tbuckley/cabot-search huggingface dataset:
Abstract 6398: Harnessing the conditional proteolytic activity of ADAM17 to generate autonomous regulatory mechanisms in CAR T cells
Authors: Jeremy R. Bjelajac, Adria Canellas Socias, Jennifer Hamad, Preeti Nehra, Meena B. Malipatlolla, Peng Xu, Sean Alexander Yamada-Hunter, Louai Labanieh, Elena Sotillo, Crystal L. Mackall
Journal: Cancer Research (2025)

Abstract Background and Purpose: Sustained and unregulated expression of CARs on the surface of T cells can result in reduced potency via exhaustion as a result of tonic signaling or prolonged response to high levels of antigen encountered in vivo. To curtail this phenomenon, we have developed the Activation Induced Release (AIR) system, a novel regulatory platform that exploits activation induced regulation of the ADAM17, to cleave proteins from the surface following activation of the T cell. We hypothesized that AIR-controlled CARs would “self-regulate” the density of CARs on their surface and thereby endogenously ameliorate the effects of tonic signaling. This system would allow for rapid and reversible protein-level regulation of functional receptors without the need for small molecule addition or the incorporation of separate exogenous regulatory genes. Methods and Results: To ascertain the effects of the AIR platform on reducing tonic signaling and improving CAR T cell function, we generated AIR versions of several tonic signaling-prone CARs targeting GD2, B7H3, and Her2 by imputing a hinge motif from CD62L, an endogenous ADAM17 substrate. All AIR-regulated CARs demonstrated reduced rates of tonic signaling, resulting in enhanced functionality over traditional CARs. This improvement was associated with AIR-CARs’ enhanced proliferative capacity, higher expression of memory markers CD62L and IL7R, and lower expression of exhaustion and activation markers CD25, CD39, TIM-3, and PD-1. AIR-GD2 CARs also demonstrated enhanced tumor control in a Nalm6 leukemia mouse model. Conclusions: The AIR platform offers a simple approach to ameliorate the issues resulting from tonic signaling, broadening the scope of CARs that can be utilized in the clinic, as well as the types of antigens that can be targeted in both liquid and solid tumor settings. The AIR system offers a unique approach to CAR T cell engineering, allowing for dynamic control over receptor expression through the use of an endogenous regulatory circuit and minimal alteration to the desired exogenous protein. Citation Format: Jeremy R. Bjelajac, Adria Canellas Socias, Jennifer Hamad, Preeti Nehra, Meena B. Malipatlolla, Peng Xu, Sean Alexander Yamada-Hunter, Louai Labanieh, Elena Sotillo, Crystal L. Mackall. Harnessing the conditional proteolytic activity of ADAM17 to generate autonomous regulatory mechanisms in CAR T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6398.
Abstract 5831: ABN202 (αTROP2), a sacituzumab-interferon-beta mutein fusion protein: a novel approach beyond antibody-drug conjugate therapeutics in ADC-naïve and ADC-refractory cancers
Authors: Hee Geon Park, Hyun Kyung Lee, Myeung Ryun Seo, Soo Jin Ryu, Sungyoul Hong, Chan Gyu Lee, Hae Min Jeong, Sae Hyung Lee, Na Young Kim, Young Kee Shin, Jun Young Choi
Journal: Cancer Research (2025)

Abstract Trophoblast cell surface antigen 2 (TROP2) is a cell-surface glycoprotein overexpressed in various solid tumors, including triple-negative breast cancer (TNBC), hormone receptor-positive breast cancer (HR+ BC), and non-small cell lung cancer (NSCLC). TROP2-targeting antibody-drug conjugates (ADCs) such as Sacituzumab-govitecan (SG) and Datopotamab deruxtecan (Dato-DXd) demonstrated promising clinical efficacy in patients with TROP2-positive cancers. However, TROP2-targeting ADCs exhibit a high incidence of adverse events, a short duration of response, and frequent recurrence. Therefore, there is an unmet medical need for treatments beyond ADC therapeutics, particularly for ADC-naïve and ADC-refractory patients. ABN202 is an antibody-cytokine fusion protein platform that fuses a potent cytotoxic and immune-modulating cytokine, interferon-beta mutein (IFN-β mutein), with an antibody via flexible protein linker. In previous studies, ABN202 utilizing the TROP2-targeting antibody, Sacituzumab (ABN202, αTROP2), demonstrated potent anti-tumor efficacy by inhibiting cancer cell growth and activating anti-tumor immunity within the tumor microenvironment. In this study, we compared the in vitro and in vivo anti-cancer efficacy of ABN202 (αTROP2) with those of SG and Dato-DXd in ADC-resistant preclinical models, as well as in xenograft and human IFNAR knock-in (hIFNAR KI) mouse models. The preclinical toxicity profiles of SG, Dato-DXd, and ABN202 (αTROP2) were evaluated using human immune cells and hIFNAR KI mouse models. In conclusion, ABN202 (αTROP2) demonstrated potent anti-cancer efficacy and a tolerable safety profile compared to SG and Dato-DXd. Our findings suggest that ABN202 (αTROP2) represents a novel therapeutic approach beyond ADCs for both ADC-naïve and ADC-refractory cancers. Citation Format: Hee Geon Park, Hyun Kyung Lee, Myeung Ryun Seo, Soo Jin Ryu, Sungyoul Hong, Chan Gyu Lee, Hae Min Jeong, Sae Hyung Lee, Na Young Kim, Young Kee Shin, Jun Young Choi. ABN202 (αTROP2), a sacituzumab-interferon-beta mutein fusion protein: a novel approach beyond antibody-drug conjugate therapeutics in ADC-naïve and ADC-refractory cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5831.
Abstract 5582: Interrogating the K-ras/p53 transcriptional readout for synthetic lethality applications
Authors: Samuel L. Schach, Farah Mazahreh, A. Mazin Safar
Journal: Cancer Research (2025)

Abstract Some Oncogenes (Onc) are physiologically indispensable or have proven difficult to inhibit (Myc and Ras, respectively). Onc addiction, reflecting the need for specific stress adaptations (SA) to accommodate constant onc signaling, provide a novel approach to disrupt the SA producing synthetic lethality (SL). Broad’s dep map CRISPR screens (CS) suggest SA is NOT monogenic. Combinatorial consideration is unavoidable and can only be fruitful if aided by biologic insights. Genetically engineered mouse models confirmed that p53 is sufficient to facilitate full oncogenic abilities of Ras. p53 transcriptional (Tr) network is a mere 110 genes and includes many repressed targets (T) but some that retain Tr activity despite the p53 DNA binding domain mutations (mu). Retained genes (g) are being considered here as putative therapeutic Ts. Identifying indispensable g in Ras onc SA is needed for CRISPR multiplexed screen. We focused on pancreatic adenocarcinoma (PA) due to high prevalence of Ras/p53 and the poor available treatment options. We hypothesize that specific set of p53 retained Tr Ts provide the SA and this may be phenocopied in few wild type (WT) p53 PA. This would guide CS for therapeutic applications. Methods: We probed TCGA and the Broad public databases for expression of the canonical p53 Tr T in Ras &amp; p53 double mutant PA. We reasoned that MDM2 represents the most rational internal control for reduced Tr in basal, unstimulated conditions; all g with higher Tr are scored as retained; the remaining as lost Tr. WT PA were analyzed to identify phenocopy providing additional strength to the hit. The table summarizes the findings at the different levels of scrutiny. Conclusion: Our work represents a rational biologic approach to select a rational set of SL g in the Ras/p53 interdependence circuitry. Such Ts need to be examined by CS to validate their cellular importance. Pathway analysis and considering the possible double negative inhibition of repressed Ts are additional approaches to this analysis. Citation Format: Samuel L. Schach, Farah Mazahreh, A. Mazin Safar. Interrogating the K-ras/p53 transcriptional readout for synthetic lethality applications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5582.
Abstract 7174: Multiomics analysis of lung adenocarcinoma manifesting as radiological part-solid features in female never-smokers
Authors: Junsu Choe, Noeul Kang, Jinyeong Lim, Eun Seop Seo, Mina Hwang, Se-Hoon Lee, Myung-Ju Ahn, Yoon-La Choi, Hong Kwan Kim, Woong-Yang Park, Sang-Won Um
Journal: Cancer Research (2025)

Abstract Purpose: Early-stage lung adenocarcinomas (LUADs) manifesting as part-solid radiological features have a slowly progressive course to invasive malignancy, but its genomic alterations and tumor microenvironment are poorly understood. Methods: We analyzed eleven part-solid type LUADs from female never-smokers. Whole-exome sequencing and whole-transcriptome analysis were conducted on samples from seven patients. Single-cell RNA sequencing was performed on samples from four patients, and spatial transcriptomics was conducted on a sample from one patient. Results: Both the ground-glass and solid components of LUADs exhibited similar characteristics of malignant cells, sharing mutations and showing no significant differences in tumor mutation burden. Compared to the GG component, the solid component showed up-regulation of epithelial-mesenchymal transition (EMT)-related and hypoxia pathways. We identified a cancer-associated secretory (CAS) cell cluster characterized by the expression of the cancer-related gene CEACAM6. CAS cells showed an increasing trend from normal to tumor regions. Interleukin (IL)-1β+ macrophages, a distinct subtype characterized by a pro-inflammatory M1-dominant gene signature, were abundant in solid components. Spatial transcriptomic analysis revealed that IL-1β+ macrophages and CAS cells were co-localized in specific invasive regions of the solid components, which had elevated EMT and hypoxia signatures. Conclusion: We identified that CAS cells and IL-1β+ macrophages are crucial during the progression from the pre-invasive (GG) to invasive adenocarcinoma (solid component). Targeting CAS cells and IL-1β+ macrophages could be preventive or therapeutic strategies for early LUADs. Citation Format: Junsu Choe, Noeul Kang, Jinyeong Lim, Eun Seop Seo, Mina Hwang, Se-Hoon Lee, Myung-Ju Ahn, Yoon-La Choi, Hong Kwan Kim, Woong-Yang Park, Sang-Won Um. Multiomics analysis of lung adenocarcinoma manifesting as radiological part-solid features in female never-smokers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7174.
Abstract 2311: Temporal trends and HPV attributability in oropharyngeal cancer: A cross-sectional study in multi-racial Singapore
Authors: Yew Mun Lee, Nhi Thi Mai Nguyen, Zhi Yong Lim, Zi Ting Corrina Tan, Jia Qi Gabie Chua, Yirong Dai, Xin Xiu Sam, Jia Hui Isabelle Jang, Eriko Yamada, Kok Hing Lim, Chwee Ming Lim
Journal: Cancer Research (2025)

Abstract Introduction: The purpose of this study is to estimate the proportion of oropharyngeal squamous cell carcinoma (OPSCC) attributable to Human Papillomavirus (HPV) in Singapore across two different time periods (2008-2011 and 2018-2021). Experimental procedures: This non-interventional, cross-sectional study involves the retrospective analysis of pre-treatment OPSCC tissue samples under Singapore General Hospital (SGH) after obtaining institutional ethics approval. Retrospective biobank records of primary OPSCC patients with archival pre-treatment tissue samples from 2008-2011 (cohort 1, n=60) and 2018-2021 (cohort 2, n=60) were retrieved. Both p16INK4a immunohistochemistry staining (IHC) and HPV-DNA testing to determine HPV genotypes for up to 32 HPV genotypes using INNO-LiPA® HPV Genotyping (Fujirebio, Japan)​ were performed. Data on patient demographics, tumor characteristics, and risk factors were collected from medical records and entered a case report form (CRF). Descriptive statistical analyses were performed to determine the HPV-attributable fractions (HPV-AFs) and their corresponding patient characteristics. The current abstract described the results from the cohort 1. Results: The primary outcome of this study is to determine the proportion of OPSCC cases attributable to HPV, defined by the presence of both HPV-DNA and p16INK4a positivity. The secondary outcome is to identify the distribution of HPV genotypes within the HPV-AFs of the two cohorts. In cohort 1, approximately 70% of diagnosed OPSCC cases were men, with HPV-attributable cases making up 20% of the total. Among the HPV-AFs, more than half of the HPV-positive cases were male. HPV16 (83.3%) was the predominant genotype in the HPV-AFs, followed by HPV26 (8.3%) and HPV58 (8.3%). The mean age of cohort 1 was 63.1 years (±11.0). Reflecting Singapore's multi-racial demographic, 68% of cohort 1 were Chinese, and 17% were Indian. Conclusion: Our study fills a critical evidence gap regarding the burden of HPV-related OPSCCs in a multi-ethnic Singaporean community. By comparing the burden of HPVs in OPSCC across the two distinct time periods, this study offers insights into the temporal changes in trends of HPV-attributable OPSCCs. Citation Format: Yew Mun Lee, Nhi Thi Mai Nguyen, Zhi Yong Lim, Zi Ting Corrina Tan, Jia Qi Gabie Chua, Yirong Dai, Xin Xiu Sam, Jia Hui Isabelle Jang, Eriko Yamada, Kok Hing Lim, Chwee Ming Lim. Temporal trends and HPV attributability in oropharyngeal cancer: A cross-sectional study in multi-racial Singapore [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2311.
Abstract 6099: STEAP1 targeting CAR-T cells equipped with collagen-binding IL-12 for advanced prostate cancer
Authors: Koichi Sasaki, Vipul Bhatia, John K. Lee, Jun Ishihara
Journal: Cancer Research (2025)

Abstract Metastatic castration-resistant prostate cancer (mCRPC) is a largely incurable, immunologically cold solid tumor. Six-transmembrane epithelial antigen of the prostate 1 (STEAP1) is a promising target specifically expressed in &amp;gt;85% of mCRPC patients. Chimeric antigen receptor (CAR)-T cells transformed the clinical landscape of blood cancers. However, CAR-T therapy is still not very effective against solid cancers including prostate cancer, in part due to immunosuppressive tumor microenvironment (TME) and antigen heterogeneity. Interleukin-12 (IL-12) is a promising cytokine to address these issues through activation and recruitment of immune cells to the tumor. IL-12 can induce epitope spreading to fight antigen heterogeneity. Previously, armored CAR-T cells that express wild-type (wt) IL-12 were developed, but there is still room for improvement in tuning potency and safety. Adoptive transfer of autologous IL-12-expressing T cells showed objective responses in melanoma patients; however, the trial was limited by toxicity. The result suggests that IL-12 secreted from CAR-T cells are locally produced but still toxic due to the cytokine’s diffusion into systemic circulation. Here, we report STEAP1-targeting CAR-T cells that conditionally express collagen-binding domain fused IL-12 (CBD-IL-12) upon recognizing STEAP1 protein. We show that CBD fusion to IL-12 significantly increased the concentration of IL-12 in mouse prostate tumors and suppressed its systemic spread following secretion from the CAR-T cells. This resulted in equivalently high intra-tumoral levels of interferon-gamma (IFN-γ), C-X-C motif chemokine ligand 9 (CXCL9) and granulocyte-macrophage colony-stimulating factor (GM-CSF) without increase of serum alanine aminotransferase (ALT) and T cell infiltration into non-target organs compared to wt IL-12. Flow cytometric analysis showed increase of T cells, NK cells and cross-presenting dendritic cells and decrease of monocytic myeloid-derived suppressor cells (M-MDSCs) in the tumor following CBD-IL-12 expressing STEAP1 CAR-T cell therapy. CBD-IL-12 expressing CAR-T cells combined with anti-PD-1 and anti-CTLA-4 antibodies eradicated an established mouse prostate cancer model without preconditioning and generated anti-tumor immune memory. CBD fusion to potent yet toxic immunotherapies may make a breakthrough in the development of CAR-T therapy that can safely overcome solid tumors. Citation Format: Koichi Sasaki, Vipul Bhatia, John K. Lee, Jun Ishihara. STEAP1 targeting CAR-T cells equipped with collagen-binding IL-12 for advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6099.
Abstract 7183: METTL1-mediated m7G modification promotes 5-FU resistance in colorectal carcinoma
Authors: Silei Sui, Yuan Li, Rui Su, Man Li, Ajay Goel
Journal: Cancer Research (2025)

Abstract Background: Colorectal cancer (CRC) ranks among the most common malignancies worldwide. Despite 5-fluorouracil (5-FU) being a cornerstone of CRC therapy, resistance to this chemotherapeutic agent occurs in approximately 50-60% of patients, significantly contributing to poor prognosis. Emerging studies have highlighted the role of METTL1, a methyltransferase mediating N7-methylguanosine (m7G) modifications, in promoting tumor progression and drug resistance. However, the specific regulatory mechanisms by which METTL1 contributes to 5-FU resistance in CRC remain poorly understood. Methods: METTL1 expression was analyzed in paired tumor and adjacent normal (AN) tissue specimens in publicly available datasets. Validation of METTL1 dysregulation in CRC tissues and cell lines was performed using qRT-PCR and western blotting (WB), while m7G levels were assessed by northwestern blot. Functional assays, including cell viability, colony formation, apoptosis, and invasion assays, were conducted to evaluate the role of METTL1 in CRC. RNA sequencing (RNA-seq) and m7G Methylated RNA Immunoprecipitation sequencing (MeRIP-seq) were used to identify downstream targets of METTL1 associated with chemoresistance. Results: METTL1 was significantly overexpressed in CRC tissues compared to AN tissues (p&amp;lt;0.001), with high METTL1 levels correlating with unfavorable clinical outcomes in both public datasets and our clinical cohort (p&amp;lt;0.05). Biologically, genetic depletion of METTL1 via CRISPR-Cas9 markedly led to reduced cell proliferation and enhanced apoptosis after 48 hours of 5-FU treatment in HCT116 and SW480 5-FU resistant cell lines. In vivo, METTL1 knockdown significantly enhanced the efficacy of 5-FU in a xenograft mouse model, leading to decreased tumor growth. Mechanistically, METTL1-mediated m7G methylation influenced the translation of mRNAs, including those involved in the TNF and NOTCH1 signaling pathways, both of which are critical in driving 5-FU resistance. Conclusion: This study identifies METTL1-mediated m7G modifications as a pivotal mechanism underlying 5-FU resistance in CRC. By regulating the translation of components in the NOTCH1 signaling pathway, METTL1 drives chemoresistance, presenting a potential therapeutic target to enhance the effectiveness of 5-FU-based treatment regimens in CRC patients. Citation Format: Silei Sui, Yuan Li, Rui Su, Man Li, Ajay Goel. METTL1-mediated m7G modification promotes 5-FU resistance in colorectal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7183.
Abstract 6100: Point-of-care manufacturing of FOLR1-directed CAR T cells for the treatment of ovarian cancer
Authors: Christoph Herbel, Manuel Martinez-Osuna, Larissa Steiner, Maria Bethke, Leon Osinski, Katrin Krischer, Janina Brauner, Cathrin Bleilevens, Jens Kopatz, Katja Petry, Dominik Eckardt
Journal: Cancer Research (2025)

Abstract Treatment options for ovarian cancer patients are limited, highlighting a significant unmet need for targeted, durable, and effective therapies. In recent years, adoptive cell transfer therapies have made tremendous progress in the past years. Genetically engineered T cells expressing a chimeric antigen receptor (CAR) are promising drugs that can be directed towards a defined target and have shown efficient, as well as persisting, anti-tumor responses in different indications. Recently, we have reported the preclinical evaluation of a novel FOLR1-targeting CAR directed against ovarian cancer and potentially other FOLR1-expressing tumors. Despite advancements in T cell therapy, producing a functional and robust cell product in the necessary quantities remains challenging. Currently available processes for the preparation of CAR T are laborious and include numerous manual handling steps, which increase the risk of errors and may impose safety risks. This underscores the need for reliable and automated manufacturing processes to ensure high-quality cellular products for immunotherapy. This study aimed to develop an automated, closed, and good manufacturing practice (GMP)-compliant process for FOLR1-specific CAR T cells. Using the CliniMACS Prodigy® Platform, we established a streamlined process in a closed system that meets stringent regulatory requirements while reducing hands-on time. We optimized culture conditions to reduce the process time to 7 days. Starting from a cryopreserved leukapheresis we achieved a clinically relevant yield of FOLR1-specific CAR-engineered T cells. The cellular product mainly consisted of highly viable CAR-expressing T cells with an early memory phenotype. FOLR1-specific CAR T cells manufactured with the optimized process showed specific killing of ovarian cancer cells in vitro and in an ovarian cancer xenograft model in vivo. Moreover, the automated CliniMACS Prodigy Platform enables point-of-care (POC) manufacturing. In conclusion, we developed a robust, rapid, and efficient process for manufacturing anti-FOLR1 CAR T cells. This platform is well-suited for automated and decentralized POC manufacturing and can be adapted for the production of other CAR T cell therapies. Citation Format: Christoph Herbel, Manuel Martinez-Osuna, Larissa Steiner, Maria Bethke, Leon Osinski, Katrin Krischer, Janina Brauner, Cathrin Bleilevens, Jens Kopatz, Katja Petry, Dominik Eckardt. Point-of-care manufacturing of FOLR1-directed CAR T cells for the treatment of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6100.
In situ implantation of type II collagen-based double-layer scaffolds for Articular Osteochondral Regeneration comprising hyaline cartilage and vascularized subchondral bones
Authors: Zhen Zhang, Ye Huang, Xu Hu, Yulei Mu, Huiqun Zhou, Liang Ma, Bangheng Liu, Hang Yao, Xieyuan Jiang, Dong-An Wang
Journal: Bioactive Materials (2025)