tbuckley/cabot-search huggingface dataset:
Abstract 6347: To develop a tumor selective INF-γ-Yervoy fusion antibody to increase the therapeutic effect and safety of current Yervoy therapy in cancer
Authors: Chih-Hung Chuang
Journal: Cancer Research (2024)

Abstract Introduction: Immune checkpoint inhibitor therapy is a highly promising strategy for clinical treatment of cancer. Among these inhibitors, yervoy stands out for its ability to induce cytotoxic T cell proliferation and activation by binding to CTLA-4. However, FDA has reported that yervoy would induce the over-activation of immune cells and cause the serious side effects. In additional, the therapeutic efficacy and application of Yervoy were still limited by the MHC expression of patient's tumor. Strategy: Therefore, we have developed a protease specific pro INF-γ-Yervoy to increase the therapeutic effect and safety of current immune checkpoint blockade therapy in cancer. We used the MMP-2/9 protease substrate as a linker between INF-γ and Yervoy. Using the concept of spatial shielding, IFNγ and Yervoy can block their functions from each other. Once the INF-γ-Yervoy arrives to the tumoral region, the INF-γ-Yervoy will be removed from Hinge Yervoy by the over-expressed MMPs protease locally so that the Yervoy will recruit its binding ability in order to increase the drug selectivity and improve the side effects. The INF-γ also can increase the MHC I expression in tumor to overcome the MHC-limitation of Yervoy. Result: On activation by MMP, IFNγ-yervoy not only restored yervoy’s binding ability but also released biologically active IFNγ. This finding confirms the reliability of IFNγ-yervoy’s functionality. In vivo studies demonstrated that IFNγ-yervoy enhances the therapeutic effect of yervoy against colorectal cancer by increasing CD8+ and CD4+ lymphocyte infiltration into the tumor area and inducing MHC-I expression in tumor cells. Mice treated with IFNγ-yervoy showed higher survival rates and body weight, as well as lower CD4+ and CD8+ lymphocyte activation rates in the blood and reduced organ damage. Conclusion: These results provide strong evidence that tumor-selective IFNγ-yervoy can improve the effectiveness of yervoy while reducing its side effects. It is likely that future immunotherapies would rely on such antibodies to activate local cancer cells or immune cells, thereby increasing the therapeutic effectiveness of cancer treatments and ensuring their safety. Keyword: Immune checkpoint inhibitor therapy, IFNγ, yervoy, rectal cancer, CTLA4 Citation Format: Chih-Hung Chuang. To develop a tumor selective INF-γ-Yervoy fusion antibody to increase the therapeutic effect and safety of current Yervoy therapy in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6347.
Abstract 3097: CETSA HT: Employing rapid high-throughput target engagement technology in primary screening of P53
Authors: Merve Kacal, Tomas Friman, Laurence Arnold, Victoria Brehmer, Daniel Martinez Molina, Stina Lundgren
Journal: Cancer Research (2024)

Abstract The confirmation of target engagement for candidate drugs is a fundamental requisite in drug discovery. A significant portion of projects fail to reach the clinic due to lack of efficacy or failure to show lead candidates interacting with the intended target in a more complex environment. The utility of using the CETSA® (CEllular Thermal Shift Assay) technology to measure target engagement in intact cells is increasingly exploited in high throughput screening, where examples demonstrate low false positive rates in screens of up to 500K compounds. The p53 tumor suppressor protein, a crucial guardian against cancer, functions as a transcription factor that mediates cancer suppression by regulating genes involved in a wide range of cellular processes such as DNA repair, cell cycle and apoptosis. Unfortunately, frequent mutations in the TP53 gene hinder p53's tumor suppressor role in human cancers, thus designating it as a promising target for anticancer therapy. However, attempts to restore p53 function for therapeutic purposes have not yet advanced to clinical approval, highlighting the complexities in leveraging p53 for cancer treatment. Its undruggable nature, attributed to the absence of accessible deep pockets, lack of enzymatic activity, and its intracellular location, further complicates targeted interventions with both low and high molecular weight drugs. Here, we demonstrate the analysis of a high-throughput plate based CETSA® HT screen on the challenging target p53, performed using AlphaLISA® SureFire® Ultra™ technology and our newly developed high-throughput screening platform. Hits identified from this screen are privileged from the onset by binding to the target in a physiologically relevant cellular matrix and in a binding-mode agnostic way. This is in contrast to traditional screening methods targeting activity or in vitro interaction where cellular activity is addressed in later stages. This assay cascade highlights a rapid target-to-hit lead generation strategy placing the emphasis on finding chemical matter that interacts with endogenous target in living cells first, followed by analysis of hit material activity. The ‘shortcut’ to chemical matter active in living cells represents significant potential cost savings in comparison to assay development time on recombinantly produced proteins and/or modified cell lines for traditional HTS screening approaches that still rely on target engagement assessment downstream. Citation Format: Merve Kacal, Tomas Friman, Laurence Arnold, Victoria Brehmer, Daniel Martinez Molina, Stina Lundgren. CETSA HT: Employing rapid high-throughput target engagement technology in primary screening of P53 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3097.
Abstract 6335: Armoring CAR-T therapy with PD-1 blockade: a powerful strategy for enhancing anti-tumor effects in pancreatic cancer
Authors: Zhixiang Zhang, Jingwei Huang, Zhifeng Zhao, Xiangyi Wang, Cnhui he, Sen Yang, Qingyang Gu
Journal: Cancer Research (2024)

Abstract Chimeric antigen receptor-modified T cells (CAR-T) have been widely applied in the treatment of hematological malignancies and are currently under investigation for their potential effectiveness against solid tumors. Nevertheless, the effectiveness of CAR-T in treating solid tumors remains unsatisfactory due to a range of factors, including CAR-T cell infiltration and heterogeneity. The efficacy of CAR-T therapy is substantially influenced by the tumor microenvironment. This is particularly evident when PD-L1 is activated through CAR-T, leading to the inhibition of CAR-T cell activity via the PD-1 pathway. In this study, we engineered a CAR-T therapy that targets mesothelin and concurrently expresses a membrane-bound PD-1 receptor. This design blocks the PD-1 on CAR-T cells, effectively counteracting the suppression of CAR-T function mediated by PD-L1. We observed a substantial upregulation of PD-L1 on AsPC-1 tumor cells after 4 hours of IFN-γ stimulation in vitro. CAR-T cells engineered to co-express PD-1 antibody (aMSLN-28BBZ-mPD-1) exhibited similar short-term cytotoxicity and cytokine secretion profiles to those of the traditional third-generation CAR-T (aMSLN-28BBZ). Notably, aMSLN-28BBZ-mPD-1 displayed significantly improved long-term target cell killing. Furthermore, in an in vivo model of pancreatic cancer, aMSLN-28BBZ-mPD-1 demonstrated enhanced anti-tumor activity when compared to the traditional aMSLN-28BBZ, as supported by RNAscope analysis and immunofluorescence assays of tumor tissues. These analyses revealed a marked upregulation of PD-L1 expression and enhanced CAR-T cell infiltration in the aMSLN-28BBZ-mPD-1 treatment group. In summary, our study demonstrates that co-expression of a membrane-bound PD-1 antibody overcomes PD-L1 mediated CAR-T suppression, as observed in both in vitro and in vivo. This innovative strategy underscores its therapeutic potential and value in treating solid tumors. Keywords: CAR-T, PD-1, Tumor Microenvironment, Pancreatic Cancer Citation Format: Zhixiang Zhang, Jingwei Huang, Zhifeng Zhao, Xiangyi Wang, Cnhui he, Sen Yang, Qingyang Gu. Armoring CAR-T therapy with PD-1 blockade: a powerful strategy for enhancing anti-tumor effects in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6335.
Abstract 6353: AM105: A novel bispecific antibody with Anti 4-1BB affibodies and EGFR antibody
Authors: Dong-Wook Kim, Hyun-Jong Lee, Seong Yeol Kim, Min Yoon, Youngha Lee, In-Sik Hwang, Yoon Lee, Jong-Hoon Kim, Jong-Seo Lee
Journal: Cancer Research (2024)

Abstract T cell engaging bispecific antibodies have emerged as promising treatments for hematologic malignancies. While most antibodies are CD3-based, offering therapeutic benefits, they are often associated with severe side effects and limited efficacy in solid tumors. To address these challenges, we present AM105, a groundbreaking anti 4-1BB affibodies based bispecific antibody designed to target EGFR. We carefully engineered AM105 with distinct binding affinities for EGFR (KD = 1.8 nM) and 4-1BB (KD = 60 nM), favoring EGFR binding. Affibody specificity was confirmed through a cross-reactivity test with proteins of TNF-receptor superfamily and 21 cell lines expressing 4-1BB or not. In cytotoxicity assays, AM105 exhibited superior tumor cell killing compared to cetuximab, particularly in EGFR-expressing cell lines. Notably, AM105 displayed remarkable efficacy in cell lines harboring RAS and/or BRAF mutations, traditionally unresponsive to EGFR-targeting treatments. In vivo experiments utilizing humanized 4-1BB mice demonstrated AM105's exceptional tumor cell elimination compared to cetuximab. The anti-tumor effects persisted even in the face of new tumor cell introductions, suggesting the induction of T cell memory function. Our findings collectively establish AM105 as a potent therapeutic agent with strong anti-tumor T cell activity. The unique 4-1BB based Affibodies (AffiMab format) of AM105 holds promise for addressing the limitations of current bispecific antibodies, positioning it as a potential breakthrough in cancer immunotherapy. Citation Format: Dong-Wook Kim, Hyun-Jong Lee, Seong Yeol Kim, Min Yoon, Youngha Lee, In-Sik Hwang, Yoon Lee, Jong-Hoon Kim, Jong-Seo Lee. AM105: A novel bispecific antibody with Anti 4-1BB affibodies and EGFR antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6353.
Abstract 6355: Urokinase plasminogen activator receptor-associated protein (uPARAP) is overexpressed in human glioblastomas and is a therapeutic target for antibody-drug conjugates (ADC)
Authors: Ida Gregersen, Cecillie R. Løkke, Jette B. Lange, Pernille Barkholt, Christophé Côme, Tina Broberg, Marianne M. Petersen, Carmel M. Lynch, Dominik Mumberg, Niels Behrendt, Lars H. Engelholm
Journal: Cancer Research (2024)

Abstract Background: Glioblastoma Multiforme (GBM), primarily arising in the brain's frontal and temporal lobes, is a devastating malignancy originating from astrocytes. Despite treatment advancements, the prognosis remains bleak, with a median survival of 15-18 months and a 10% five-year survival rate.Our study explored a novel targeted approach to combat this challenge. uPARAP is an endocytic receptor expressed at low levels on selected mesenchymal cell types but highly overexpressed on the majority of Soft-Tissue- and Bone Sarcomas. It internalizes fragments of collagen and transfers them to the lysosome for degradation. Methods &amp; Results: First, we analyzed formalin-fixed paraffin-embedded (FFPE) tumors from GBM patients through immunohistochemistry (IHC) staining. Interestingly, a majority of the samples showed strong but varying uPARAP expression. In parallel, we detected and quantified uPARAP receptor expression in GBM cell lines by flow cytometry, underscoring its potential as a therapeutic target.Next, we generated an antibody-drug conjugate (ADC) linked to monomethyl auristatin E (MMAE), a potent antimitotic agent. Confocal microscopy showed rapid internalization of the ADC in several GBM cell lines in vitro. Cellular cytotoxicity was demonstrated in Incucyte and Alamar Blue in vitro assays. Finally, anti-tumor activity of the uPARAP-ADC was studied in a GBM patient-derived xenograft (PDX) model in vivo, where it resulted in significant tumor regression with a tumor growth inhibition (TGI) of 92 and 97% at 3 and 6 mg/kg, respectively. Conclusions: Our findings show that uPARAP is overexpressed on GBM tumors and that a uPARAP-targeted ADC has anti-tumor activity in a PDX model of GBM. This research provides initial evidence that uPARAP-ADCs could become a novel treatment option for this highly aggressive disease. Citation Format: Ida Gregersen, Cecillie R. Løkke, Jette B. Lange, Pernille Barkholt, Christophé Côme, Tina Broberg, Marianne M. Petersen, Carmel M. Lynch, Dominik Mumberg, Niels Behrendt, Lars H. Engelholm. Urokinase plasminogen activator receptor-associated protein (uPARAP) is overexpressed in human glioblastomas and is a therapeutic target for antibody-drug conjugates (ADC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6355.
Abstract 26: An HLA-class II restricted HPV18 E7 specific TCR cloned from a long-term surviving cervical cancer patient
Authors: Jianting Long, Xihe Chen, Shudan Ou, Minjun Ma, Junjun Chu, Yanyan Han
Journal: Cancer Research (2024)

Abstract T cell receptor (TCR)-engineered T cell therapy is a promising approach for the treatment of solid malignancy, with multiple clinical trials reporting impressive responses using affinity-matured TCRs. However, artificially mutated TCRs can increase the risk of off-target toxicities due to unexpected cross-reactions, which limits the overall safety of this approach. To tackle this challenge, we have developed a novel strategy for cloning tumor-specific endogenous therapeutic TCRs from long-term surviving patients who have responded to immunotherapy. Specifically, we have identified a TCR (10F04) that is specific to human papillomavirus type 18 (HPV18) E784-98 and restricted to human leukocyte antigen (HLA) class II molecular DRA/DRB1*09:01 from the peripheral blood of a patient with HPV-positive metastatic cervical cancer who received multiple antigens stimulating cellular therapy (MASCT) and exhibited sustained T-cell immunological responses. Upon transduction into human T cells, the 10F04 TCR demonstrated robust antitumor activity in both in vitro and in vivo models. Notably, the TCR effectively redirected both CD4 and CD8 T cells to specifically recognize tumor cells and induced multiple cytokine secretion along with durable antitumor activity. Importantly, no cross-reactivity was detected in toxicity studies. As a result, this TCR is currently being investigated in a phase I clinical trial for treating HPV18-positive cancers (NCT05787535). The first-in-human infusion had been just completed. No severe adverse event had been observed, while an early proliferation of TCR-T was detected several days after infusion. Our approach of cloning tumor-specific and safe endogenous therapeutic TCRs from long-term surviving patients offers a promising strategy for developing safe and effective TCR-engineered T-cell therapies for solid tumors. These findings provide important insights into the potential of HLA class II-restricted TCR-T therapy as a novel cancer treatment modality. Citation Format: Jianting Long, Xihe Chen, Shudan Ou, Minjun Ma, Junjun Chu, Yanyan Han. An HLA-class II restricted HPV18 E7 specific TCR cloned from a long-term surviving cervical cancer patient [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 26.
Abstract 3405: CT-assessed body composition and tumor immunologic characteristics in patients with non-small-cell lung cancer
Authors: Ting-Yuan David Cheng, Cuthbert Mario Mahenge, Rand T. Akasheh, Ayse Selen Yilmaz, Ben Kinder, Xuan Nguyen, Maciej Pietrzak, Carolyn J. Presley, Peter G. Shields
Journal: Cancer Research (2024)

Abstract Objectives: Obesity is associated with higher immunotherapy efficacy, but body mass index is a convoluted marker of adipose and muscle tissue. We conducted a discovery scale study to assess the association of skeletal muscle and adipose tissue areas annotated on computed tomography (CT) scan images with selected tumor immunologic characteristics among patients with non-small-cell lung cancer (NSCLC). Methods: We analyzed publicly available data from 102 patients (mean age = 67.2, 47.1% female, and 70.6% stage I-II) who had diagnostic CT images in The Cancer Image Archive. All patients had the 12th thoracic vertebra (T12) image, and a subset (62 patients) had the 3rd lumber vertebra (L3) image. Paravertebral muscle areas on T12 and skeletal muscle and adipose tissue areas on L3 were annotated using Slice-O-Matic. RNA-seq data were provided by The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium; percentages of CD8, regulatory T cells, and activated NK cells were identified using the CIBERSORT. ESTIMATE algorithm was used to derive the stromal score and the immune score. Differences in the immune markers were examined using ANOVA adjusting for stage, histology, and study. Results and Conclusion: Patients with higher paravertebral muscle area (3rd tertile) had the lowest stromal scores, compared to the 2nd and 1st tertile (P&amp;lt;0.05). Patients in the 2nd tertile of paravertebral muscle areas had the highest immune score and CD274 (PD-L1) gene expression. Among the body composition types classified using L3 images, low muscle/high adiposity was associated with lower stromal scores, and low muscle was associated with lower immune scores, compared to high adiposity and high muscle/low adiposity types. Other immunological markers did not differ across the body composition types. Significance: These findings suggest associations between deconvoluted skeletal and adipose tissue components and tumor markers relevant to immune checkpoint inhibitor efficacies in NSCLC. Further validation using immune phenotyping in a large patient sample is warranted. Funding: The study is in part supported by NIH/NCI R37CA248371 and OSU Comprehensive Cancer Center - James. Citation Format: Ting-Yuan David Cheng, Cuthbert Mario Mahenge, Rand T. Akasheh, Ayse Selen Yilmaz, Ben Kinder, Xuan Nguyen, Maciej Pietrzak, Carolyn J. Presley, Peter G. Shields. CT-assessed body composition and tumor immunologic characteristics in patients with non-small-cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3405.
Abstract 3104: A NanoBRET target engagement assay for querying domain selectivity at full-length polymerase theta in live cells
Authors: Steven Edenson, Michael Slater, Cesear Corona, Michael Beck, James Vasta, Kelly Teske, Ani Michaud, Matthew Robers
Journal: Cancer Research (2024)

Abstract In HR-deficient cells, Polymerase Theta (Pol-theta) serves to repair double strand breaks and has emerged as a therapeutic target in HR-deficient cancers. Encoded by the POLQ gene, Pol-theta is a large (290 Kda) protein with two distinct functional domains (polymerase, helicase), separated by an unstructured region. Each domain of Pol-theta has proven vulnerable to small molecule inhibitors, with a number of molecules undergoing clinical evaluation. Unlike the helicase domain, target engagement at the polymerase domain requires cooperativity with DNA fragments. Here we describe a novel NanoBRET Target Engagement assay that enables domain-specific analysis of small molecule occupancy in live cells. To observe the high affinity-state of small molecule inhibitors to the polymerase domain, we have developed a cell-permeable pol domain NanoBRET probe, along with a novel work flow to introduce small DNA fragments into live cells. Together these components form a nucleoprotein complex with full length polymerase theta. This assay method can be used to quantify and rank-order engagement to the polymerase domain in live cells. To enable domain-selectivity analysis, we have developed a second NanoBRET probe directed to the helicase domain. Together these two NanoBRET probes allow for the mechanism of action studies at Pol-theta in living cells. Citation Format: Steven Edenson, Michael Slater, Cesear Corona, Michael Beck, James Vasta, Kelly Teske, Ani Michaud, Matthew Robers. A NanoBRET target engagement assay for querying domain selectivity at full-length polymerase theta in live cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3104.
Abstract 4517: Novel chemical degraders targeting NSD2 in head and neck squamous cell carcinoma (HNSCC)
Authors: Amr Ismail, Ekaterina Roshchina, Iuliia Topchu, Gary Schiltz, Yanis Boumber
Journal: Cancer Research (2024)

Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Despite advances in treatments and significant efficacy of immunotherapy drugs in HNSCC, no effective targeted therapies have been approved in this disease yet. NSD2 is a histone lysine methyltransferase, which is overexpressed in HNSCC and is implicated in tumor growth, cell cycle regulation, epithelial-mesenchymal transition (EMT) and metastasis not only in HNSCC, but also in many other solid tumors. Development of inhibitors to the catalytic activity of NSD2 has been rather limited to date, which necessitates an alternative approach. To target NSD2, we have recently developed a series of novel proteolysis targeting chimeras (PROTACs), which chemically degrade NSD2 utilizing native cellular machinery - ubiquitin-proteasome system - with VHL as an E3 ligase. A series of &amp;gt;40 compounds were tested in HNSCC cell lines (JHU-011 and FaDu) and NSD2-dependent multiple myeloma cell line (KMS11) for degradation activity against NSD2 protein, and H3K36me2 chromatin mark reduction, using Western blot. We also tested their anti-proliferative activity in cell viability assay (CTB) and clonogenic assay. Compounds NUCC-0227381, NUCC-0227384, NUCC-0227414 and NUCC-0227383 show promising results by reducing NSD2 and H3K36me2 levels. NUCC-0227383 compound was highly promising, as it was the most potent in reducing NSD2/K36me2 levels without affecting NSD1/NSD3 levels and had profound effects on HNSCC cell growth. Lead compound NUCC-0227383 was chosen for further testing and in preliminary testing, showed a dose-dependent, VHL-mediated, and proteasome dependent function. Proteomics analysis, testing for specificity of NUCC-0227383 against a panel of histone methyltransferases, and in vivo testing of this promising compound against HNSCC is planned. Citation Format: Amr Ismail, Ekaterina Roshchina, Iuliia Topchu, Gary Schiltz, Yanis Boumber. Novel chemical degraders targeting NSD2 in head and neck squamous cell carcinoma (HNSCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4517.