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

{"title":"Abstract A137: The innate/adaptive immune response triggered in response to local immunotherapy of orthotopically growing bladder cancer tumors","authors":"Iliana Kyriaki, S. Mangsbo","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A137","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A137","url":null,"abstract":"The mouse bladder 49 (MB49) syngeneic tumors respond to various immunotherapies, both stimulatory immunotherapies and check-point blockers; when tumors are cured it is often an antitumor memory response established (previous publications by our group and others). Herein we present data suggesting that bladders of orthotopic MB49 tumor-bearing mice hold a reservoir of lymphocytes surrounding the tumor, wherein they migrate rapidly upon immune adjuvant stimulation. The tumors appear to form an accessible immune microenvironment rich in vessels that mediate the homing of leukocytes to the tumor site. This is in contrast to MB49 tumors that grow subcutaneously and do not appear to provide the same rapid immune cell infiltration capacity. Herein we further examined the immune cell populations of tumors locally treated with CpG ODN 1668, a type B CpG and a strong immunostimulatory agent or dilution buffer, as a control. Interestingly, we identified markers of high-endothelial venules (HEVs) in the vessels present in tumors from both untreated and treated animals. Thus we conclude that HEVs develop naturally in the orthotopic MB49 model and we wished to explore whether manipulation of the tumor microenvironment (TME) can induce HEVs and how this stimuli affect the infiltration of immune cells. Immunohistochemical profiling revealed that CD11c+ dendritic cells, CCL21+ cells along with B and T lymphocytes are present in various ways in different zones of the tumor with HEVs and CD31+ vessels. A correlation with vessel density and the presence of HEVs was identified in untreated animals. In immune-stimulated tumors, this correlation was lost in the early phase post stimuli. We could also identify that CpG treated bladder displayed increased vascularization around the tumor 24 hours post treatment. Interestingly, it appeared as CCL21 expression intratumorally aligned with increased recruitment of CD11c+ DCs in the TME. Intratumorally it was a clear correlation between CCL21 expression with both CD11c+ and CD8+ cell infiltration. As CD11c+ dendritic cells migrate towards gradients of CCL21 via their CCR7 receptor, enabling antigen presentation, it is plausible that antigen-presentation takes place in the TME in relation to this finding. By these preliminary data we conclude that in the orthotopic MB49 tumor model, CCL21 appears to play a role in the induction of adaptive immune responses through the CCL21/CCR7 axis. The role of HEVs, or alternatively lymphatic vessels, for this recruitment is yet to be determined. Currently we are investigating multiplex analyses on bladder tumors, urine and blood from tumor-bearing animals to identify cytokines in the TME or systemically that are correlated the formation of an adaptive immune response. Our future goal is to examine what is the key to raise an effective immune response to the so called immune \"hot\" orthotopic MB49 tumor. Citation Format: Iliana Kyriaki, Sara M. Mangsbo. The innate/adaptive immune response tr","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","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":"85622443","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 A136: AST-008, a novel TLR9 agonist SNA, induces abscopal antitumor effects in mouse tumor models","authors":"E. Kandimalla, S. Nallagatla, Bart R. Anderson, R. Kang","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A136","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A136","url":null,"abstract":"Spherical nucleic acids (SNA) are a novel class of therapeutic agents in which oligonucleotides are densely packed and radially arranged on the surface of liposomal nanoparticles providing a 3D-architecture. This architecture provides increased cellular uptake and nuclease stability compared to linear oligonucleotides that are not in SNA format. AST-008 is an SNA configuration of a Toll-like receptor 9 (TLR9) agonist that induces potent Th1-type immune responses in vitro, and in mice and nonhuman primates. Subcutaneous (SC), intratumoral (IT) and intravenous (IV) administration of AST-008 has shown potent antitumor activity as a monotherapy and enhanced checkpoint inhibitor (CPI) activity in a number of mouse tumor models. Our previous studies have shown that AST-008 induces potent innate and adaptive immune responses and increases tumor infiltrating lymphocytes, interferon-inducible gene expression, and activation and expansion of CD8+ T-cells with reduced T-regulatory cells in the tumor microenvironment facilitating increased effectiveness of CPI. In the present studies, we have evaluated i) sequence-specific antitumor effects of AST-008 following SC delivery in an EMT-6 breast tumor model, ii) abscopal antitumor effects of a murine version of the TLR9 agonist SNA following SC delivery in a two-flank EMT-6 tumor model, and iii) abscopal antitumor effects of AST-008 following SC and IT administrations in an MC38 colon cancer model. Treatment of EMT-6 breast tumors in mice with SC administration of AST-008 showed dose-dependent tumor growth inhibition that was statistically significant compared with vehicle-treated tumor-bearing mice. A control oligonucleotide-SNA had no effect on tumor growth compared with the vehicle group. In a two-flank EMT-6 breast tumor model, SC administration of TLR9 agonist SNA showed about 59% and 37% tumor growth inhibition at the injected and distant tumors, respectively, compared to the vehicle-treated mice. The tumor growth inhibition was statistically significant at both the injected and uninjected tumors compared to vehicle-treated tumor-bearing mice. In a two-flank MC38 colon cancer model, either SC or IT administration of AST-008 resulted in 69% and 68% tumor growth inhibition, respectively, at the injected tumor. In this study, distant tumor that was not treated with AST-008 showed 59% and 46% tumor growth inhibition for SC and IT routes of administration, respectively. The tumor growth inhibition at both the treated and untreated tumors was statistically significant compared to the vehicle-treated tumors. These data demonstrate sequence-specific antitumor activity of AST-008 and that SC or IT administration at one tumor lesion leads to systemic antitumor activity at distant uninjected tumors. The current results, together with our previous studies in combination with CPI in several tumor models, support the potential utility of the TLR9-mediated innate immune stimulator AST-008 in combination with CPI in cance","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82114993","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 A142: Anti-mesothelin immunotoxins induce markers of immunogenic cell death and when injected locally into AE17M mesothelioma tumors enhance the effect of CTLA-4 blockade","authors":"Y. Leshem, E. King, Y. Reiter, I. Pastan","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A142","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A142","url":null,"abstract":"Background: SS1P and LMB-100 are anti-mesothelin immunotoxins composed of a targeting antibody fragment genetically fused to a truncated pseudomonas exotoxin A. We have previously repotrted a synergistic antitumor effect when SS1P or LMB-100 were injected locally into tumors of murine breast cancer in combination with antibodies that block the immune check point CTLA-4. In this study our goal is to explore if this treatment can be applied in a murine mesothelioma model. Method: The mouse mesothelioma AE17M cell line, expressing human mesothelin, was treated in culture with anti-mesothelin immunotoxins. We collected data on the cytotoxic activity and ability to induce markers of immunogenic cell death. In vivo effects were performed on AE17M tumors growing in C57/Bl6 mice. Results: AE17M cells are sensitive to both SS1P and LMB-100 in culture, but when injected IV, the immunotoxins did not affect AE17M tumor growth rate. To overcome obstacles in drug penetration we injected immunotoxins directly into AE17M tumors and found that they only increased the survival of mice from 16 days to 20 days. In addition, anti-CTLA-4 monotherapy failed to control AE17M tumor growth rate in most mice. But when locally injected SS1P or LMB-100 was combined with i.p. anti-CTLA-4, tumor regressions occurred and the median survival increased to 80 days or longer. In search for possible mechanisms enabling immunotoxins to contribute to anti-CTLA-4 activity, we examined their ability to induce markers of immunogenic cell death. We found that both LMB-100 and SS1P increased release of ATP from AE17M cells. In addition, LMB-100 induced calreticulin expression on the surface of both AE17M cells and KLM-1 cells. These results point to possible pathways allowing immunotoxins to promote anti-tumor immunity and sensitize tumors for anti-CTLA-4 effect. Conclusion: Our findings in the AE17M model provide additional support for the use of local immunotoxins in combination with anti-CTLA-4. Citation Format: Yasmin Leshem, Emily King, Yoram Reiter, Ira Pastan. Anti-mesothelin immunotoxins induce markers of immunogenic cell death and when injected locally into AE17M mesothelioma tumors enhance the effect of CTLA-4 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 A142.","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":" 7","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91411202","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 A160: Deep immunoprofiling of mouse lung cancer models in steady state and upon drug treatment.","authors":"F. V. Maldegem, Karishma Valand, V. Tsang, E. Mugarza, D. Caswell, P. Hobson, J. Downward","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A160","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A160","url":null,"abstract":"With the advancement of immunotherapies for lung cancer, it has become apparent how insufficient our knowledge is surrounding the interactions between the tumor and the immune system. In particular in the context of combining immunotherapy with conventional chemotherapy or novel targeted therapies, it is of the utmost importance that we understand the effects that those therapies have on the tumor immune infiltrate and how that would counteract or synergize with immunotherapy. We have used multiplex flow cytometry to characterise the basal tumor immune infiltrate of various spontaneous and orthogonous syngeneic mouse models for lung cancer, with different levels of immunogenicity. With imaging mass cytometry, visualizing and quantifying >30 markers simultaneously in mouse tumor tissue sections, we studied the localization and interactions of the immune cells within and surrounding the tumors. This has highlighted the level to which tumors are regulating their microenvironment, actively excluding all potential effector cells while attracting protumoral myeloid cells, and how this is amplified as the tumors progress. We have observed differences between the various models and seen how the tumors make adaptations when they are intrinsically more immunogenic. Furthermore, we have started to address how these balances are perturbed by various immune and chemotherapies in short- and long-term experiments and preliminary data will be presented. Citation Format: Febe van Maldegem, Karishma Valand, Victoria Tsang, Edurne Mugarza, Deborah Caswell, Philip Hobson, Julian Downward. Deep immunoprofiling of mouse lung cancer models in steady state and upon drug treatment. [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 A160.","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"259 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77139508","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 A157: Preclinical pharmacokinetic and pharmacodynamic characterization of AB680, a small-molecule CD73 inhibitor for cancer immunotherapy","authors":"J. Tan, Jie Chen, E. Ginn, D. Ashok, A. Anderson, J. Banuelos, Kristen Zhang, Amber T. Pham, Tim Park, Ada Chen, Xiaoning Zhao, K. Lawson, J. Jeffreys, J. Kalisiak, M. Leleti, M. Walters, J. Powers","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A157","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A157","url":null,"abstract":"Introduction: Extracellular adenosine (ADO), present at high concentrations in the tumor microenvironment (TME), suppresses immune function via inhibition of T-cell, natural killer (NK) cell, and dendritic cell (DC) activation. Intratumoral generation of ADO depends on the sequential catabolism of ATP by two ecto-nucleotidases CD39 (ATP→AMP) and CD73 (AMP→ADO). Inhibition of CD73 eliminates a major pathway of ADO production in the TME and can reverse ADO-mediated immune suppression. Here we present the preclinical characterization of AB680, a novel, highly potent, reversible and selective small-molecule inhibitor of CD73, currently in preclinical development as a potential antitumor agent. The link between CD73 levels present in different tissues, efficacy in mouse tumor models, plasma and tumor exposure, and projected human pharmacokinetic (PK) profile can be combined to provide an expected AB680 dosing strategy for the upcoming first-in-human clinical trial. Methods: The potency of AB680 against human CD73 was determined using CHO-CD73 cells, blood CD8+ T-cells, recombinant human CD73, and serum/plasma using either malachite green assay, AMP-Glo assay, or LCMS/MS. The selectivity of AB680 against related ecto-nucleotidases was also assessed using similar methods. Quantitation of soluble CD73 in mouse and human serum, and mouse tumor homogenates, was performed via in-house developed and validated ELISA or Western blot methods. Syngeneic mouse tumor models were established to assess the efficacy of AB680 at multiple doses. AB680 levels in plasma and tumor associated with each dosing regimen were determined via LCMS/MS. The potency of AB680 in an intratumoral setting was determined using various biochemical methods. The effects of AB680 on syngeneic tumor volumes were assessed in prophylactic and therapeutic settings. The PK properties of AB680 were evaluated in multiple preclinical species and a projected human dosing schedule for AB680 was determined via allometric scaling. Results: AB680 is a highly potent, reversible and selective inhibitor of CD73 activity (IC50 Citation Format: Joanne B.L. Tan, Jie Chen, Elaine Ginn, Devika Ashok, Amy E Anderson, Jesus Banuelos, Kristen Zhang, Amber Pham, Timothy Park, Ada Chen, Xiaoning Zhao, Kenneth K.V. Lawson, Jenna Jeffreys, Jarek Kalisiak, Manmohan R. Leleti, Matthew J. Walters, Jay P. Powers. Preclinical pharmacokinetic and pharmacodynamic characterization of AB680, a small-molecule CD73 inhibitor for 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 A157.","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"66 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77953195","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 A135: Combining low-dose chemotherapy with an NK cell-based immunotherapy as a treatment for triple-negative breast cancer","authors":"Sarra Idri, G. Pawelec, Y. Barnett, G. Pockley","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A135","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A135","url":null,"abstract":"In addition to being less toxic and having a lower impact on a patient’s quality of life, evidence suggests that low-dose or metronomic chemotherapy modulates adaptive and innate antitumor immune responses. In this study, we examined whether the treatment of breast cancer cells and animals bearing breast cancer cell-derived tumors with low, nontoxic doses of chemotherapies promotes sensitivity to natural killer (NK) cells, based on target cell killing in vitro and the control of tumor growth and metastasis in vivo. We have developed a low-dose doxorubicin treatment protocol that sensitizes triple-negative breast cancer (TNBC) cells (MDA-MB-231, MDA-MB-468) to killing by NK cells. Specifically, low-dose doxorubicin treatment induced a “senescent-like” state in breast cancer cells concomitant with an impaired proliferative capacity, as shown by a decreased expression of Ki-67. Treatment of breast cancer cells also upregulated their expression of ligands for activatory NK cell receptors (e.g., MICA/B, ULBP1, ULBP2, ULBP3) and markedly increased their sensitivity to lysis by donor-derived, primary NK cells and the NK-92 cell line, as assessed using an in vitro flow cytometry-based assay. The cytotoxicity of donor-derived NK cells was markedly increased by prior stimulation with IL-2. The therapeutic potential of low-dose chemotherapy alone and in combination with adoptively transferred resting and activated NK cells was evaluated using immunodeficient NSG mice bearing MDA-MB-231/RFP/LUC-derived human TNBC xenografts. Although low-dose doxorubicin treatment alone reduced the growth of the primary tumors, as assessed using caliper measurements and in vivo imaging, the growth of the primary tumor was more markedly reduced following the adoptive transfer of healthy-donor derived NK cells (mean tumor volume: 70.56mm3 versus 228.8mm3 in control groups at day 49). Importantly, although treatment with low-dose doxorubicin alone also delayed the onset of metastasis by 7 days (day 49 in control animals, day 56 in treated animals), no signs of metastasis were observed in healthy-donor derived NK cell-treated animals at the time of culling on day 50. The expression of MICA/B was 8.5 times greater on tumor cells derived from mice that received the combination treatment (p=0.0001) and these cells were more sensitive to killing by NK-92 cells in vitro (3-fold increase at E:T 1:5). Furthermore, in vitro studies demonstrating that the treatment of MDA-MB-231 cells with low-dose doxorubicin reduces the number of CD44High/CD24−/low/EpCAM+ Cancer Initiating Cells (CICs) were confirmed by there being a significantly lower number of CICs in tumors derived from treated mice. These novel findings indicate that this approach has the capacity of preventing the primary tumor “fueling” the dissemination of aggressive, metastatic disease. Taken together, these studies demonstrate that the treatment of breast cancer with low, nontoxic doses of chemotherapies promotes their sensit","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"166 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":"75519596","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 A151: Immunotherapy against cancer using iNKT ligands in combination with an attenuated Listeria monocytogenes in humanized mouse models","authors":"N. Saavedra-Ávila, Shalu Sharma, Christopher T. Johndrow, Tony W. Ng, C. Gravekamp, S. Porcelli","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A151","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A151","url":null,"abstract":"Listeria monocytogenes (Lm) is a gram-positive bacterium associated with gastrointestinal infections. Initially, infects epithelial cells in the small intestine, then migrates to other organs where it is taken up mainly by phagocytic cells. Once phagocytized, Lm may then be processed in the phagosome to generate peptides presented on MHC Class II for activation of Lm-specific CD4+ T-cell responses. Lm can also escape the phagosome, leading to secretion of protein antigens into the cytosol. These are processed and presented by MHC Class I molecules to CD8+ T-cells, generating strong protective immunity that can clear the infection and prevent subsequent reinfection. Lm has been exploited for its use as a vaccine vector, particularly for the delivery of tumor-associated antigens. Our previous work showed that the efficacy of Lm as an anti-umor therapeutic vaccine could be significantly improved by incorporation of synthetic glycolipid activators of CD1d-restricted invariant natural killer T-cells (iNKT-cells) into the bacteria. Using an attenuated Lm strain expressing the tumor-associated antigen Mage-B, this approach gave improvements in prevention of metastasis in the 4T1 breast carcinoma model in BALB/c mice, and also gave modest reductions in the size of primary tumors. Currently, our efforts are directed at further improving this approach to more effectively target primary tumors, and also at validating the effects in a more humanized experimental models. To this end, we are using two models: 1. human CD1d knock-in (hCD1dKI) mouse line in which the mouse CD1d protein has been replaced by human CD1d, and 2. VaKI mouse, which is a new model made by our lab that is a hCD1dKI mouse that has as a transgene the α-chain of the human iNKT TCR (Vα24Jα18) and is deficient of endogenous murine iNKT-cells due to a murine Jα18 KO. These mice models have diminished percentages of iNKT-cells closely resembling what is seen in most humans, and thus mount iNKT-cell responses that are comparable to those seen in humans. We found that incorporation of iNKT-cell activating glycolipids into Lm leads to improved iNKT-cell-dependent immune responses in our models, and induces synergistic antitumor immune mechanisms against implanted primary syngeneic tumors (B16 F10 and MC38). Besides, administration of iNKT-cell activating glycolipids in association with Lm did not induce anergy or exhaustion of the responding cells, thus enabling repeated treatment to boost antitumor immune responses. Citation Format: Noemi Alejandra Saavedra-Avila, Shalu Sharma, Christopher T. Johndrow, Tony Ng, Claudia Gravekamp, Steven A. Porcelli. Immunotherapy against cancer using iNKT ligands in combination with an attenuated Listeria monocytogenes in humanized mouse models [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","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"95 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83695308","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 A158: Delivering type I interferon to dendritic cells empowers tumor eradication and immune combination treatments","authors":"J. Tavernier","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A158","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A158","url":null,"abstract":"An ideal generic cancer immunotherapy should mobilize the immune system to destroy tumor cells without harming healthy cells and remain active in case of recurrence. Furthermore, it should preferably not rely on tumor-specific surface markers, as these are only available in a limited set of malignancies. Despite approval for treatment of various cancers, clinical application of cytokines is still impeded by their multiple toxic side effects. Type I interferon (IFN), for instance, has a long history in the treatment of cancer, but its multifaceted activity pattern and complex side effects prevent its optimal clinical use. Here we develop AcTakines (Activity-on-Target cytokines), optimized (mutated) immunocytokines that are up to 1000-fold more potent on targeT-cells, allowing specific signaling in selected cell types only. As conventional dendritic cells (cDC) are essential for IFN antitumor efficacy, we targeted type I IFN-derived “AcTaferon (AFN)” to Clec9A+ cDC. Clec9A-AFN therapy displayed strong antitumor activity in murine melanoma (B16), breast carcinoma (4T1) and lymphoma models (A20), as well as against human RL lymphoma in immunodeficient NSG mice reconstituted with a human immune system. In sharp contrast to wild-type IFN therapy, the antitumor efficacy of Clec9A-AFN was not accompanied by any detectable toxicity, assessed by body weight and several hematologic parameters. Clec9A-AFN effects were lost in CD8-depleted or Batf3-/- mice, and depended on IFN signaling in cDCs but not in T lymphocytes. Combined with anti-PDL1 immune checkpoint blockade, Treg-depleting anti-CTLA4 + anti-OX40 therapy, immunogenic chemotherapy, or low-dose TNF, complete tumor regressions and long-lasting tumor immunity (memory) were obtained, still without any adverse effects. Our findings thus indicate that DC-targeted AFN provides a highly efficient, off-the-shelf and safe cancer immunotherapy, with possible application in a broad range of malignancies. Citation Format: Jan H. Tavernier. Delivering type I interferon to dendritic cells empowers tumor eradication and immune combination treatments [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 A158.","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"65 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83447762","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 IA18: Inactivation of DNA repair to improve immune surveillance","authors":"A. Bardelli","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-IA18","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-IA18","url":null,"abstract":"When metastatic cancers are challenged with targeted agents almost invariably a subset of cells insensitive to the drug emerges. As a result, in most instances, targeted therapies are only transiently effective in patients. Strategies to prevent or overcome resistance are therefore essential to design the next generation of clinical trials. How can we overcome the near-certainty of disease recurrence following treatment with targeted agents? Addressing this question means considering as a target not “only” individual oncogenes but also the evolving nature of human tumors. We used colorectal cancer (CRC) as a model system to test the hypothesis that by understanding tumor’s evolution, the emergence of drug resistance can be controlled. We find that to have long-term efficacy, the use of targeted therapies must take into account the continuous evolution of cancer cells, that is to say, therapies must adapt to tumor evolution. Another approach is to unleash the ability of the immune system to recognize drug resistant cells. We tested this possibility in syngeneic mouse models of CRC sensitive to targeted therapies. Our findings indicate that inactivation of DNA repair mechanisms and manipulation of mutational loads can trigger immune surveillance and prolonged therapeutic responses. We postulate that rationally combined targeted and immuno-therapies can restrain tumor evolution, and can limit the emergence of drug resistance thus leading to long-term responses. Citation Format: Alberto Bardelli. Inactivation of DNA repair to improve immune surveillance [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 IA18.","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"109 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77636845","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 A144: The transcriptomic profile of peripheral T-cells that maintain dormant state of melanoma cells in patients treated with allogenic melanoma vaccine","authors":"A. Mackiewicz, Partycja Czerwinska, M. Ruciński, K. Gryska, Iga Grządzielewska, A. Jaworska, J. Mackiewicz","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A144","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A144","url":null,"abstract":"Melanoma (MM) cells leave primary tumors early and evolve at different sites in parallel. However, timing in human MM is unknown. Lymphatic dissemination is fast shortly after the dermal invasion, but metastases may occur late. Such delay in metastases formation suggests possible host defense mechanism, or particular nature of non-actively proliferative (dormant) MM stem cell (MSC) population. T lymphocytes may also induce tumor dormancy. The proposed mechanism involves a cytostatic mode of tumor silencing resulting from the suppression of both neoplastic cell proliferation and cell cycle progression. Significant progress in the development of novel advanced MM therapies was made. However, not all patients benefit from the therapy, developing late metastases decades after treatment ends. Moreover, using the immunotherapy-based model of MM dormancy in mouse, vaccination against MM prevented tumor growth but failed to prevent tumor cell dissemination or elimination of all MM cells. We have developed therapeutic gene modified allogenic MM vaccine (AGI-101H) that has been tested since 1997 and resulted in long-term survival of a substantial fraction of patients. Genetic modification of vaccine cells to express designer cytokine cDNA encoding Hyper-IL-6 protein (comprising of IL-6 linked with a soluble IL-6 receptor) has altered AGI-101H cells phenotype towards MSC-like with high activity of aldehyde dehydrogenase isoenzyme (ALDH1A1). We have found significant induction of anti-MSCs response in immunized patients by a generation of functionally active cytotoxic CD8+T-cells and antibodies specific for ALDH1A1 in circulation. However, the AGI-101H mode of action is complex: besides inducing a direct anticancer response to MSC population, long-term vaccination may induce MM dormancy through T-cell mediated immunity. The above hypothesis is based on clinical observations of AHI-101H treated patient who was progression-free for many years, but injury induced metastases formation in the bruise. This patient developed skin MM in 1999. In 2002 in transit metastases appeared (resected). The patient was enrolled into AGI-101H program. In 2003 metastases in liver (resected), 2004 metastasis in ovary (resected). 11 years (2004-2015) no progression. In Nov. 2015 she had bicycle accident, trauma, and MM metastasis presenting with a bruise (resected). The treatment continues with no progression. The aim was to determine the molecular mechanisms of peripheral T-cell-mediated induction of MM dormancy induced by vaccination. Therefore, T-cell mRNA expression profiling of long-term surviving patients was carried out. PBMCs were isolated from treated patients (18), untreated MM patients (13) and healthy controls (8). Untouched T-cells were separated by magnetic beads and total RNA isolated. The transcriptome profiling was performed with Affymetrix HG U219 microarray (19,285 markers). Differential gene expression (DGE) analysis between all groups was conducted and validat","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78453789","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}