bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A075: Immunotherapy of malignant pleural mesothelioma using cMET specific T-cells
Authors: Thayaparan Thivyan , Stegen Sjoukje J.C. van der , Puri Ana C. Parente Pereira , Petrovic Roseanna Maria , Spicer James , Maher John 
Published: May 2016

Abstract
Background: Malignant pleural mesothelioma (MPM) is an incurable cancer predominantly induced by asbestos exposure. This aggressive tumour commonly presents at an advanced stage of disease. Although surgery, combination chemotherapy and radiotherapy may be used in disease management, median survival from diagnosis is less than 12 months. New therapeutic approaches are required to improve outcome in this disease.
Chimeric antigen receptors (CAR) are fusion molecules that couple the HLA- independent binding of a selected cell surface target antigen to the delivery of a tailored T-cell activating signal. Using CAR technology, we aim to develop a novel immunotherapy for MPM that is both safe and effective. These molecules are delivered to patient T-cells using retroviral gene-transfer, thereby stably re-directing their specificity for antigen. The receptor tyrosine kinase MET is overexpressed in &gt;80% of MPM patients making it an attractive candidate for CAR directed immunotherapy.
Methods: Three second-generation cMet-targeted CARs (containing a fused CD28/CD3ζ endodomain) have been developed, distinguished by peptide-binding motifs. Functionality of MET-re targeted T-cells has been assessed by co-cultivation of genetically enhanced test and control T-cells with MPM cell lines that express MET at various levels.
Results: Studies to date have shown that human T-cells engineered to express cMet CARs can destroy mesothelioma tumour cell monolayers, accompanied by T-cell proliferation and cytokine production. To further potentiate the activity of the cMet targeted CARs, a dual targeting approach to both cMet and the ErbB family is currently under evaluation. The second advantage of this approach is in diminishing the potential toxicity risks associate with “on target, off tumour” toxicity. An MPM xenograft model has been established utilising bioluminescence to further evaluate functionality and toxicity in vivo.
Conclusions: These findings demonstrate proof of concept for the utility of CAR engineered T-cells to recognise and destroy cMet-expressing MPM tumour cells. We envisage that regional i.e. intrapleural delivery of human CAR positive T-cells could be used to maximise therapeutic index of this approach.
Citation Format: Thivyan Thayaparan, Sjoukje J.C. van der Stegen, Ana C. Parente Pereira Puri, Roseanna Maria Petrovic, James Spicer, John Maher. Immunotherapy of malignant pleural mesothelioma using cMET specific T-cells. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A075.
Abstract A080: Targeted genome modifications for improved adoptive immunotherapy
Authors: Valton Julien , Gautron Anne-Sophie , Juillerat Alexandre , Duchateau Philippe , Poirot Laurent 
Published: May 2016

Abstract
Chimeric antigen receptor (CAR)-redirected T-cells have given rise to long-term durable remissions and remarkable objective response rates in patients with refractory leukemia, raising hopes that a wider application of CAR technology may lead to a new paradigm in cancer treatment. Similarly, transcription activator-like effector nuclease (TALEN™)-mediated gene editing has emerged as powerful strategy to introduce targeted mutations and holds great promise in therapeutics and offers multiple opportunities to improve CAR T-cell therapies. The knockout of the TCR alpha gene eliminates TCR expression and abrogates the donor T-cell's potential for graft-versus-host disease (GvHD) while maintaining a potent anti-tumoral activity. Thus it is possible to manufacture T-cells from third-party healthy donors to generate allogeneic “off-the-shelf” engineered CAR T-cells. Disruption of CD52 or deoxycytidine kinase genes may be a useful approach to makes T-cells compatible with concurrent oncology treatments such as alemtuzumab or Fludarabine while the bypass of key immune checkpoint regulators such PD1/PDL1 by inactivation of T-cells receptors would potentiate the antitumor T-cell response by impairing the interaction of the inhibitory receptor PD-1 on T cells with PD-L1 expressed on tumor cells. Here, we will present in vitro and in vivo proof of concepts demonstrating the potential of TALEN™-mediated gene editing for adoptive T-cell therapy.
Citation Format: Julien Valton, Anne-Sophie Gautron, Alexandre Juillerat, Philippe Duchateau, Laurent Poirot. Targeted genome modifications for improved adoptive immunotherapy. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A080.
Abstract A083: Modulation of the immune system as a strategy to treat EGFR mutant lung adenocarcinoma
Authors: Ayeni Deborah , Ho Ping-Chih , Perry Curtis , Kaech Susan , Politi Katerina 
Published: May 2016

Abstract
Fifteen percent of lung adenocarcinomas harbor mutations in the Epidermal Growth Factor Receptor (EGFR). Although EGFR mutant tumors show sensitivity to specific tyrosine kinase inhibitors (TKIs) like erlotinib, resistance develops after an average of 12 months and there are currently no approved therapeutic strategies to overcome resistance. Therefore, novel approaches to delay resistance and improve patient survival are crucial. Recent discoveries in tumor immunology have revealed the potential of immune-based therapies to treat lung malignancies. In particular, immune checkpoint inhibitors such as anti-PD-1 have shown efficacy in a subset of patients with metastatic lung adenocarcinoma with minimal toxicity. These promising data led us to investigate the benefit of immune modulatory agents in EGFR mutant lung cancer. As a first step, we set out to explore the role of the immune system in this lung adenocarcinoma subset using a tetracycline-inducible mouse model of EGFR mutant lung cancer. We found, in these models, that lung-specific expression of mutant EGFR and consequent tumor formation leads to the establishment of an immunosuppressive tumor microenvironment characterized by an overall decrease in CD4 T cells, infiltration of Tregs, up-regulation of PD-1 expression on both helper and cytotoxic T cells and a diminished cytokine production by these T cells. Additionally, by flow cytometry and quantitative PCR of FACS-sorted cells, we have observed increased expression of PD-L1 on alveolar macrophages, which represent over 60% of the CD45+ cells in these tumors, suggesting an engagement of the adaptive and innate arms of the immune system to mediate immunosuppression via the PD-1/PD-L1 axis. Furthermore, when the tumor suppressor gene p53 was deleted, we observed a marked decrease in tumor infiltrating CD8 T cells when compared to p53 wild-type tumors. Currently, we are evaluating the functional role of elements of the immune system in these models to delineate their effects on tumor progression and therapeutic response. Moreover, we are investigating whether the observed immunosuppression in these tumors can be altered by immunomodulatory agents such as the anti-PD-1 and anti-PD-L1 immune checkpoint inhibitors alone or in combination with EGFR TKIs.
Citation Format: Deborah Ayeni, Ping-Chih Ho, Curtis Perry, Susan Kaech, Katerina Politi. Modulation of the immune system as a strategy to treat EGFR mutant lung adenocarcinoma. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A083.
Abstract A088: Increase lymphocyte infiltration overcomes tumor resistance to checkpoint blockade
Authors: Tang Haidong , Wang Yang , Fu Yang-Xin 
Published: May 2016

Abstract
Spontaneous T cell-inflamed tumor microenvironment is associated with clinical responses to immunotherapies, including immune checkpoint blockades. However, majority of established tumors often inhibit peripheral T cells entering tumor tissues for tumor destruction and/or prevent effective T cell priming. Previous studies in our lab have shown that upregulation of the tumor necrosis factor superfamily member LIGHT (also known as TNFSF14) in peripheral tissues results in T cell activation and migration into non-lymphoid tissues and formation of lymphoid-like structures, which lead to rapid T cell-mediated tissue destruction. Furthermore, local expression of LIGHT by tumor cells may promote the formation of lymphoid-like structures for direct T-cell sequestration and activation, leading to tumor regression. Those data suggest LIGHT as an interesting candidate to create T cell-inflamed tumor environment. To better evaluate the therapeutic efficacy of human LIGHT protein in both murine and human systems, we engineered human LIGHT by random mutation using yeast-display system, and were able to generate a human LIGHT mutant which binds to both murine and human receptors while remains stable. To specifically target LIGHT to tumor tissues, an antibody-LIGHT fusion protein was generated. In different mouse models, we found that antibody-LIGHT induces a T cell inflamed tumor environment. This is correlated with an upregulation of inflammatory cytokines and adhesion molecules, and leads to the rejection of established tumors. More importantly, we observed that LIGHT-mediated T cell inflamed environment is critical for restoring the efficacy of checkpoint blockade therapy. When we blocked lymphocyte trafficking, a tumor previously responding to checkpoint blockade became resistant to therapy. This process can be reversed by treating with LIGHT. Our study indicates that targeting LIGHT may be an effective strategy for cancer immunotherapy, especially those who do not response to checkpoint blockade due to the lack of infiltration.
Citation Format: Haidong Tang, Yang Wang, Yang-Xin Fu. Increase lymphocyte infiltration overcomes tumor resistance to checkpoint blockade. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A088.
Abstract A100: Cooperative defense against acute Clostridium difficile infection is mediated by two innate lymphoid cell subsets
Authors: Abt Michael C. , Lewis Brittany B. , Ling Lilan , Carter Rebecca A. , Susac Boj , Pamer Eric G. 
Published: May 2016

Abstract
Clostridium difficile, an opportunistic pathogen that infects the gastrointestinal tract following perturbation of the microbiota, damages the intestinal epithelium and can cause debilitating and potentially fatal colitis. Antibiotic treatment of C. difficile is often ineffective and whether innate immune defenses can be exploited to promote C. difficile clearance is unknown. Innate lymphoid cells (ILCs) are early responders to enteric infection, however, their role during C. difficile infection is undefined. To identify immune pathways that mediate recovery from C. difficile infection, we compared C57BL/6, Rag1-/-, and Rag2-/- Il2rg-/- (Ragγc-/-) mice challenged with C. difficile. In contrast to C57BL/6 and Rag1-/- mice, ILC-deficient Ragγc-/- mice rapidly succumbed to infection. Protection against infection was restored by transferring ILCs into Ragγc-/- mice. While ILC3s made a minor contribution to resistance, loss of T-bet-expressing ILC1s or IFN-γ in Rag1-/- mice increased susceptibility to C. difficile. These data demonstrate a critical role for ILC1s in defense against C. difficile.
Citation Format: Michael C. Abt, Brittany B. Lewis, Lilan Ling, Rebecca A. Carter, Boj Susac, Eric G. Pamer. Cooperative defense against acute Clostridium difficile infection is mediated by two innate lymphoid cell subsets. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A100.
Abstract A109: Exploring neo-antigens and immunological response in GBM patients after individualized Prophage vaccination
Authors: Castle John , Levey Dan , Drouin Elise , Wilson Nicholas , Schoenfeld Steven , Bloch Orin , Buell Jennifer 
Published: May 2016

Abstract
The Prophage therapeutic platform generates an individualized therapeutic cancer vaccine for each patient. The vaccine for a patient is generated by isolating heat-shock proteins (HSPs) from the patient's individual tumor. Tumor HSPs are complexed to the milieu of material in the tumor, such as mutation neo-antigens. We use NGS, bioinformatics, computational immunology, and immuno-monitoring to explore the ‘omics space of GBM tumors and blood from patients treated with Prophage. We find between 104 and 214 non-synonymous mutations per tumor, including mutations in BRCA1 and EGFR, such as EGFRvIII, and large DNA copy number variations. Integrating patient HLA types, we predict mutation immunogenicity and prioritize mutations as neo-antigens. We correlate neo-antigens to clinical response. Using longitudinal blood samples taken pre- and post-vaccination, we explore both spontaneous and vaccine-induced immunogenicity to neo-antigens. Across the tumors, there are no neo-antigens in common, underscoring the need for individualized vaccination.
Citation Format: John Castle, Dan Levey, Elise Drouin, Nicholas Wilson, Steven Schoenfeld, Orin Bloch, Jennifer Buell. Exploring neo-antigens and immunological response in GBM patients after individualized Prophage vaccination. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A109.
Abstract A130: Immune regulation of EMT and metastatic competence in breast tumor progression
Authors: Joseph Robiya , Soundararajan Rama , Paranjape Anurag , Mani Sendurai 
Published: May 2016

Abstract
Dynamic interactions between cancer cells and their surrounding microenvironment influence tumor survival, growth and metastasis. The tumor microenvironment harbors a complex variety of cells including lymphocytes and macrophages that produce a host of cytokines, chemokines, growth factors or interleukins, all of which presumably work in coordination to determine net tumor biology. Immune cells can offer a critical check-point in tumor progression. Interestingly however, infiltration of the tumor by immune cells appears to have dual functionality - they can reportedly either be pro-metastatic or anti-metastatic in their contribution. These clearly conflicting roles of immune cells limit our comprehension of their actual input to tumor advancement. The presence of tumor infiltrating lymphocytes has emerged as a good prognostic marker for a variety of cancers. However, the key molecular factors that regulate the cross-talk between tumor cells and lymphocytes, and the underlying signaling pathways are still ill-defined. Moreover, the impact of lymphocytes of the inflammatory tumor microenvironment, on the epithelial-mesenchymal plasticity and associated metastatic traits in breast cancer cells, is incompletely understood. We previously demonstrated that two key EMT/CSC factors - FOXC2 and Twist - are critical requirements for breast carcinoma cells to metastasize. The objective of this study is to systematically investigate the role of immune cells in EMT/CSC-dictated breast tumor progression using two isogenic breast cancer cell lines (67NR and 4T1) that form primary mammary tumors similarly, but differ drastically in their ability to metastasize.
Citation Format: Robiya Joseph, Rama Soundararajan, Anurag Paranjape, Sendurai Mani. Immune regulation of EMT and metastatic competence in breast tumor progression. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A130.
Abstract A133: Imaging in cancer immunology: Phenotyping of multiple immune cell subsets in-situ in FFPE tissue sections
Authors: Mansfield James R. , Hoyt Clifford C. , Stack Edward , Feldman Michael , Bifulco Carlo , Fox Bernard 
Published: May 2016

Abstract
There has been a rapid grown in the field of tumor immunobiology in recent years as a result of recent successes in cancer immunotherapies, and it is clear that immune cells play many sometimes conflicting roles in the tumor microenvironment. However, obtaining phenotypic information about the various immune cells in and around the tumor has been a challenge. Existing methods can deliver phenotypic information on homogenous samples (e.g., flow cytometry or PCR) or morphologic information in single stain IHC. We present here a methodology for delivering quantitative per-cell marker expression and phenotyping, analogous to that obtained from flow cytometry, but from cells imaged in situ in FFPE tissue sections. This methodology combines: the sequential multi-marker labeling of up to 6 antigens using antibodies all of the same species (with a goal of reaching 8 markers); automated multispectral imaging to remove problematic FFPE tissue autofluorescence and correct cross-talk between fluorescent channels; and an automated image analysis that can quantitate the per-cell marker expression, determine the cellular phenotype, count these cells separately in the tumor compartment and in the stroma, provide high-resolution images of their distributions and provide x,y coordinate data from which spatial distance calculations can be made. We will show a 6-plex assay in breast cancer showing the application of the multiplexed staining, per-cell quantitation and cellular phenotyping in FFPE tissue sections, as well as methods to explore the spatial distributions of the phenotyped cells in and around the tumor.
Citation Format: James R. Mansfield, Clifford C. Hoyt, Edward Stack, Michael Feldman, Carlo Bifulco, Bernard Fox. Imaging in cancer immunology: Phenotyping of multiple immune cell subsets in-situ in FFPE tissue sections. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A133.
Abstract A140: Viral-like nanoparticles for tumor immunotherapy by in situ vaccination mediate potent antitumor immunity
Authors: Lizotte Patrick , Wen Amy , Steinmetz NIcole , Fiering Steven 
Published: May 2016

Abstract
Tumors are recognized by the immune system, but tumors that reach clinically relevant size have established mechanisms to suppress the immune response and protect themselves from immune attack. One approach to enable effective immune response is to change the immunosuppressive tumor microenvironment into an immunostimulatory environment by introducing immunostimulatory reagents directly into tumors. This is essentially an antitumor therapeutic “in situ vaccination”, because the tumors provide the antigens and the adjuvants are the immunostimulatory reagents. The overall goal of the approach is to not only stimulate an anti-tumor immune response against the directly treated tumor, but more importantly to stimulate a systemic anti-tumor response to treat unseen metastases. There are many immunostimulatory reagents that can be used and each has different capabilities. Here we report on plant-derived viral-like nanoparticles from Cowpea Mosaic Virus used in mouse cancer models. These particles are only composed of viral capsid proteins, have no nucleic acids and have no recognized immunostimulatory reagents. However, they are strongly immunostimulatory through unknown pathways and cause dramatic changes in the tumor microenvironment that lead to primary tumor reduction and resistance to metastatic tumors. The treatment is immune-mediated since it requires IFN-γ, IL-12, and adaptive immunity and also involves neutrophils. Tumor reduction or elimination occurs in many anatomic locations and with multiple tumor types. Most importantly, treatment of a primary tumor by direct intratumoral injection mediates robust rejection of a rechallenge with the same tumor. The mechanisms and pathways of immunostimulation are under investigation. In addition to the inherent immunostimulatory adjuvant properties of these nanoparticles, they are a versatile platform to which other reagents for immune modulation can be attached. This demonstration of the value of viral-like nanoparticles for treatment of cancer opens a new avenue of cancer immunotherapy.
Citation Format: Patrick Lizotte, Amy Wen, NIcole Steinmetz, Steven Fiering. Viral-like nanoparticles for tumor immunotherapy by in situ vaccination mediate potent antitumor immunity. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A140.