bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B010: Targeting Metastatic Prostate Cancer with STEAP1 CAR T Cells and Tumor-Localized Immunomodulation
Authors: Bhatia Vipul , Koichi Sasaki , Jun Ishihara , Lee John K 
Published: February 2025

Abstract
Metastatic castration-resistant prostate cancer (mCRPC) is a major cause of cancer-related deaths among men in the United States, with limited effectiveness from current cancer immunotherapies due to prostate cancer’s immunologically ‘cold’ nature. Chimeric antigen receptor (CAR) T cell therapies have transformed treatment paradigms in hematologic cancers, but achieving similar success in solid tumors like prostate cancer remains challenging. Most current CAR T cell therapies for prostate cancer target prostate-specific membrane antigen (PSMA) or prostate stem cell antigen (PSCA); however, the heterogeneous expression of these antigens in mCRPC underscores the need for new, more widely expressed targets. Six-transmembrane epithelial antigen of the prostate 1 (STEAP1) presents a promising alternative target, with more consistent expression in mCRPC compared to PSMA. Here, we report the development of a second-generation STEAP1 CAR T cell therapy optimized for activity even at low antigen densities. Our STEAP1 CAR T cells demonstrated potent anti-tumor efficacy and prolonged persistence in preclinical mCRPC models, including human-in-mouse (C4-2B, 22Rv1) and mouse-in-mouse (RM9) systems. Safety was confirmed using a human STEAP1 knock-in mouse model, where no significant toxicities were observed. Despite this efficacy, antigen escape mechanisms remain a barrier to sustained response. To counter this, we explored the combination of STEAP1 CAR T therapy with tumor-localized interleukin-12 (IL-12) therapy. We engineered an “armored” variant by combining STEAP1 CAR T cells with a tumor-localized collagen binding domain (CBD)-IL-12 fusion protein, which promotes anti-tumor immunity, remodels the immunosuppressive tumor microenvironment, and reduces antigen escape through enhanced host immunity and epitope spreading. Our develpoed STEAP1 CAR T cell therapy has entered clinical trials, supported by the NCI NExT Program, with open enrollment now underway. These trials will explore CAR T cell persistence, expansion, trafficking, tumor microenvironment interactions, and mechanisms of resistance. In parallel, research is underway to further optimize metabolic fitness and efficacy through innovative strategies, including armored CARs with pro-inflammatory cytokines, and dual antigen targeting next-generation CAR T designs. This comprehensive approach aims to overcome the current limitations of CAR T cell therapy in treating mCRPC and enhance durable responses in this challenging disease.
Citation Format: Vipul Bhatia, Sasaki Koichi, Ishihara Jun, John K Lee. Targeting Metastatic Prostate Cancer with STEAP1 CAR T Cells and Tumor-Localized Immunomodulation [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B010.
Abstract B031: CD27-independent tonic immune checkpoint CD70 signaling provides anti-cancer drug resistance to malignant B cell lymphoma
Authors: Kim Jaemin , Lee Jaewoong 
Published: February 2025

Abstract
CD70 and its ligand CD27 are immune checkpoint molecules that are abnormally expressed in various hematological malignancies. Simultaneous expression of CD70 and CD27 in cancer cells promotes stemness, proliferation, and survival of these malignancies. Moreover, CD70 in cancer cells binds to CD27 in Treg, leading to survival of Treg, which contributes to immune evasion within the tumor microenvironment. We found that the expression of CD70, but not CD27, is induced upon engagement of B cell receptor (BCR). Malignant B cells that harbor constitutively active BCR signaling, therefore, highly expressed CD70 with no correlation of CD27 expression. Interestingly, we found CD70 was a CD27-independent biomarker predicting poor clinical outcomes in diffuse large B-cell lymphoma (DLBCL). To analyze how CD70 independently contributes to malignancy in DLBCL, we generated CD70-deficient DLBCL cells using non-viral CRISPR electroporation. Surprisingly, CD70-deficient lymphoma cells exhibit downregulation of BCL2 family expression, increased apoptosis, and increased sensitivity to vincristine, doxorubicin, and cyclophosphamide. These results indicate that CD70 contributes to chemotherapy resistance independently of CD27. To target the high expression of CD70 that contributes to chemotherapy resistance, we analyzed public Chip-seq data. This analysis revealed that STAT3 acts as a transcription factor for CD70. Consistently, CRISPR-mediated deletion of STAT3 in lymphoma cells dramatically downregulated surface expression of CD70 in parallel with increased anti-cancer drug sensitivity. Therefore, Ruxolitinib, a JAK1/2 kinase inhibitor, leads to decreased CD70 expression by disrupting the JAK-STAT3 signaling pathway, further overcomes chemotherapeutic drug resistance. Ultimately, to effectively eliminate cd70-high malignant b cells that are resistant to conventional chemotherapy, we developed a bike (bispecific nk cell engager) targeting both CD70 and CD16, and testing its immuno therapeutic efficacy.
Citation Format: Jaemin Kim, Jaewoong Lee. CD27-independent tonic immune checkpoint CD70 signaling provides anti-cancer drug resistance to malignant B cell lymphoma [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B031.
Abstract B040: Transcriptomic meta-analysis identifies robust, tissue-agnostic gene expression signature of immune checkpoint blockade response
Authors: Guo Yu Amanda , Tan Aaron , Kulshrestha Tanmay , Chang Mei Mei , Lau Dawn , Wang Lan Ying , Tay Timothy , Kassam Irfahan , Revkov Egor , Rizzetto Simone , Tan Iain , Tan Daniel , Skanderup Anders 
Published: February 2025

Abstract
Immune-checkpoint therapy (ICB) has conferred significant and durable clinical benefit to some cancer patients. However, most patients do not respond to ICB, and reliable biomarkers of ICB response are needed to improve patient stratification. Here, we performed a transcriptome-wide meta-analysis across 1,486 tumors of 5 cancer types from ICB-treated patients and tumors with expected ICB outcomes based on microsatellite status. Using a robust transcriptome deconvolution approach, we inferred cancer and stroma-specific gene expression differences and identified cell-type specific features of ICB response across cancer types. Our analysis revealed a lack of cancer-cell intrinsic gene expression signatures associated with ICB response across tumor types. Strikingly, PD-L1 expression in stromal cells, but not cancer cells, is correlated with ICB response across cancer types. In stromal cells, we identified multiple immunomodulators and checkpoint genes associated with ICB response across cohorts and tumor types. Many of these genes, such as CXCL9, CXCL13, and IFNG, have previously been linked with ICB response. In addition, we uncovered a subset of novel and potentially immune-suppressive genes, including FCER1A, that negatively correlated with response. Using these conserved stromal-specific gene signatures, we developed a multivariate classifier of ICB response that demonstrated improved accuracy over existing biomarkers in unseen patient cohorts and tumor types, including a cohort of 50 newly sequenced late stage lung cancer patients treated with ICB. In summary, our unbiased transcriptome-wide analysis failed to identify cancer-cell intrinsic expression signatures of ICB response conserved across tumor types, suggesting that cancer cells lack tissue-agnostic transcriptomic features of ICB response. Our results challenge the prevailing dogma that cancer cells present tissue-agnostic molecular markers that modulate immune activity and ICB response, which has implications on the development of improved ICB diagnostics and treatments.
Citation Format: Yu Amanda Guo, Aaron Tan, Tanmay Kulshrestha, Mei Mei Chang, Dawn Lau, Lan Ying Wang, Timothy Tay, Irfahan Kassam, Egor Revkov, Simone Rizzetto, Iain Tan, Daniel Tan, Anders Skanderup. Transcriptomic meta-analysis identifies robust, tissue-agnostic gene expression signature of immune checkpoint blockade response [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B040.
Abstract B045: Siglec receptors suppress T cell immunity via trogocytosis and represent degradable targets for cancer immunotherapy
Authors: Wang Chao 
Published: February 2025

Abstract
Cancer therapy has been rapidly transformed by the development of immune checkpoint inhibitors targeting CTLA-4 and PD-1/PD-L1. However, many patients fail to respond, particularly those with an immunosuppressive tumor microenvironment (TME), suggesting the existence of additional immune checkpoints that act through orthogonal mechanisms. To overcome therapeutic resistance, identifying and targeting new types of checkpoints, such as glycan-binding immune checkpoints, may offer a promising strategy to reprogram the TME by suppressing tumor-promoting factors. Sialic acid-binding immunoglobulin-like lectin (Siglec) receptors, especially the inhibitory members constitutively expressed on myeloid cells, play an immunosuppressive role in innate immunity. Here, we identify Siglec-7 and -9 immunosuppressors as novel glyco-immune checkpoints that inhibit T cell function and anti-tumor immunity. We discovered that T cells in the TME acquire these Siglec checkpoints from myeloid cells via trogocytosis, impairing T cell activity by dephosphorylating T cell receptor (TCR)-related signaling pathways through engagement with tumor-associated sialoglycans. Using sulfur(VI) fluoride exchange (SuFEx) click chemistry, we developed a high-affinity ligand specific for Siglec-7 and -9, and converted it into a degrader for targeted lysosomal degradation of both Siglecs. This degrader efficiently reduced Siglec levels in T cells and myeloid cells, significantly restoring T cell function and enhancing anti-tumor immunity. The degrader, particularly when combined with anti-CTLA-4, reshaped the TME and generated durable T cell memory, resulting in excellent tumor control in multiple murine models. These findings underscore the significance of degrading exogenously acquired Siglec checkpoints on T cells as a novel strategy to overcome resistance to established checkpoint inhibitors in cancer immunotherapy.
Citation Format: Chao Wang. Siglec receptors suppress T cell immunity via trogocytosis and represent degradable targets for cancer immunotherapy [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B045.
Abstract B047: Stromal senescence and response to immune checkpoint inhibition in melanoma
Authors: Sojo Giselle Burton , Schmidt Marcel O 
Published: February 2025

Abstract
Melanoma is the 8th most commonly diagnosed cancer in the United States, predominantly driven by exposure to UV radiation leading to an abundant oncogenic mutational burden. However, very few models incorporate these mechanisms in their representation of the disease significantly influencing treatment responses. To address this, our lab uses the Yale University Melanoma Model (YUMM) irradiated cell line that contains clinically represented mutations that are imperative to melanoma development. As a result, these cells are sensitive to combination immune checkpoint inhibition making them a superior system to study the immune response in melanoma over less representative lines such as B16. These cells are injected into a syngeneic in vivo murine system C57/Bl6 INK-ATTAC mice with a senescent cell depletion cassette exclusively expressed in the host stroma, incorporating cellular senescence as a key contributor to the host response to cancer. This dual system allows for the exploration of the immune response that patients experience after receiving ICI treatment in concert with senescent stromal cell burden in the tumor microenvironment (TME). INK-ATTAC mice bearing single cell clone YUMM tumors are treated with a combination of immune checkpoint inhibitors (aPD-1+aCTLA-4) to generate both responder and non-responder phenotypes. Upon clearance of senescent cells from the TME via injection of AP20187, the proportions of these response phenotypes shift in both pro- and anti-tumor directions. Immunohistochemical analyses show a significant negative correlation of immune infiltration with tumor size, where T cells show a 2-fold increase as tumor size is reduced as a result of ICI and AP+ICI treatment. More in-depth analysis of tumor infiltrating lymphocytes and myeloid cells through Cytometry Time of Flight (CyTOF) of a specific single cell clone reveal that the proportions of immunosuppressive myeloid cells to cytotoxic T cells are key drivers of response phenotypes in AP+ICI treated tumors. Our findings suggest that stromal cellular senescence potentially have pro- and anti-tumor effects, thus influencing both treatment efficacy and resistance mechanisms that prevent response to immune checkpoint inhibition.
Citation Format: Giselle Burton Sojo, Marcel O Schmidt. Stromal senescence and response to immune checkpoint inhibition in melanoma [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B047.
Abstract B067: An antigen-specific t cell stimulation and expansion platform for immunological investigation of the Ad5.F35-GUCY2C-PADRE vaccine in gastrointestinal cancers
Authors: Sun Zhengyang , Singh Jagmohan , Cao Miao , Glowacki Anne , Zhan Tingting , Bashir Babar , Waldman Scott A , Snook Adam E 
Published: February 2025

Abstract
Background: Collectively, cancers of the esophagus, stomach, pancreas, and colorectum (“GI cancers”) are the leading cause of cancer-related death. Despite standard of care, 30-90% of GI cancer patients experience tumor recurrence. In colorectal cancer (CRC), guanylyl cyclase C (GUCY2C), a transmembrane heat-stable enterotoxin receptor, is overexpressed in more than 95% of colorectal tumors and in subsets of gastroesophageal and pancreatic tumors. We are conducting a Phase 2A, dose-finding, single-center, open-label, randomized trial (NCT04111172) to evaluate the safety and immunogenic activity of three dose levels of the Ad5.F35-GUCY2C-PADRE vaccine in adult patients with select solid tumors (colorectal, pancreatic, or gastroesophageal) who are at high risk of relapse following definitive surgery and adjuvant therapy. To further investigate the immunogenicity of the GUCY2C-targeting vaccine across diverse patient populations and facilitate downstream laboratory-based studies—such as autologous T cell expansion, TCR sequencing and cloning, and in vivo patient-derived xenograft (PDX) models—we explored the feasibility of a protocol for the stimulation and expansion of antigen-specific T cells derived from peripheral blood mononuclear cells (PBMCs). Methods: PBMCs from healthy donors were used as a pilot to optimize this protocol and assess its efficacy. PBMCs were cultured in vitro for approximately 10 days with adjuvants, cytokine cocktails, and antigen-specific peptides. The enriched T-cell populations were then evaluated for antigen-specific targeting using flow cytometry and ELISPOT analysis. Results and Conclusion: The stimulation protocol successfully expanded both CD4+ and CD8+ effector T cells. The final T cell population was predominantly CD8+ T cells, which secreted IFNγ following CEF (CMV, EBV, Influenza), but not MOG (self-antigen myelin oligodendrocyte glycoprotein) peptide stimulation, indicating antigen-specific reactivity of the expanded T cells. Further studies, including cytotoxicity assays and antigen-presenting cell (APC)-based longitudinal expansion, are necessary to support the high-throughput application of this protocol for future preclinical and clinical investigations.
Citation Format: Zhengyang Sun, Jagmohan Singh, Miao Cao, Anne Glowacki, Tingting Zhan, Babar Bashir, Scott A Waldman, Adam E Snook. An antigen-specific t cell stimulation and expansion platform for immunological investigation of the Ad5.F35-GUCY2C-PADRE vaccine in gastrointestinal cancers [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B067.
Abstract B072: Circulating tumor DNA as a prognostic, diagnostic, and clinical assessment tool for evaluation and management of Ewing's sarcoma: a systematic review
Authors: Yerigeri Keval 
Published: February 2025

Abstract
Introduction: Circulating tumor DNA (ctDNA) can be analyzed noninvasively to obtain valuable information for genetic profiling, prognostication, and disease progression/ response to treatment. Use of ctDNA is not routine for Ewing’s sarcoma (EWS), but well-known driver mutations (e.g., EWSR1-FLI1, EWS-ERG) makes for straightforward identification by genomic sequencing or PCR techniques. We review the current literature on applications of ctDNA for EWS. Methods: The PubMed database was queried for all articles on Ewing sarcoma and circulating tumor DNA; 81 hits were identified per the search strategy. Articles were then screened by the eligibility criteria: (1) human patients with definitive, histopathological EWS, (2) analysis of ctDNA (not RNA) from peripheral blood specimens (e.g., serum, plasma), (3) articles are original; not reviews, editorials, or duplicates. N=32 articles met all criteria. Results: 7 studies were case reports or series with single EWS cases. 3 studies specifically used ctDNA to assess for stem cell contamination prior to harvesting; ctDNA was used to associate tumor cell contamination with increased risk of recurrence (including in non-metastatic primary disease per one study). 2 studies use ctDNA to trend disease response to treatments (10 patients each). Of the remainder, 3 studies used whole genome sequencing (116 patients total), 2 used next generation sequencing (86 patients), 6 used digital droplet PCR (168 patients), 4 used real-time PCR (115 patients), and 1 used multiplex PCR (3 patients). Conclusion: This review provides comprehensive evidence for the utility of ctDNA in identifying driver translocations, copy number alterations, and other genetic targets for trending disease state and response to treatment. Digital droplet PCR is the most widely used and appears to be the most efficient method. Further analysis will integrate the results with the aims of standardizing ctDNA use in EWS management.
Citation Format: Keval Yerigeri. Circulating tumor DNA as a prognostic, diagnostic, and clinical assessment tool for evaluation and management of Ewing's sarcoma: a systematic review [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B072.
Abstract B073: MOMP-dependent cytotoxicity and immunogenicity of radiation therapy in breast cancer
Authors: Beltrán-Visiedo Manuel , Soler-Agesta Ruth , Guilbaud Emma , Sato Ai , Galluzzi Lorenzo 
Published: February 2025

Abstract
In 2023, an estimated 297,790 new cases of invasive breast cancer (BC) have been diagnosed to women in the US, causing an estimated 55,720 deaths, most of which originated from hormone receptor (HR+) BC. In this sense, radiation therapy (RT) has attracted attention as a potential tool to convert HR+ BCs that are scarcely infiltrated by immune cells (so-called ‘cold’) into highly infiltrated (so-called ‘hot’) immune checkpoint blockers (ICB)-responsive tumors thanks, among other factors, to the release of damage-associated molecular patterns (DAMPs), which promote the recognition of cancer cell death as immunogenic. In line with this notion, RT has been shown to positively interact with ICBs in preclinical models of mammary carcinoma, melanoma, glioma and glioblastoma, among others. Mitochondrial outer membrane permeabilization (MOMP) as mediated by BCL2 associated X, apoptosis regulator (BAX) and BCL2 antagonist/killer 1 (BAK1) and antagonized by BCL2, apoptosis regulator (BCL2) has been shown to regulate both the cytotoxicity and immunostimulatory potential of various anticancer agents. Here, we harnessed mouse mammary carcinoma TS/A cells bearing genetic alterations that affect the molecular machinery for MOMP to demonstrate their implications in the cytotoxic effect of RT and short-term release of the cell death-related DAMPs. In our hands, RT did not induce cell death in Bax -/- Bak1 -/- TS/A cells 48 h after exposition and in contrast to wild type (WT) cells, but it completely stopped their proliferation. Moreover, (1) MOMP defects failed to alter the ability of RT to elicit the immunogenic cell death (ICD)-associated exposure of calreticulin (CALR) on the outer leaflet of the plasma membrane. Additionally, (2) MOMP-deficient cells completely reduced their ability to release ATP after RT and (3) increased the levels of the co-inhibitory ligand CD274 (best known as PD-L1) on their surface in contrast to WT cells. These results highlighted the potential involvement of MOMP in the immunogenicity of RT-driven cell death.
Citation Format: Manuel Beltrán-Visiedo, Ruth Soler-Agesta, Emma Guilbaud, Ai Sato, Lorenzo Galluzzi. MOMP-dependent cytotoxicity and immunogenicity of radiation therapy in breast cancer [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B073.