bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A088: Dual-agonist loaded "super adjuvant” nanoparticles as a modular platform for cancer vaccination
Authors: Kane Griffin I , Naylor Tiana E , Lusi Christina F , Brassil Meghan L , Wigglesworth Kim , Mori Haruka , Atukorale Prabhani U 
Published: February 2025

Abstract
We report on the utility of a “super adjuvant” nanoparticle (NP) system as a modular, customizable platform for next-generation cancer vaccination. Using nanomaterials engineering technology, we aim to harness the effective adjuvanticity of whole-pathogen vaccines combined with the safety profile of subunit vaccines. This lipid-based platform uniquely co-encapsulates agonists of the Stimulator of Interferon Genes (STING) and Toll-like Receptor 4 (TLR4) pathways to promote synergistic production of Type I interferons and other proinflammatory cytokines in antigen-presenting dendritic cells (DCs) and macrophages. Compared to empty NPs and free agonists, dual-adjuvant NPs promoted increased antigen processing and presentation, drained efficiently to nearby lymph nodes, increased polyfunctional T and B cells, and improved tumor-free outcomes upon vaccination and subsequent challenge with multiple aggressive tumor cells.
Citation Format: Griffin I Kane, Tiana E Naylor, Christina F Lusi, Meghan L Brassil, Kim Wigglesworth, Haruka Mori, Prabhani U Atukorale. Dual-agonist loaded "super adjuvant” nanoparticles as a modular platform for cancer vaccination [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 A088.
Abstract A090: Novel immunotherapy targeting tumor-induced immune disorder reverses cancer cachexia and prolongs survival
Authors: Zhang Lingbing 
Published: February 2025

Abstract
Introduction: Cancer cachexia is generally recognized as a complex syndrome due to the multiple symptoms that patients suffer including body weight loss, muscle wasting, anorexia, fatigue etc. Despite intense efforts to investigate the mechanisms of those symptoms, the cause of cancer cachexia is still not fully understood. The lack of understanding of the causative mechanisms of cancer cachexia has hindered the development of successful treatments. Given cachexia’s profound effect on multiple organs, it’s clear that the driving mechanism impacts the whole body. Also, since cancer cachexia and immune system disorder coexist in late-stage cancer patients, we look to investigate the role of the immune disorder in cancer cachexia and explore novel immunomodulatory interventions. Methods: To establish cancer cachexia model, 7-week-old BALB/c mice were inoculated with 1 x106 C26 tumor cells subcutaneously. Immunomodulator, R-Ketorolac was given through oral gavage. Results: Significant and multifaceted abnormalities of the immune system underlines cancer cachexia onset and development, including abnormal expression of destructive inflammatory cytokines and dysregulation of multiple immune cell populations. Abnormal expression appears earlier than mice showing cachectic symptoms. Cachexia symptoms begin to manifest when immune abnormalities exceed a certain threshold. Using a newly identified immunomodulator, R-Ketorolac, we found that severe cancer cachexia could be fully reversed. Survival was maintained until termination due to protocol limitation on tumor size. Further studies revealed that R-Ketorolac modulated both cytokine expression and immune cell populations toward a balanced state, thus representing a new type of immunotherapy. This interesting finding from animal studies has been clinically validated on advanced pancreatic cancer patients with cachexia. Conclusion: Cancer cachexia could be completely reversed by a novel immunomodulator, which not only opens a new direction to understanding the mechanism of cancer cachexia and developing long-awaited effective treatments for this lethal syndrome, but also provides a new avenue to create life-saving cancer immunotherapies.
Citation Format: Lingbing Zhang. Novel immunotherapy targeting tumor-induced immune disorder reverses cancer cachexia and prolongs survival [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 A090.
Abstract A091: Rapid engineering of soluble T cell receptors for enhanced affinity via a high-throughput yeast-based platform
Authors: Reyes Saira , Qiao Vivien , McGurk Elizabeth , Lilov Asparouh , Champney Elizabeth , Ahonen Cory , Sivasubramanian Arvind , Krauland Eric , Geoghegan James , Rappazzo C. Garrett 
Published: February 2025

Abstract
T cell receptors (TCRs) enable T cell immunosurveillance of intracellular proteins via recognition of peptide-HLA (pHLA) complexes. Soluble TCR-based CD3 bispecific therapeutics co-opt this recognition and can drive T cell killing of cancerous and infected cells, making them a powerful class of drugs with diverse potential applications. However, native TCRs require substantial affinity maturation against their target pHLAs for use in these therapeutics. Here, we leverage an extensively engineered yeast strain to rapidly generate and characterize TCR variants. Through iterative cycles of affinity maturation, we can identify TCR variants with hundreds-of-thousands-fold improved affinity to their target pHLA, accelerating the pre-clinical development of soluble TCR-based CD3 bispecific therapeutics.
Citation Format: Saira Reyes, Vivien Qiao, Elizabeth McGurk, Asparouh Lilov, Elizabeth Champney, Cory Ahonen, Arvind Sivasubramanian, Eric Krauland, James Geoghegan, C. Garrett Rappazzo. Rapid engineering of soluble T cell receptors for enhanced affinity via a high-throughput yeast-based platform [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 A091.
Abstract A103: Local immunotherapy for endometrial cancer via CD47 blockade
Authors: Yucebas Kerem , Ko Sooah , Khan Omair , Weissman Irving , Jin Shi-Ying 
Published: February 2025

Abstract
A persistent increase in endometrial cancer incidence and mortality reflects the limitations of current therapeutic measures. In this study, we developed a local immunotherapy targeting the immune checkpoint molecule, CD47, which utilizes tissue resident macrophages for the elimination of endometrial cancer (EC). CD47 is a transmembrane protein that serves as a ligand for receptor signal regulatory protein-α (SIRPα) expressed on macrophages. The interaction between CD47 on malignant cells and SIRPa on macrophages inhibits phagocytosis of tumor cells. Our data reveals a high density of tumor-associated macrophages (TAMs) within the human endometrial cancer microenvironment, and that human EC cells upregulate their surface CD47 expression. In vitro functional assay shows that the anti-CD47 monoclonal antibody (mAb) enhances the phagocytosis of human EC cells by macrophages. Both systemic treatment via intraperitoneal injection and local treatment via transvaginal administration with the anti-CD47 mAb effectively reduces tumor burden in vivo in PR-cre +/- ;Pten flox/flox female mice, a genetically engineered mouse model of endometrial cancer. Further efficacy comparison reveals that the local anti-CD47 mAb treatment results in improved outcomes without displaying overt signs of adverse effects. In current practice, transvaginal delivery of treatments for gynecological conditions is used extensively. Thus, local treatment via transvaginal administration of anti-CD47 mAb to facilitate direct and maximal targeting of primary endometrial cancer cells is a feasible and promising avenue for the treatment of EC.
Citation Format: Kerem Yucebas, Sooah Ko, Omair Khan, Irving Weissman, Shi-Ying Jin. Local immunotherapy for endometrial cancer via CD47 blockade [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 A103.
Abstract A108: Sub-clonal copy number variations between on-treatment lesions in immunotherapy resistant melanoma patients
Authors: Yang Muyi , Kolbeinsdottir Solrun , Hammarlund Katarina , Grozman Vitali , Enge Martin , Egyhazi-Brage Suzanne , Helgadottir Hildur 
Published: February 2025

Abstract
Metastatic melanoma is a lethal form of cancer. Immunotherapy is recommended for metastatic melanoma and known to elicit beneficial response even after disease progression per RECIST. On-treatment samples hold irreplaceable predictive value. We collected needle biopsies from the metastases of different body sites from the same patient that progressed upon PD-1 treatment. Leveraging Direct Nuclear Tagmentation and RNA sequencing (DNTR- seq), we conducted single-cell genomic analyses on melanoma metastases and jointly sequenced the transcriptomes of each single melanoma cell. After 3 months of PD-1 inhibitor treatment, single-cell DNA-seq analyses on melanoma metastases from different anatomic locations displayed distinct cancer subclones evidenced by their copy number aberrations. Joint transcriptomic analyses of the dominant genomic subclones from each body site showed converging phenotypes, under the selective pressure of immunotherapy. Our preliminary analyses of on-treatment needle biopsies shed light on the challenges of treating heterogeneous tumors and underscore the pressing need to identify an ideal denominator to reach disease control.
Citation Format: Muyi Yang, Solrun Kolbeinsdottir, Katarina Hammarlund, Vitali Grozman, Martin Enge, Suzanne Egyhazi-Brage, Hildur Helgadottir. Sub-clonal copy number variations between on-treatment lesions in immunotherapy resistant melanoma patients [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 A108.
Abstract A124: Deciphering RIOK2 as a Potential Target for Hepatocellular Carcinoma via Enhancing Tumor Immune Infiltration and experimental in vitro validation
Authors: He Jian 
Published: February 2025

Abstract
Background: RIOK2 is a principal transcription factor (TF) that is a key component of the pro-40S ribosomal complex in its final maturation step. But few studies have proved the rule of RIOK2 in carcinoma, especially in liver cancer. Furthermore, the relationship between RIOK2 and the prognostic potential and tumor-infiltrating immune cells of various cancers remains unclear. Methods: The clinical characteristics and mRNA expression level of RIOK2 were appraised among different databases. The relationship between RIOK2 and immunological infiltration of various types of cancer was determined via TIMER 2.0. Furthermore, RIOK2 inhibitors virtual screening was conducted from the 13633 natural compounds (L6020) and implemented secondary library construction according to the types of top results, then secondary virtual screening was conducted for 367 alkaloids. Finally, in vitro assays of RIOK2 ATPase activity assay, cell viability assays, and colony formation assay were performed to demonstrate the pharmacological potency of the screening RIOK2 inhibitors. Results: RIOK2 expression is higher in most types of tumors than in paracancerous tissues, including liver hepatocellular carcinoma (LIHC). Higher RIOK2 expression correlated with poorer OS, as well as a significant positive association between RIOK2 expression levels and infiltration levels of macrophages, neutrophils, and dendritic cells in LIHC patients. Moreover, we also found that K-252c and 2,3-Bis(3-indolylmethyl)indole are potent inhibitors of RIOK2. We have demonstrated in vitro that K-252c and 2,3-Bis(3-indolylmethyl)indole can inhibit the proliferation and clone formation of HepG2 cell lines by suppressing the expression of RIOK2. Conclusions: The findings showed that RIOK2 appears to be a promising prognostic biomarker for LIHC patients. Besides, K-252c and 2,3-Bis(3-indolylmethyl)indole may be effective therapeutic RIOK2 inhibitors for LIHC patients, providing a theoretical basis for the clinical treatment of LIHC.
Citation Format: Jian He. Deciphering RIOK2 as a Potential Target for Hepatocellular Carcinoma via Enhancing Tumor Immune Infiltration and experimental in vitro validation [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 A124.
Abstract B005: Identification of tumor-reactive TILs from lung cancer organoids co-culture through ruthenium-based proximity labeling
Authors: Hu Weilei , Bian Yifei , Zhao Zihan , Ouyang Shian , Li Jie P. , Ji Hongbin 
Published: February 2025

Abstract
Tumor-reactive T cells are crucial for the success of tumor-infiltrating lymphocyte (TIL) therapies. Currently, identifying tumor-reactive T cells and their corresponding TCRs typically relies on pre-characterized tumor antigens. Many solid tumors, including lung cancer, exhibit considerable heterogeneity and consequently possess diverse tumor antigenic profiles. Markers such as PD-1 and CD39 are commonly used to identify tumor-reactive TILs, yet these empirically derived markers can produce false positives or fail to capture rare tumor-reactive populations. We here used an unbiased ruthenium-based photocatalytic proximity labeling approach to do co-culture of TILs derived from lung cancer and autologous tumor organoids to identify and validate tumor-specific T cells and their TCRs in six NSCLC samples. We found that labeled TILs were significantly enriched for tumor antigen-reactive T cells, which could be readily separated from bystander T cells via flow cytometry. Single-cell TCR and RNA sequencing revealed that labeled TILs, in contrast to bystander TILs, exhibited a distinct TCR repertoire and transcriptional profile, characterized by effector cytotoxic and activation signatures with partial expression of exhausted T cell markers. We selected the top 10 CD8+ TCR clones with the highest labeling intensity and assessed the reactivity of their corresponding TCR-transduced, CD8-overexpressing Jurkat cells against autologous organoids. We identified 5 novel tumor antigen-reactive TCRs that demonstrated tumor responsiveness and these T cells displayed a mixed transcriptional profile, including hallmark markers of exhaustion. Additionally, we identified clonally expanded, cytotoxic CD4+ T cell states within the labeled TILs that could kill autologous tumors in an MHC class II-dependent and/or Fas-FasL-dependent manner. The ruthenium-based photocatalytic proximity labeling approach, which requires no gene editing, enables identification of tumor-reactive TILs and TCRs independent of specific antigen/HLA contexts. This platform, especially when combined with organoid technology, has the potential to streamline the development of personalized TIL and TCR-T cell therapies.
Citation Format: Weilei Hu, Yifei Bian, Zihan Zhao, Shian Ouyang, Jie P. Li, Hongbin Ji. Identification of tumor-reactive TILs from lung cancer organoids co-culture through ruthenium-based proximity labeling [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 B005.
Abstract B007: Targeting the evolving immunopeptidome of metastatic colorectal cancer
Authors: Lee Jaeyop , Scheinberg David A , Ganesh Karuna 
Published: February 2025

Abstract
Chimeric antigen receptor (CAR) T cell therapies have achieved limited success in solid tumors, in part due to challenges in identifying cancer-specific targets. Investigating the immunopeptidome, peptides presented by human leukocyte antigen (HLA) class I molecules, offers an opportunity to expand the repertoire of targetable antigens. Recent findings reveal that metastatic colorectal cancer (mCRC) cells adopt a highly stereotyped fetal-like phenotype, characterized by the activation of a developmental WNT-signaling signature as a mechanism of cell-fate reprogramming. This transcriptional signature, accentuated in metastasis-initiating cells and conserved across diverse patients, is hypothesized to translate into a cancer-specific immunopeptidome. Utilizing an integrated platform, we collected and analyzed resected normal colon, primary tumor, and metastatic lesions from CRC patients, establishing patient-derived organoids (PDOs) that recapitulate CRC cell states ex vivo. Mass spectrometry profiling of PDOs from HLA-A*02:01+ patients identified peptide targets derived from fetal WNT-pathway gene states, referred to as oncofetal protein 1 (OFP1). These peptides were specific to CRC, absent in healthy tissues, and demonstrated immunogenicity through healthy donor T cell reactivity and expansion assays. To further harness these findings, we aim to systematically profile the immunopeptidome evolution from normal colon to metastatic CRC to identify conserved CRC-specific peptides for therapeutic targeting. Furthermore, we employed large-scale yeast display technology to isolate peptide-centric T cell receptor mimics (TCRms) that specifically recognize OFP1 peptides presented by HLA-A*02:01. Preliminary results demonstrate the successful isolation of OFP1-specific, HLA-A02:01-restricted TCRms, paving the way for the development of TCRm-based CAR T cells tailored for CRC therapy. This work provides the first comprehensive atlas of immunopeptidome evolution in CRC, elucidates CRC-specific intracellular molecular signatures as potential therapeutic targets, and advances the preclinical development of TCRm-engineered CAR T cells, paving the way for precision immunotherapies in metastatic CRC.
Citation Format: Jaeyop Lee, David A Scheinberg, Karuna Ganesh. Targeting the evolving immunopeptidome of metastatic colorectal 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 B007.
Abstract B015: Local delivery of mRNA lipid nano particles encoding an autoactivated cGAS mutant and membrane-tethered IL-12 enhances local and distal tumor control
Authors: Zhang Anli , Chen Zhijian (James) 
Published: February 2025

Abstract
Local cancer treatments are often effective in controlling primary tumor growth. However, the abscopal effect induced by local treatment—critical for treating metastatic tumors—is rarely achieved and particularly challenging in less immunogenic tumors. Here, we report that local administration of lipid nanoparticles (LNPs) containing mRNAs encoding an autoactivated cyclic GMP-AMP (cGAMP) synthase (cGAS) R241E mutant and membrane-tethered IL-12 (IL-12TM) induces potent local and systemic tumor control in multiple non-immunogenic murine models, including B16 and TC-1 tumors. The cGAS R241E mutant but not wild-type cGAS mRNA LNPs spontaneously produce cGAMP in vivo and predominately activate conventional DC1, enhancing innate immune sensing and inhibiting tumor growth in a host STING-dependent manner. IL-12TM mRNA LNPs synergize with cGAS R241E mRNA LNPs to promote local IFN-γ production while minimizing systemic exposure compared to soluble IL-12 mRNA LNPs. Mechanistically, combining cGAS R241E and IL-12TM mRNA LNPs (Combo) enhances dendritic cell activation and stimulates antigen-specific CD8+ T cells within the tumor, facilitating their migration to draining lymph nodes. While the multiple immune cell populations contribute to anti-tumor efficacy against local tumors, CD8+ T cells and intact IFN-γ signaling are responsible for distal tumor control. Additionally, Combo treatment synergizes with PD-L1 checkpoint blockade to further reduce distal tumor burden. Taken together, these findings demonstrate that mRNA LNP-mediated delivery of the autoactivated cGAS mutant and IL-12TM provides a safe and effective strategy for treating both primary and metastatic tumors.
Citation Format: Anli Zhang, Zhijian (James) Chen. Local delivery of mRNA lipid nano particles encoding an autoactivated cGAS mutant and membrane-tethered IL-12 enhances local and distal tumor control [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 B015.
Abstract B018: Ex vivo modeling of precision immuno-oncology responses in lung cancer
Authors: Alsaed Bassel , Smolander Johannes , Linh Lin , Bobik Nina , Laitinen Hanna , Lahtinen Lilja , Räsänen Mikko , Jansouz Shadi , Peltonen Karita , Jokinen Emmi , Klievink Jay , Ainola Mari , Sutinen Eva , Saharinen Pipsa , Mustjoki Satu , Ilonen Ilkka , Haikala Heidi 
Published: February 2025

Abstract
Immunotherapy has transformed cancer treatment, offering promising outcomes even in previously incurable cancers. However, responses to immuno-oncology (IO) treatments remain limited, with only a fraction of patients benefiting from these therapies. This limited efficacy arises from a lack of predictive biomarkers, unknown mechanisms of immune resistance, and the complex tumor-immune interactions, making it challenging to predict which patients will benefit from these costly treatments. To address these issues, we developed a precision ex vivo platform that integrates patient-specific tumor and immune cells to study the mechanisms of antitumor immune response, predict immunotherapy outcomes, and identify effective treatments. In order to establish this, we first stimulate patient-derived immune cells with autologous tumor organoids, followed by a tumor-killing assay using the stimulated immune cells in the presence or absence of different IO combinations. Lastly, single-cell sequencing is performed across different treatment conditions to reveal changes in immune and tumor cells following their interactions. Our ex vivo model demonstrated the ability to mimic primary resistance to anti-PD-1 therapy in lung cancer, enabling the identification of individual responders to anti-PD-1 combination with chemotherapy agents. Additionally, we identified a synergistic IO-drug combination: anti-PD-1 with a Cbl-b inhibitor, which successfully overcame anti-PD-1 resistance in some patients. Moreover, interferon gamma-stimulated cytokines were predictive of combination efficacy, whereas the presence of immunosuppressive cytokines correlated with poor response. Finally, single-cell sequencing revealed immune response mechanisms and sensitivities to standard of care immunotherapies. Our findings underscore the platform's potential in tailoring immunotherapies and advancing drug development, offering new avenues for personalized cancer treatment.
Citation Format: Bassel Alsaed, Johannes Smolander, Lin Linh, Nina Bobik, Hanna Laitinen, Lilja Lahtinen, Mikko Räsänen, Shadi Jansouz, Karita Peltonen, Emmi Jokinen, Jay Klievink, Mari Ainola, Eva Sutinen, Pipsa Saharinen, Satu Mustjoki, Ilkka Ilonen, Heidi Haikala. Ex vivo modeling of precision immuno-oncology responses in lung 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 B018.