Maintenance of Immune Balance: Effects of Targeted and Immune Therapies最新文献

{"title":"Abstract A149: EµTel-Jak2 T-ALL mouse model is dependent upon Myb function and susceptible to immune checkpoint therapy","authors":"S. Roth, Shienny Sampurno, M. Waibel, L. Cluse, L. Pereira, R. Johnstone, R. Ramsay","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A149","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A149","url":null,"abstract":"T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer, predominantly in children but patients over 50 years are also affected. While high-intensity combination chemotherapy is effective in 90% of young patients, only 30–40% of adult patients with ALL will achieve long-term remission. Furthermore, the severe side effects observed in young and old patients highlight the need for alternative therapy options. To explore the role of drivers of ALL and thus the potential for other therapy options we crossed EµTEL-JAK2 mice, a mouse model of T-ALL, with MybPlt4/Plt4 mice, which express hypomorphic alleles of Myb resulting in 40% of WT Myb function. EµTEL-JAK2 x MybPlt4/Plt4 mice showed a significant prolonged survival compared to EµTEL-JAK2 Myb+/+ mice, indicating that EµTEL-JAK2 cells are dependent upon fully functional Myb. Hence, we initiated a preclinical study targeting Myb with our TetMyb DNA vaccine combined with immune checkpoint inhibitors in C57BL/6 mice bearing transplanted Eµ TEL-JAK2 T-ALL cells. Interestingly, therapeutic treatment with TetMyb DNA vaccine and anti-PD-1 antibody therapy did not enhance overall survival. However, therapeutic monotherapy with anti-CTLA-4 antibody therapy on day 2, 7, 12, 16 and 21 after EµTEL-JAK2 transplant significantly reduced leukemic cell frequency in the peripheral blood and significantly prolonged survival. Further evaluation, especially in combination with current standard of care, is needed, but our results suggest a promising therapeutic option of anti-CTLA-4 antibody therapy in T-ALL. Citation Format: Sara Roth, Shienny Sampurno, Michaela Waibel, Leonie Cluse, Lloyd A. Pereira, Ricky W. Johnstone, Robert G. Ramsay. EµTel-Jak2 T-ALL mouse model is dependent upon Myb function and susceptible to immune checkpoint therapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A149.","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81920292","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 A154: Flow cytometric analysis of immune responses in the melanoma tissue biopsies before or during anti-PD1 immunotherapy","authors":"E. Shklovskaya, Jenny H. Lee, S. Lim, S. Alavi, J. Thompson, R. Saw, M. Carlino, R. Scolyer, A. Menzies, G. Long, R. Kefford, H. Rizos","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A154","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A154","url":null,"abstract":"Antibodies directed against the programmed cell death protein 1 (PD-1) immune checkpoint have significantly improved survival of patients with advanced metastatic melanoma. Innate and acquired resistance to anti-PD-1 treatment represents a significant treatment obstacle, yet the mechanisms of resistance are poorly understood and remain difficult to model at the cellular level. Here we used multiparameter flow cytometry to examine the immune profiles of 39 tumor biopsies obtained from 31 patients with stage III-IV metastatic melanoma prior to (baseline, n = 21) or during (n = 18) single-agent anti-PD1 immunotherapy; twelve patients developed resistance to treatment. Samples were enzymatically dissociated and cryopreserved until thawed and stained with fluorescently labeled antibodies to enable a comprehensive analysis of melanoma cells and tumor infiltrating lymphocytes (TILs). Mean melanoma cell content was 57+4.7% (mean+s.e.m.) while mean immune infiltrate (CD45 positive cells) was 31.5+4.5%. Analysis of melanoma cell expression of antigen presenting molecules and PD-1 ligands revealed frequent downregulation of HLA-ABC expression in both baseline (9/21, 43%) and on-treatment tumors (10/18, 56%), including a complete HLA-ABC loss in 2/39 samples. HLA-ABC up-regulation was observed in 9/39 (23%) tumors. Expression of HLA-DR and PD-L1 strongly correlated with that of HLA-ABC (Spearman r=0.68 and =0.89, respectively), indicative of local interferon exposure. Unlike PD-L1, melanoma cell expression of PD-L2 was low in the biopsied tissue. In contrast, PD-L2 expression was readily induced by gamma interferon and correlated with HLA-ABC expression in matching melanoma cell lines established from the dissociated biopsies (9/39). We found multiple correlations between parameters characterizing the immune profiles of tumor cells and TILs in both baseline and on-treatment samples. Among significant treatment-associated changes, conventional T-cells bearing the αβ T-cell receptor were 1.4-fold higher in the on-treatment group compared to baseline (65+2.7% versus 46.2+4.1%, P Citation Format: Elena Shklovskaya, Jenny Lee, Su Yin Lim, Sara Alavi, John Thompson, Robyn Saw, Matteo Carlino, Richard Scolyer, Alexander Menzies, Georgina Long, Richard Kefford, Helen Rizos. Flow cytometric analysis of immune responses in the melanoma tissue biopsies before or during anti-PD1 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 A154.","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82035198","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 A130: Metastatic melanoma patients responding to PD1 therapy have higher proportion of peripheral blood NKT-cells","authors":"Henna Hakanen, M. Hernberg, S. Mäkelä, B. Yadav, O. Brück, S. Juteau, L. Kohtamäki, Mette Ilander, S. Mustjoki, K. Anna","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A130","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A130","url":null,"abstract":"Anti-PD1 therapy has proven to be effective in various cancer types, but not all patients benefit from the therapy. Further, no comprehensive immunologic monitoring during anti-PD1 treatment has yet been published. In this study, we aimed to discover the effects of anti-PD1 therapy on the immune system, especially on NK and NKT-cells, which are less studied, but known to be involved in antitumor immune events. Peripheral blood samples from immuno-oncology (IO) naive metastatic melanoma patients (n=20) were obtained before the first infusion of pembrolizumab or nivolumab (D0), then 1 and 3 months after the initiation of treatment. From each time-point, complete blood counts (CBC) were obtained, and comprehensive immunophenotyping of NK, NKT, and T-cells was performed with multicolor flow cytometry. Moreover, 92 different serum cytokines were measured using the Olink inflammation panel. The protein levels are presented as arbitrary units of normalized protein expression, NPX, on Log2 scale. The CBC revealed that the proportion of lymphocytes (mean D0 30.6% vs. 3mo 24.9%, p=0.02), decreased during the treatment but no changes were observed in absolute numbers or in other leukocytes. Immunophenotyping of lymphocyte subpopulations revealed that the frequency of NKT brighT-cells was increased (D0 1.8% vs. 1mo 2.3%, p=0.01) and that cytotoxic NK CD56dim cells expressed more CD25 (D0 19.5% vs. 1mo 23.7%, p=0.02) and CD45RO (D0 14.7% vs. 1mo 21.1%, p=0.03) surface markers after 1 month of therapy. The cytokine assay indicated that during anti-PD1 treatment the levels of CXC family cytokines were increased in the serum; CXCL9 (D0 470 vs. 1mo 1070, p=0.0003, D0 470 vs. 3mo 1227, p=0.0007), CXCL11 (D0 49.8 vs. 1mo 81.8, p=0.005), CXCL10 (D0 1000 vs. 1mo 2078, p=0.0003). Also, an increase in IL-12B (D0 31.6 vs. 1mo 41.2, p=0.003, D0 31.6 vs. 3mo 32.4, p=0.04) and TNFRSF9 (D0 126.4 vs. 1mo 181.0, p=0.01, D0 126.4 vs. 3mo 149.0, p=0.04) levels was observed.To further examine these results, patients were categorized into two cohorts: responders (R, n=6, PFS=17.0 months) and patients with progressive disease (PD, n=9, PFS=5.0 months) in terms of the duration of progression-free survival (PFS) and decrease in tumor burden. 5 patients were excluded due to challenging clinical evaluation of response. When examining the differences between these cohorts, CBC indicated a significant decrease in the mean frequency of lymphocytes in PD (D0 26.9% vs. 3mo 19.2%, p=0.04), but not in the R cohort. The responders had also higher frequency of lymphocytes at 1- and 3-month time-points (R 34.5% vs. PD 25.4%, p=0.02, R 32.4% vs. PD 19.2%, p=0.01, respectively) and lower frequency of neutrophils before initiation and after 1 and 3 months of treatment (R 50.8% vs. PD 58.6%, p=0.04, R 45.3% vs. PD 59.4%, p=0.01, R 49.8% vs. PD 64.5%, p=0.04, respectively). The CBC absolute counts revealed that the responders had less neutrophils (R 2.8 109/L vs. PD 4.9 109/L, p=0.04) and monocytes ","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77384130","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 A145: Study of mechanisms of immune evasion of oncogenic KRAS in NSCLC","authors":"E. Mugarza, F. V. Maldegem, M. Sopena, M. M. Arcas, J. Downward","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A145","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A145","url":null,"abstract":"Cancer immunotherapies such as immune checkpoint blockade have yielded long-term durable responses in some patients. Nevertheless, the majority of cancer patients do not respond to such therapies, which constitutes a large unmet need in the clinic. Tumors develop mechanisms by which they are able to evade the actions of the immune system, some of which may render them unresponsive to drugs aimed to boost antitumor immunity. Lung cancer is a highly immunogenic tumor type in which, if effective, cancer immunotherapies have proven to be superior to other treatment modalities. KRAS is an oncogene mutated in a third of lung cancer patients and has been previously shown to trigger immunosuppressive actions by tumour cells. We aim to study the immunosuppressive effects of KRAS mutations in vitro and in clinically relevant mouse models of lung adenocarcinoma. We have generated a tumor cell autonomous KRAS- dependent gene expression profile using in vitro systems. We have set a particular focus on genes playing a role in tumor immune evasion, whose function we are aiming to elucidate using immunogenic in vivo models. We have developed a derivative of the transplantable KRAS mutant murine Lewis lung adenocarcinoma (LLC) cell line in which KRAS activity can be specifically blocked using a small-molecule inhibitor. We aim to unravel the immune infiltration of such tumors and elucidate the specific role of KRAS in shaping its microenvironment. By combining simplistic in vitro models to unravel mechanisms of action and more complex mouse models to prove their clinical relevance, we aim to increase immune visibility of KRAS-mutated lung tumors to make them more susceptible to immune and other therapies. Citation Format: Edurne Mugarza, Febe van Maldegem, Miriam Llorian Sopena, Miriam Molina Arcas, Julian Downward. Study of mechanisms of immune evasion of oncogenic KRAS in NSCLC [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 A145.","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"36 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89266715","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}