tbuckley/cabot-search huggingface dataset:
Abstract 1557: Intratumoral plasmid IL-12 enhanced the systemic anti-tumor effect of anti-PD-1 antibody in triple-negative breast cancer
Authors: Hiroshi Nagata, Takuya Osada, Erika J. Crosby, David A. Canton, Chris G. Twitty, H. Kim Lyerly
Journal: Cancer Research (2021)

Abstract Background: Triple-negative breast cancer (TNBC) is an aggressive disease with limited therapeutic options. Although immune checkpoint inhibitors (ICI) have entered the therapeutic landscape in TNBC, their benefits are limited to a minority of patients. We hypothesized the combination of ICI with the intratumoral administration of plasmid IL-12 (tavokinogene telseplasmid; TAVOTM) followed by electroporation could enhance the therapeutic efficacy based on our previous observation of the anti-tumor effect of TAVO in TNBC. The purpose of this study was to clarify the potency of TAVO as an additive local treatment to systemic anti-PD-1 immunotherapy. Methods: A murine TNBC cell line, E0771, was implanted bilaterally into flanks of female C57BL/6 mice, which were randomized into four groups: control (control plasmid + control antibody), anti-PD-1 (control plasmid + anti-PD-1), Tavo (Tavo + control antibody), and combination (TAVO + anti-PD-1). TAVO or control plasmid (50 µg/injection) was administered into a single tumor followed by electroporation on days 0, 3, and 7, as we previously reported (SITC abstract), while tumors on the other side were left untreated. Anti-PD-1 or control antibody (200 µg/injection) was administered by intraperitoneal injection on days 2, 6, 9, and 13. Tumor volume was measured every other day, and the survival of mice was monitored. The local microenvironment of both treated and untreated tumors and systemic effect on splenocytes were evaluated using flow cytometry and single-cell RNA-sequencing. Results: The combination of intratumoral administration of TAVO with anti-PD-1 suppressed the tumor growth more effectively compared to the other groups not only in treated local tumors but also in untreated remote tumors. Higher rates of tumor regression and better survival were observed in the combination group. TAVO locally increased effector CD8+ T cells while reducing regulatory T cells in both treated tumors and distant untreated tumors. The systemic expansion of effector CD8+ T cells was also observed in splenocytes. Conclusions: Intratumoral electroporation of TAVO with anti-PD-1 improved systemic anti-tumor efficacy by modifying the immunosuppressive tumor microenvironment. Clinical studies of this combination treatment in TNBC are underway. Citation Format: Hiroshi Nagata, Takuya Osada, Erika J. Crosby, David A. Canton, Chris G. Twitty, H. Kim Lyerly. Intratumoral plasmid IL-12 enhanced the systemic anti-tumor effect of anti-PD-1 antibody in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1557.
Haemospermia in the real-life setting: Challenging the EAU guidelines
Authors: E. Pozzi, E. Ventimiglia, G. Fallara, L. Boeri, F. Belladelli, D. Cignoli, L. Candela, P. Capogrosso, N. Schifano, M. Raffo, G. Colandrea, J. Cornelius, A. Mattei, C. Abbate, F. Montorsi, A. Salonia
Journal: European Urology (2021)
Abstract LB093: Incident heart failure among young adult cancer survivors
Authors: Yoshihiro Tanaka, Phlip Greenland, Sadiya Khan, Elizabeth A. Hibler
Journal: Cancer Research (2021)

Abstract Background: Risk of heart failure (HF) is known to be higher among childhood cancer survivors as well as older adult cancer survivors who may already have cardiovascular disease risk factors. However, the risk of HF among young adult cancer survivors is not known. Aim: To examine incident HF in adult cancer survivors between 18-39 years of age. Methods: We identified patients who were aged 18-39 years when diagnosed with cancer based on the International Classification of Diseases (ICD) 9 and 10 at an integrated multisite single health system (Northwestern Medicine) between January 2000 and January 2019. We stratified by cancer types predominantly linked with anthracycline exposure (leukemia, lymphoma, sarcoma, breast, kidney, and bone cancers) compared with those less likely to have anthracycline exposure. We estimated the cumulative incidence of HF using the Kaplan-Meier method then calculated unadjusted and adjusted hazard ratios (HRs) for incident HF using Cox proportional hazard models. HRs were adjusted for demographic factors and cardiovascular risk factors. Results: Of 12,879 eligible patients, 35% were men and 68% White. The mean age was 31.5±5.7 years. Cardiovascular comorbidities were present in &amp;lt;5% of cancer survivors. During a median follow-up period of 3.4 (IQR, 1.3-7.1) years, 180 incident HF events were observed. Five-year cumulative incidence of HF was significantly higher in those cancer types more likely to have anthracycline exposure compared without (2.5% vs 0.6%, Log-rank p-value &amp;lt;0.01) with an adjusted HR for incident HF of 3.31 (95% confidence of interval 2.36-4.64, p&amp;lt;0.01). Conclusion: While cardiovascular comorbidities and HF are rare in the young adult population, undergoing cancer treatment with anthracycline exposure is associated with significantly higher risk for HF in young adult cancer survivors. Citation Format: Yoshihiro Tanaka, Phlip Greenland, Sadiya Khan, Elizabeth A. Hibler. Incident heart failure among young adult cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB093.
Abstract 1649: Mechanistic understanding of HPK1 inhibition on enhanced human T cell activation and tumor immunity in a syngeneic model
Authors: David Ciccone, Vad Lazari, Ian Linney, Michael Briggs, Samantha Carreiro, Christine Loh, Peter Tummino, Joshua McElwee, Alan Collis, Neelu Kaila
Journal: Cancer Research (2021)

Abstract Background: HPK1, a member of the MAP4K family of protein serine/threonine kinases, is involved in negatively regulating signal transduction cascades in cells of hematopoietic origin. Recent data generated using potent and highly selective HPK1 inhibitors underscores the role of HPK1 in negatively regulating T, B, and dendritic cell activation and thus orchestrating a comprehensive anti-tumor immune response. In the present study, we seek to further understand the biological effects of HPK1 inhibition in primary human T cells and in syngeneic models. Methods: RNA sequencing and multiplex cytokine analyses were utilized to profile both primary human T cells and the MC38 syngeneic model. In vivo efficacy, target engagement and pharmacodynamic data were generated using murine syngeneic tumor models. Results: In vitro, HPK1 small molecule inhibition resulted in enhanced cytokine production in primary human T cells. In vivo, HPK1 inhibition abrogated T cell receptor-stimulated phospho-SLP-76, enhanced cytokine production, and mediated robust tumor growth inhibition in a murine syngeneic tumor model. Conclusion: Pharmacological blockade of HPK1 kinase activity represents a novel and potentially valuable immunomodulatory approach for anti-tumor immunity. Citation Format: David Ciccone, Vad Lazari, Ian Linney, Michael Briggs, Samantha Carreiro, Christine Loh, Peter Tummino, Joshua McElwee, Alan Collis, Neelu Kaila. Mechanistic understanding of HPK1 inhibition on enhanced human T cell activation and tumor immunity in a syngeneic model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1649.
Abstract 1179: MSH2 is necessary for temozolomide-induced ATR activation in MGMT-methylated cancers
Authors: Sachita Ganesa, Amrita D. Sule, Christopher B. Jackson, Ranjini K. Sundaram, Ranjit S. Bindra
Journal: Cancer Research (2021)

Abstract The methylation status of the O6-methyl guanine methyltransferase (MGMT) gene promoter is a prognostic biomarker for treatment with the alkylator, temozolomide (TMZ) in many solid tumors including gliomas and colorectal cancers. It is well established that patients with a methylated MGMT promoter (MGMT-) who are treated with the TMZ have a better overall survival than patients with an unmethylated MGMT promoter (MGMT+). The enzyme produced by the MGMT gene is responsible for removing cytotoxic O6-methylguanine (O6-meG) lesions formed by TMZ. In the MGMT- setting, the O6-meG lesion activates the mismatch repair (MMR) pathway which functions to remove the damage. Published work from our group reported differential activation of the ataxia telangiectasia and RAD3 related protein (ATR) in MGMT- and MGMT+ glioblastoma multiforme (GBM) cells in response to TMZ treatment, as demonstrated through the phosphorylation of CHK1. Though it is known that MMR proteins are involved in ATR activation, the specific MMR proteins required for ATR activation by TMZ-induced alkyl lesions remain unknown in the MGMT- setting. Here, we demonstrate that the MMR protein MSH2 plays a role in ATR activation in the presence of O6-meG lesions. We show that there is potent synergy with ATRi and TMZ in the MGMT- MSH2-proficient GBM cell line, which is abrogated in an shMSH2 MGMT- GBM cell line. Additionally, we observe decreased levels of pCHK1 in the shMSH2 MGMT- setting compared to the MGMT- MSH2-proficient cells, suggesting that MSH2 is integral in the activation of ATR upon TMZ treatment. This study elucidates a potential role for MSH2 in ATR activation. Mechanistic understanding of how the MMR system is involved in ATR activation by TMZ can ultimately be exploited for therapeutic gain. Citation Format: Sachita Ganesa, Amrita D. Sule, Christopher B. Jackson, Ranjini K. Sundaram, Ranjit S. Bindra. MSH2 is necessary for temozolomide-induced ATR activation in MGMT-methylated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1179.
Abstract 2282: Rapid and accurate variant calling of FFPE samples with the genexus system
Authors: Iris Casuga, Jason Gioia, Janice Au-Young, Frances Chan, Milton Huynh, Michael Crowe
Journal: Cancer Research (2021)

Abstract Next Generation Sequencing technology has enhanced oncology research by enabling the detection of relevant variants for clinical and drug discovery programs. The Oncomine Comprehensive Assay v3, a pan-cancer panel, used with the Ion Torrent Genexus System allows for formalin-fixed paraffin embedded (FFPE) samples to be examined across 161 unique genes in an automated workflow from sample to result in 30hrs. This study demonstrates ≥ 90% accuracy for detecting SNV/Indel/CNV and Fusion variants. The Genexus System consists of two software linked instruments, the Genexus Purification System and the Genexus Integrated Sequencer. The purification system is used first to extract and quantify 6 FFPE sections from human colon and lung tissue for matching DNA &amp; RNA pairs. The nucleic acid output plate from the purification instrument is directly transferred to the sequencer for library preparation and sequencing using the Oncomine Comprehensive Assay v3. Variant calling analysis of 6 DNA &amp; RNA pairs are completed the following day. Results show that the variants were detected with ≥ 90% Sensitivity when compared to the Ion Torrent GeneStudio S5 System as an orthogonal method. All variants report p-values ≤ 10^-5 signifying more confidence that the variant call is correct. The Genexus System is a seamless solution for sample to variant calling results. Citation Format: Iris Casuga, Jason Gioia, Janice Au-Young, Frances Chan, Milton Huynh, Michael Crowe. Rapid and accurate variant calling of FFPE samples with the genexus system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2282.
Clinical utility of ExosomeDx with or without multiparametric magnetic resonance imaging for the detection of clinically significant prostate cancer
Authors: V. Fasulo, C.M. De La Calle, M. Maggi, J.E. Cowan, R.A. Yeung, K. Shinohara, N.M. Buffi, P.R. Carroll, H.G. Nguyen
Journal: European Urology (2021)
Abstract 694: Novel conditionally active bispecific EpCAM x CD3 T cell engagers targeting solid tumors
Authors: Ana Paula G. Cugnetti, Haizhen Liu, Jing Wang, Charles Xing, Christina Wheeler, Matthew Lucas, Cathy Chang, Gerhard Frey, William Boyle, Jay Short
Journal: Cancer Research (2021)

Abstract Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein that plays many roles in cancer biology. EpCAM is an attractive therapeutic target due to its expression on most solid tumors. However, targeting of EpCAM protein has been limited since it is also expressed on normal epithelial tissues. In fact, initial attempts to develop EpCAM-specific T cell engagers were not successful due to severe cytokine release effects as well as serious on-target off-tumor drug related toxicities. Conditionally Active Biologic (CAB) technology is a proprietary platform that generates bispecific antibodies which have no or very little binding to CD3 or to the target antigen in healthy tissue (normal physiological conditions), but have strong binding in the context of diseased tissues (tumor microenvironment) based on the glycolytic tumor metabolism (Warburg effect). Using our CAB technology, we have developed CD3 mono-CAB (WT EpCAM x CAB CD3) and CD3/EpCAM dual-CAB (CAB EpCAM x CAB CD3) bispecific antibodies. In vitro and in vivo efficacy data as well as toxicology studies in non-human primates for mono- and dual-CAB EpCAM x CD3 bispecific antibodies targeting EpCAM will be presented. Our data demonstrate that both mono- and dual-CAB EpCAM x CD3 bispecific antibodies have potent anti-tumor activities in vivo and have much lower toxicity compared to non-CAB bispecific antibodies. The mono- and dual-CAB EpCAM x CD3 bispecific antibodies generated by the CAB technology represent a new class of potent, effective T-cell engagers with potential for increased safety margin and therapeutic index in the clinic. Citation Format: Ana Paula G. Cugnetti, Haizhen Liu, Jing Wang, Charles Xing, Christina Wheeler, Matthew Lucas, Cathy Chang, Gerhard Frey, William Boyle, Jay Short. Novel conditionally active bispecific EpCAM x CD3 T cell engagers targeting solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 694.
単一センターにおけるシロリムス溶出ステント(SES)の長期間臨床成果とステント血栓症の頻度
Authors: Shimomura Mitsuhiro, Nakama Tatsuya, Mine Daigo, Nishihira Kensaku, Kuriyama Nehiro, Nomura Katsumasa, Ishikawa Tetsunori, Matsuyama Akihiko, Shibata Yoshisato, Node Koichi
Journal: Circulation (2009)
心筋症ハムスター(BIO14.6)の心肥大および筋線維症を減少させないアンジオテンシンAT1受容体拮抗作用:ACE阻害薬の作用との比較
Authors: Kurihara T, Karita M, Matsuda T, Okuto K, Kagiya T, Kusuoka H
Journal: Circulation (1996)
Abstract 18219: Endothelial Canonical Sonic Hedgehog Signaling is Not Required for Sonic Hedgehog Mediated Angiogenesis or Ischemic Tissue Repair
Authors: Rajesh Gupta, Sol Misener, Alexander Mackie, Christine E Kamide, Kathryn M Schultz, Tina Thorne, Ekaterina Klyachko, Douglas W Losordo
Journal: Circulation (2011)

Introduction: Hedgehog signaling is a critical mediator of development, ischemic tissue repair, and carcinogenesis. Sonic hedgehog (Shh) signaling has been shown to mediate ischemic tissue repair in experimental models. However, there is controversy on whether Shh signaling improves tissue perfusion by the canonical hedgehog pathway in endothelial cells or via indirect effects on stromal cells. We tested the hypothesis that direct canonical endothelial Shh signaling via the Hedgehog signal transducer Smoothened (Smo) is required for Shh mediated angiogenesis and ischemic tissue repair. Methods: We utilized Cre-Lox mouse models to test this hypothesis. Two endothelial Cre mouse lines, the Tie2-Cre and Vascular Endothelial Cadherin-Cre lines were crossed with mice in which Smo was homozygously floxed to generate endothelial specific Cre+ Smo flox/flox (eSmoNull) mice. Baseline cardiac phenotype was assessed with echocardiography. eSmoNull and SmoWT mice were compared using the corneal angiogenesis and hind limb ischemia (HLI) mouse models. Results: eSmoNull mice were viable and appeared normal. Baseline echo demonstrated normal LV function (fractional shortening: 34.39±1.9 vs. 34.07±1.1, P=0.93). Collagenase digestion of eSmoNull and SmoWT hearts followed by CD31+ cell selection and RT-PCR confirmed effective deletion of Smo. Corneal angiogenesis was induced with Shh pellets revealing similar degrees of Shh induced angiogenesis in eSmoNull and WT mice. HLI was induced to determine the role of endothelial, Smo-mediated hedgehog signaling after ischemic injury. In striking contrast to the impairment in recovery following antibody-mediated global blockade of Shh (Pola, Nature Med, 2001), laser Doppler perfusion demonstrated no significant difference in perfusion at days 7, 14, 21, and 28 (Day 28 perfusion ratio ischemic/nonischemic: 0.56 vs. 0.74, P=0.07). Limb preservation and functional scores were not significantly different. The ratio of lectin+ capillaries per muscle fiber in the ischemic limb was similar (1.58±0.15 vs. 1.65±0.11, P=0.36). Conclusion: Endothelial canonical Shh signaling is dispensable for vascular development, resting cardiac function, Shh induced angiogenesis, and recovery after ischemic injury.
Increased 68Ga-FAPI Uptake in Ankylosing Spondylitis in a Patient With Rectal Cancer
Authors: Lanlin Yao, Long Zhao, Yizhen Pang, Qihang Shang, Haojun Chen
Journal: Clinical Nuclear Medicine (2021)

Ankylosing spondylitis represents an inflammatory arthropathy with a predilection for the axial skeleton. We reported 68Ga-FAPI PET/CT finding of ankylosing spondylitis in a 65-year-old patient with rectal cancer. In addition to accumulating in primary tumor and metastatic lymph nodes, increased 68Ga-FAPI uptake was also observed in the sacroiliac and costovertebral joints, indicating sacroiliitis and spondylitis. However, no abnormal 18F-FDG uptake was observed in the inflammatory lesions. This case highlighted that 68Ga-FAPI PET/CT is useful for the evaluation of inflammatory conditions in ankylosing spondylitis.
Abstract 1492: Chimeric antigen receptor (CAR) T cell donor dependent dysfunction modulation with activation of autophagy and inhibition of trogocytosis
Authors: Jiyong Liang, Dexing Fang, Amy B. Heimberger
Journal: Cancer Research (2021)

Abstract Introduction: Effective anti-tumor immunity requires the presence of abundant effector T cells in the tumor microenvironment with both cancer cell specificity and cytotoxic potency. Chimeric antigen receptor (CAR) T cells engineered ex vivo to fulfill such quintessence are effective in both experimental and clinical settings with curative potential. However, the efficacy of CAR T cells can be limited by trogocytosis whereby CAR T cells extract cognate antigens from target cells thereby eliciting antigen escape and then express the target antigen on the CAR triggering fratricide that reduces the CAR persistence and efficacy. Methods: Epidermal growth factor variant III (EGFRvIII) specific CAR T cells were generated from various donors and analyzed for EGFRvIII cytotoxicity, trogocytosis, and in vivo therapeutic activity which was modulated with verteporfin, an inducer of autophagy and bafilomycin A1, an inhibitor of autophagy. A three-way co-culture system modeling the glioblastoma microenvironment of the CAR T cell interaction with targets (U87-EGFRvIII) and bystanders (U87-EGFR) was used to evaluate phagocytic and autophagy functions of the CAR T cells. Results: Glioblastoma-specific EGFRvIII CARs induce trogocytosis of the cognate tumor antigen upon engaging target tumor cells within 2 hours. Trogocytic activity varies in a donor-dependent manner and correlates with impaired CAR performance in murine models of orthotopic gliomas expressing EGFRvIII. Trogocytosis is blocked with verteporfin which restores cytolytic capacity of the CAR. In the three-way co-culture system, therapeutically effective in vivo CARs demonstrate superior phagocytic clearance of U87-EGFRvIII released mitochondria that is blocked by autophagy inhibition. The induction of immune checkpoints such as PD-L1 during CAR-target interaction is enhanced when autophagy is blocked. Furthermore, autophagy blockade prevents phagocytic clearance of cytolytic target release of mitochondria. We further demonstrate that pharmacological facilitation of autophagy with verteporfin inhibits trogocytic expression of target tumor antigen on CARs and thereby markedly increases CAR persistence in the glioma microenvironment in mice. Conclusions: Our data establish autophagy as an antagonizing mechanism counteracting CAR-induced trogocytosis and immune checkpoint activation, providing evidence for a new strategy to innovate high-performance CARs. Citation Format: Jiyong Liang, Dexing Fang, Amy B. Heimberger. Chimeric antigen receptor (CAR) T cell donor dependent dysfunction modulation with activation of autophagy and inhibition of trogocytosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1492.