bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3494: Characterizing the relationship between genotype and phenotype in DNA damage response-altered pancreatic cancer models
Authors: Carroll James R. , Link Jason M. , Brody Jonathan R. 
Published: June 2022

Abstract
Alterations in DNA damage response (DDR) proteins are prevalent across cancers and present unique opportunities for the therapeutic induction of synthetic lethality (i.e., two gene deficiencies in the same pathway synergize to kill tumor cells). In pancreatic adenocarcinoma, patients harboring alterations in DDR genes, such as in homology-directed repair (HDR), comprise the 10-20% of patients that may benefit from the recent FDA approval of Olaparib, a poly (ADP-ribose) polymerase inhibitor that disrupts non-homologous end joining (NHEJ). Despite being the best-in-class targeted therapy for DDR-altered pancreatic cancers, a subset of patients fails to respond to Olaparib and those that initially respond eventually go on to develop resistance. The mechanisms underlying resistance are poorly elucidated but suggest that some patients harboring DDR-altered tumors are HDR-proficient or revert to HDR-proficiency during therapy, bypassing the second gene deficiency requisite for synthetic lethal induction with targeted therapy (e.g., Olaparib). Utilizing patient-derived models of cancer, we are actively investigating DDR-altered, pancreatic tumor cell lines and exploring the relationship between DDR-alterations and HDR-deficiency with three goals: [1] To evaluate the prevalence of HDR-proficiency in BRCA-altered tumors, [2] to understand the extent to which patient-derived models of cancer are concordant and predictive of clinical outcomes, and [3] to identify novel therapeutic strategies for resistant patients. So far, we have observed HDR-proficiency by functional assays (e.g., RAD51 foci formation) in DDR-altered patient-derived cell lines that corresponds with poor response to Olaparib in vitro, and resistance to platinum therapy clinically. Whereas DDR-altered HDR-deficient lines had greater sensitivity to Olaparib and platinum therapy. These early data suggest that measures of HDR by functional assay may be more predictive of clinical therapeutic responses than the use of genetic signatures alone.
Citation Format: James R. Carroll, Jason M. Link, Jonathan R. Brody. Characterizing the relationship between genotype and phenotype in DNA damage response-altered pancreatic cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3494.
Abstract 3512: Immunotherapy by STING activation in a CRISPR induce mouse model of GBM decrease tumor progression by CD8 T-cells and altered vascularity
Authors: Joseph Justin V. , Cai Huiqiang , Hansen Brian , Paludan Soren R. , Vendelbo Mikkel , Thomsen Martin K. 
Published: June 2022

Abstract
Intrinsic malignant brain tumors, such as glioblastoma (GBM) are frequently resistant to immunotherapy with few hyper-mutated glioblastomas showing response. Here we have applied a long-term treatment with STING agonist and PD-1 inhibitors alone and in combination towards eliciting enhanced host immune response to combat GBM progression. To address these questions we generated mouse models of GBM by intracranial implantation of a murine GBM stem cell line or orthotopic CRISPR induced mutation to astrocytes. Systemic administration of STING agonist crosses the blood-brain barrier and induces a type-1 IFN signature in the brain and this was further enhanced in the tumor milieu. Treatment outcomes were addressed by MRi and treated animals showed a significant reduction in tumor volume and hence improved survival in comparison to the animals in the control group. Histochemical evaluation of tumor samples from the animals that received treatment showed elevated necrosis and aberrant/leaky vasculature in comparison to the control tumor samples. The presence of cytotoxic T-cells were similar between the groups but activated PD-1 positive T-cells were increased in treated tumors. Ex-vivo analysis of isolated T-cells from tumor baring mice confirms cytotoxic T-cells targeting the GBM cells. In conclusion, application of STING agonist promotes alteration of vasculitis and priming of T-cells in GBM results in increased survival and decreased tumor progression. These results reveal that GBM can be targeted by immune therapy through systemic activation of STING/IFN pathway.
Citation Format: Justin V. Joseph, Huiqiang Cai, Brian Hansen, Soren R. Paludan, Mikkel Vendelbo, Martin K. Thomsen. Immunotherapy by STING activation in a CRISPR induce mouse model of GBM decrease tumor progression by CD8 T-cells and altered vascularity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3512.
Abstract 3546: DFMO based improvement in survival of pancreatic cancer-bearing mice is associated with modulation of immune suppression in the tumor microenvironment
Authors: Nakkina Sai Preethi , Gitto Sarah B. , Beardsley Jordan M. , Pandey Veethika , Rohr Michael M. , Parikh Jignesh , Phanstiel Otto , Altomare Deborah A. 
Published: June 2022

Abstract
Existing therapeutics have failed to improve pancreatic ductal adenocarcinoma (PDAC) patient outcomes, in part due to tumor associated immune suppression and upregulation of compensatory mechanisms. KRAS and c-MYC are important oncogenes in PDAC linked to tumor immune suppression. We describe the use of difluoromethylornithine (DFMO) and a c-RAF inhibitor (GW5074) to indirectly target c-MYC and KRAS, respectively. DFMO in combination with GW5074 was tested for ability to improve pancreatic cancer outcomes. Pancreatic cancer cells showed decreased cell viability and increased apoptosis in response to a combination of DFMO + GW5074. In vivo orthotopic models of pancreatic tumors had decreased tumor weight in DFMO + GW5074 treated mice, when compared to control group. However, only treatment with single agent DFMO resulted in improved survival of immunocompetent pancreatic tumor bearing mice with respect to control, in contrast to treatment with GW5074 alone or DFMO + GW5074. To understand why the in vivo data was contrary to in vitro results, immunohistochemical analysis of immune cells in the tumor microenvironment was used to reveal increased expression of markers associated with anti-tumor effects such as CD86, CD3, CD4 and CD8 in DFMO treated tumors. Tumors treated with DFMO also displayed decreased expression of MYC, suggesting that DFMO-associated MYC suppression could be linked to decreased immune suppression in the tumor microenvironment and improved survival. In contrast, GW5074 treatment maintained MYC expression in tumors. Overall, the present study points to DFMO being an immunomodulatory agent, and a need for further understanding of DFMO-based therapeutic strategies in PDAC.
Citation Format: Sai Preethi Nakkina, Sarah B. Gitto, Jordan M. Beardsley, Veethika Pandey, Michael M. Rohr, Jignesh Parikh, Otto Phanstiel, Deborah A. Altomare. DFMO based improvement in survival of pancreatic cancer-bearing mice is associated with modulation of immune suppression in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3546.
Abstract 3547: IL-12-based cytokine factories modulate tumor microenvironment to eradicate pancreatic tumors in mice and are well tolerated in non-human primates
Authors: Nash Amanda , Aghlara-Fotovat Samira , Castillo Bertha , Nguyen Annie , Cui Andrew , Hernandez Andrea , Rios Peter , Ghani Sofia , Joshi Ira , Xu Chunyu , Sheth Rahul , Peng Weiyi , Oberholzer Jose , Jazaeri Amir , Veiseh Omid 
Published: June 2022

Abstract
Pancreatic cancer is often diagnosed at advanced stages and responds poorly to chemotherapy. Because high tumor T cell infiltration corresponds with better clinical outcomes in pancreatic cancer patients, immunotherapy has gained significant interest over the last decade for the treatment of recurrent pancreatic cancer. IL-12 is a proinflammatory cytokine with pleiotropic effects including activation of CD8+ T cells and NK cells. Unfortunately, systemic high dose IL-12 administration led to severe toxicities in clinical trials which has limited further development of this cytokine as a cancer therapeutic. To address this limitation, we developed an implantable cytokine delivery platform to allow for local administration of IL-12. These cytokine factories, composed of genetically engineered epithelial cells encapsulated in biocompatible polymers, allow for safe and controlled dosing in vivo. Tumor adjacent administration of IL-12-based cytokine factories caused reduction of intraperitoneal pan02 tumor burden by 80% after only 1 week of treatment in mice with pancreatic cancer. Single cell RNAseq of the tumor adjacent immune cells at this time point showed 2x more T and NK cells present in the IL-12 treated mice than untreated mice suggesting modulation of the tumor microenvironment via immune cell infiltration. Importantly, the necessary IL-12 dose was well tolerated in all mice without signs of toxicity for 180 days. In efforts to evaluate the translatability of this platform, we further tested IL-12-based cytokine factories in a non-human primate. The cytokine factories produced a high local IL-12 concentration without substantial leakage into the systemic circulation and were well tolerated by the primates as shown by the lack of fever or weight loss, as well as the lack of renal or liver toxicity. Our findings highlight the therapeutic potential of IL-12 treatments when administered locally via cytokine factories in preclinical animal models. Further, these findings provide rationale for future development and clinical testing of cytokine factories for treatment of a wide range of metastatic peritoneal cancers in humans.
Citation Format: Amanda Nash, Samira Aghlara-Fotovat, Bertha Castillo, Annie Nguyen, Andrew Cui, Andrea Hernandez, Peter Rios, Sofia Ghani, Ira Joshi, Chunyu Xu, Rahul Sheth, Weiyi Peng, Jose Oberholzer, Amir Jazaeri, Omid Veiseh. IL-12-based cytokine factories modulate tumor microenvironment to eradicate pancreatic tumors in mice and are well tolerated in non-human primates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3547.
Abstract 3548: Role of the cancer cell proteome and tumor microenvironment in the hyperprogression (HP) phenotype response to immune checkpoint blockade
Authors: George Andrew , Sahin Ilyas , Zhang Shengliang , El-Deiry Wafik S. 
Published: June 2022

Abstract
Immune checkpoint blockade (ICB) immunotherapy strategies have yielded significant successes in recent years. Unfortunately, such treatments are not always successful. While tumor resistance to immunotherapy is often the reason, a subpopulation of patients treated with ICB show an acceleration in tumor growth rate, termed hyperprogressive disease (HPD) or hyperprogression (HP). Different studies have evaluated the incidence rate of HPD at 4% to 30%, though clear predictors have been elusive. An impediment to progress on investigating HPD has long been the lack of a reliable disease model. We recently reported a humanized mouse model of hyperprogression using mismatch repair deficient (MMR-d) p53-/- HCT-116 colorectal cancer cells implanted subcutaneously into athymic mice humanized with human CD8+ T-cell line TALL-104 and treated with anti-PD-1 Pembrolizumab. Flow cytometry was used to ensure the systemic establishment of the TALL-104 CD8+ human T-cells used to humanize the athymic mice and characterize immune tumor infiltration, which was not different between groups. Immunoperoxidase staining revealed increased expression of proliferation marker Ki67 within the HPD xenografts, supporting the finding that HPD tumors were exhibiting accelerated growth. Initial human cytokine analysis revealed a significant elevation in three cytokines (IFN-γ, TRAIL R2, and RANK L) and a significant decrease in four (CCL2, Chitinase 3-like 1, IL-4, and TNF-α). We attempted to mitigate HP through administration of anti-EGFR Panitumumab based on some clinical studies linking EGFR aberration to HPD but found worsened HPD in cotreated mice. We are conducting RNA sequencing to identify any changes in the RNAome of the HPD model, and immunoperoxidase analysis of resected tumor tissue for cytokine expression and cell death markers that may provide clues for accelerated growth within the HPD tumor microenvironment. Future studies will also focus on the interplay between Pembrolizumab and Panitumumab observed preliminarily to exacerbate the HPD with more comprehensive in vivo studies including of patient-derived xenotransplants.
Citation Format: Andrew George, Ilyas Sahin, Shengliang Zhang, Wafik S. El-Deiry. Role of the cancer cell proteome and tumor microenvironment in the hyperprogression (HP) phenotype response to immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3548.
Abstract 3568: Robust and potent dendritic cells for cancer immunotherapy
Authors: Azeem Waqas , Lellahi Seyed Mohammad , Hua Yaping , Øyan Anne Margrete , Gabriel Benjamin , Kalland Karl-Henning 
Published: June 2022

Abstract
Background: Dendritic cells (DCs) are fundamental to adaptive immunity by detecting, engulfing and presenting foreign or changed antigenic peptides to lymphocytes that thereafter initiate antigen-specific immune attacks. DC-based immunotherapy against cancer has been promising for a long time, but has not yet met expectations. Cancer cell heterogeneity and numerous immune evasion mechanisms represent challenges. According to textbook renderings, DCs may induce either tolerance or immune activation depending upon the nature of the encountered antigen and the status of the microenvironment. Recently, we have discovered a more complicated scenario according to which monocyte-derived DCs (moDCs) exhibit dual pro- and anti-inflammatory features, suggesting that selected conditions that enhance pro-inflammatory features and counteract tolerogenic features could generate more robust and potent DCs for cancer therapy.
Materials and Methods: Healthy blood donor buffy coats were used for the isolation of monocytes and conventional CD141+ and CD1c+ natural circulating DCs. IL-4 and GM-CSF were used to differentiate monocytes into immature moDCs. Toll-like receptor agonists were used to induce DC maturation, and specific agonists and inhibitors were tested in different DC variants. Flow cytometry, ELISA determination of cytokine secretion, HPLC-based quantitation of kynurenine secretion, genome-wide gene expression analyses and functional assays, such as antigen uptake, migration and the mixed leukocyte reaction were used for evaluation of treated DCs.
Results: Conventional DCs were more susceptible to apoptosis, and dependent upon culture conditions, than moDCs. Inhibition of β-catenin signaling stimulated several pro-inflammatory features, e.g. increased IL-12 and decreased IL-10 secretion, with reciprocal effects caused by β-catenin stimulation. Maturation of moDCs was accompanied by very strong induction of indoleamine 2, 3-dioxygenase 1 (IDO1) transcription and paralleled by increased kynurenine secretion, but this was partially counteracted by β-catenin stimulation.
Conclusions: Preparation of more potent DCs for cancer therapy needs to take into account DC longevity and conflicting activation patterns of pro- and anti-inflammatory abilities.
Citation Format: Waqas Azeem, Seyed Mohammad Lellahi, Yaping Hua, Anne Margrete Øyan, Benjamin Gabriel, Karl-Henning Kalland. Robust and potent dendritic cells for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3568.
Abstract 3570: Prospects for personalized cancer vaccines: The oncolytic and immunotherapeutic HSV-1(VC2) virus expressing an ovalbumin (OVA) antigen elicits robust anti-OVA immune responses
Authors: Uche Ifeanyi K. , Stanfield Brent , Rudd Jared , Kousoulas Konstantin , Rider Paul J. 
Published: June 2022

Abstract
Cancers result from unique cellular transformation events resulting in the expression of cancer antigens that vary widely among different types of cancers. Ideally, a personalized cancer treatment approach needs to target specific cancer antigen. Efforts to induce specific immune responses against tumor associated antigens (TAAs) include the expression of TAAs through viral vectors capable of expressing multiple antigens. We have previously shown that the HSV-1(VC2) vaccine vector can induce potent antitumor immune responses utilizing the B16F10-derived syngeneic melanoma mouse model. To investigate whether heterologous antigens expressed by this vaccine vector could elicit potent immune responses, we generated the recombinant virus VC2-OVA that expresses the ovalbumin antigen (OVA) fused in-frame at the amino terminus of the viral VP26 protein. Western blot analysis of infected cells in cell culture showed efficient expression of the OVA-VP26 protein. The anti-tumor efficacy of the VC2-OVA virus was tested in the B16cOVA and E.G7-OVA mouse models that constitutively express the OVA antigen to test whether this vaccine can either prevent the formation of new tumors (prophylactic modality) or reduce tumor metastasis (therapeutic modality). In addition, we evaluated the differences between intradermal, subcutaneous, and intramuscular routes of vaccination with VC2-OVA. Treatment with VC2-OVA resulted in significant reduction of tumor formation and metastasis in both the prophylactic and therapeutic modalities. Importantly, the anti-tumor efficacy was dependent on the specific mouse tumor model. Further, we found that subcutaneous and intradermal was superior to intramuscular vaccination. The VC2 virus is available as a bacterial artificial chromosome allowing for the rapid isolation of recombinant VC2-derived virus expressing multiple tumor antigens. Therefore, these results demonstrate that the VC2 vaccine virus can be used to produce personalized cancer vaccines targeting specific TAAs.
Citation Format: Ifeanyi K. Uche, Brent Stanfield, Jared Rudd, Konstantin Kousoulas, Paul J. Rider. Prospects for personalized cancer vaccines: The oncolytic and immunotherapeutic HSV-1(VC2) virus expressing an ovalbumin (OVA) antigen elicits robust anti-OVA immune responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3570.
Abstract 3571: Prevention of non-small cell lung cancer with kras mutation using a novel peptide vaccine
Authors: Wang Suhe , Cao Zhengyi , Chen Jesse , Katarzyna Janczak , Baker James 
Published: June 2022

Abstract
Non-small cell lung cancer (NSCLC) is a significant health issue associated with morbidity and mortality. One of the important findings to emerge in NSCLC is that specific genetic mutations that lead to cancer development occur early in the disease process. Unfortunately, identifying NSCLC at its earliest stages when it is curable has been a challenge even in high risk individuals. These gene mutations, especially those involving the Kras protein, can “drive” the development of NSCLC cancer as they alter the regulation of cell growth or block programmed cell death. Mutations in Kras have been reported in 30% of lung cancer cases and are associated with worse outcomes. This neo-antigen cannot generate effective anti-tumor immunity, suggesting lack of a cellular, cytotoxic immune response to cancer cells on mucosal/epithelial surfaces. No effective therapies specifically targeting mutant Kras have been developed. To overcome poor immunogenicity of neo-antigen, newer adjuvants (NA), biocompatible nanoparticles, were used to enhance immune response. It has been reported NA can produce cytotoxic and mucosal immunity safely in humans. Producing this type of immune response to mutated Kras through immunization could produce a significant anti-tumor effect. In the current study, we first tested NA combined with mutated and wild type (MHC II) Kras peptides vaccine for immunogenicity on the same genetic background as the animals in the inducible tumor model. Our data have demonstrated that NA in combination with multiple Kras peptides can increase CD4+ and CD8+ T cell numbers in the draining lymph node cells and enhance antigen specific TH1 and TH17 responses by luminex and ELISpot to increase the ability of the vaccine to kill tumor cells and elicit long-lasting immune memory. Furthermore, we evaluated anti-tumor efficacy of this vaccine in tetracycline-inducible mouse model with Kras mutation. In this challenge model, vaccinated mice showed higher IFNɤ and IL-17 levels and decreased the tumor incidence significantly compared to PBS or peptides alone group. In conclusion, we have demonstrated the antigen-specific cellular immune responses and mononuclear cell infiltrates correlate with tumor prevention. Our data suggest that this novel vaccine could prevent the development of NSCLC after validation in an appropriate animal model.
Citation Format: Suhe Wang, Zhengyi Cao, Jesse Chen, Janczak Katarzyna, James Baker. Prevention of non-small cell lung cancer with kras mutation using a novel peptide vaccine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3571.
Abstract 359: Pharmacologically induced polyploidy triggers BCL2 dependence in lymphomas
Authors: Portelinha Ana , Ferreira Mariana da Silva , Erazo Tatiana , Asgari Zahra , de Stanchina Elisa , Younes Anas , Wendel Hans-Guido 
Published: June 2022

Abstract
Spontaneous whole genome duplication (WGD) and the adaptive mutations that disrupt cell death and proliferation checkpoints are infrequent events in aggressive B cell lymphomas. This indicates that lymphomas may be especially sensitive to therapeutics that trigger genomic instability. Here, we report the powerful therapeutic combination of Polo-like kinase 4 (PLK4) and BCL2 inhibitors for aggressive lymphomas. Mechanistically, the PLK4 inhibitor CFI-400945 impairs centrosome duplication leading to genomic instability and tetraploidy (4n) in lymphoma cells. Elimination of polyploid lymphoma cells is mediated by the pro-apoptotic BAX protein resulting in increased BCL2 dependence for cell survival. The selective BCL2 inhibitor, venetoclax, acts in a synthetic lethal manner with PLK4 inhibition in both CFI-400945 sensitive and in CFI-400945 resistant lymphomas. As PLK4 is dispensable in non-proliferating cells, synthetic lethality is preferentially observed in tumor cells, while sparing vital organs. Hence, B cell lymphomas are ill-prepared for the rapid, pharmacologic induction of polyploidy resulting in a synthetic and tumor-specific dependency on BCL2.
Citation Format: Ana Portelinha, Mariana da Silva Ferreira, Tatiana Erazo, Zahra Asgari, Elisa de Stanchina, Anas Younes, Hans-Guido Wendel. Pharmacologically induced polyploidy triggers BCL2 dependence in lymphomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 359.