDSC) infiltrate while monotherapy does not affect the ratio of CD8 to G-MDSC. Conclusions: Immune checkpoint blockade of both PD-1 and CTLA-4 provides survival benefit whereas monotherapies are ineffective in our genetically engineered mouse model of GBM. Studies aimed at revealing the mechanisms of immune-mediated anti-tumor activity from combination blockade are ongoing. Analyses of tumor infiltrating immune cells suggest that the ratio of CD8 to G-MDSCs correlate with efficacy of combination blockade of PD-1 and CTLA-4. Depletion experiments are ongoing to address the role of CD8 and MDSCs in mediating anti-tumor immunity upon single and combination blockade of PD-1 and CTLA-4 in EGFR-driven GBM. Cita","PeriodicalId":9948,"journal":{"name":"Checkpoints and Immunomodulation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79833902","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 A13: Optimization of a dendritic cell-targeting MIP3α-antigen fusion vaccine in the B16F10 mouse melanoma model","authors":"James T. Gordy, K. Luo, R. Markham","doi":"10.1158/2326-6074.TUMIMM17-A13","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-A13","url":null,"abstract":"Background: The chemokine MIP-3α (CCL20) binds to CCR6 found on immature dendritic cells. Vaccines fusing MIP-3α to gp100 have been shown to be effective in therapeutically alleviating melanoma in mouse models. However, that protection was not complete. To optimize the therapy, our laboratory is exploring two avenues. First, we added agents designed to modulate the tolerogenic tumor microenvironment. Here, we report that neutralizing IL-10 at the tumor site enhances the therapeutic anti-melanoma efficacy of a MIP-3α-gp100 DNA vaccine. Secondly, we are optimizing the antigenic profile of the vaccine to help reduce the probability of immunoediting processes leading to tumor therapy escape. Methods: The current studies utilize the B16F10 syngeneic, transplantable, mouse melanoma model system. The MIP-3α-antigen DNA vaccine is administered intramuscularly (i.m.) into the tibialis muscle, followed immediately by i.m. electroporation. Constructs utilized include MIP-3α fused to gp100 alone or in addition to TRP-2. Vaccinations are given therapeutically, beginning at day 3 or 5 post challenge. Tumor sizes, growth, and survival were all assessed. Treatment responses were characterized by flow cytometric analysis of tumor infiltrate. Vaccine-specific T-cells were delineated by gp10025-33 stimulation followed by intracellular cytokine staining for IFN-γ and assessment by flow cytometry. The mechanism of αIL-10 efficacy was explored by RT-PCR and confirmed with a knockout mouse model. Results: With this therapeutic protocol, we demonstrate for the first time that by either neutralizing IL-10 or adding a second antigen to our construct, we are able to enhance the antitumor efficacy of a MIP-3α-gp100 vaccine, leading to significantly smaller tumors, slower growing tumors, and overall increases in mouse survival. Surprisingly, the additive effects of αIL-10 were not shown to be directly mediated by any T-cell parameter tested, including vaccine-specific tumor infiltrating lymphocytes (TILs), total TILs of either CD4+ or CD8+ subset, regulatory T-cells, granzyme positive T-cells, and others. We discovered, however, that IFNα-4 transcripts in the tumor were significantly upregulated in mice given vaccine and αIL-10 compared to vaccine alone. A mouse model with IFNαR1 knocked out eliminated the protection provided by αIL-10, demonstrating that the additional therapeutic value of αIL-10 is primarily mediated by type-I interferons. The immunologic details of the added TRP2 antigen are currently being explored. Conclusions: Efficient targeting of antigen to immature dendritic cells with a chemokine fusion vaccine offers a potential alternative approach to the ex vivo dendritic cell antigen loading protocols currently undergoing clinical investigation. Adding multiple antigens or combining this approach with an IL-10 neutralizing antibody therapy that modulates the tolerogenic tumor microenvironment both enhance vaccine efficacy. Further potential therapy optimizatio","PeriodicalId":9948,"journal":{"name":"Checkpoints and Immunomodulation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85202643","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 A22: Augmentation of a novel adenoviral vaccine strategy by checkpoint inhibitors","authors":"Erika J. Crosby, Gang-jun Lei, Junping Wei, X. Yang, Tao Wang, Congxiao Liu, H. Lyerly, Z. Hartman","doi":"10.1158/2326-6074.TUMIMM17-A22","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-A22","url":null,"abstract":"The immunologic hurdles for a vaccine targeting cancer are much higher than for those targeting an infectious disease. The profoundly immunosuppressive tumor microenvironment, the lack of microbial danger signals, and the need to break tolerance without causing catastrophic autoimmunity are all considerations that must be made when designing an effective anti-cancer vaccine. Immune checkpoint blockade (ICB) including programmed death 1 (PD1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) monoclonal antibodies have revolutionized cancer treatment as a whole, including the potential for a successful cancer vaccine. Human epidermal growth factor receptor 2 (HER2) is an oncogene that is overexpressed in 20-25% of breast cancers and has been successfully targeted with therapeutic anti-HER2 therapies, particularly antibody combinations like trastuzumab and pertuzumab. However, even the most potent anti-HER2 therapy available is often accompanied by a high rate of recurrence, with the many responders eventually becoming resistant. Given the relative success of combination therapy using antibodies targeting different epitopes of HER2, we hypothesized that a HER2 targeting vaccine approach could further broaden the immune repertoire and reduce rates of resistance and recurrence. We developed both an implantable and a mammary specific spontaneous tumor model driven by an oncogenic isoform of HER2 (HER2Δ16). Using these models we tested a novel adenoviral vaccine platform encoding an inactive HER2Δ16 variant. We have shown that this isoform is significantly more oncogenic than full length HER2 and plays a role in anti-HER2 therapeutic resistance. Using the implantable tumor model, we found that therapeutic vaccination elicits a robust anti-HER2 specific cellular and humoral response, as well as significantly inhibits tumor growth of HER2Δ16-positive tumors. While effective at reducing tumor growth, we observed that our vaccine was typically not capable of eliciting tumor regression in mice, due to the immunosuppressive tumor microenvironment of established tumors. As such, we tested our vaccine platform in combination with two recently approved checkpoint inhibitors anti-CTLA-4 and anti-PD-1. This combination greatly enhanced the HER2-specific immune response as well as the antitumor effect seen post vaccination, with many tumors exhibiting complete regression. Our spontaneous model provides the ideal setting to test our vaccine platform as it is tolerant to human HER2, driven by HER2 expression, and grows at a rate that provides sufficient time to intervene with an immune targeting therapy. Using this model we have further shown that vaccination against HER2Δ16 can prevent spontaneous tumor formation and work is ongoing to test therapeutic vaccine strategies in combination with ICB. Future studies will be focused on determining the exact mechanism of regression and evaluating the impact on de novo and acquired resistance by combining this novel therapeutic ","PeriodicalId":9948,"journal":{"name":"Checkpoints and Immunomodulation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79618782","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}