tbuckley/cabot-search huggingface dataset:
Abstract 36: The discovery of a novel CD19xCD22 dual-targeting CAR for the development of an IPSC-derived cell therapy
Authors: Jill M. Carton, John Wheeler, Chris Dower, Liam Campion, Hillary J. Millar, Marilda Beqiri, Barry Morse, Buddha Gurung, Rebecca Genovese, Steven DeLuca, Charles Dominick, Michael Naso, Hy Levitsky
Journal: Cancer Research (2024)

Abstract Dual-targeting cell therapies to address CD19 antigen loss in heme malignancies are being explored by Century Therapeutics and others for unmet clinical need in hematological malignancies. CD22 chimeric antigen receptor (CAR) T-cell therapies have shown promising efficacy in relapsed or refractory B-lineage acute lymphoblastic leukemia (B-ALL) alone and in combination with CD19 CAR-T cell therapies (1,2). CD22 is a multi-domain glycoprotein expressed on B-cells. Natural splice variants of CD22 can exclude domains near the N-terminus, allowing for therapeutic resistance when these domains are targeted. We identified novel single domain antibodies (VHH) to CD22 that bind to multiple epitopes on different domains of CD22, including membrane proximal binders. The VHHs were affinity matured to enhance cell-based binding and formatted as CARs in monovalent and tandem, bivalent formats. Our data demonstrates the best efficacy against CD22+ tumor cells with a biparatopic, tandem VHH CAR format. Through additional engineering, bispecific CARs that combined three CD22-binding VHH and the anti-CD19 scFv, FMC63, in a loop CAR configuration were designed and tested. This CD19xCD22 bispecific, CD22 biparatopic CAR was engineered into primary T-cells and demonstrated cytotoxicity activity against CD19 and CD22 positive tumor cells as well as CD19 knockout and CD22 knockout cell lines. CD19xCD22 bispecific primary CAR-T cells were efficacious in controlling tumors in mouse xenograft models. This novel CAR is being tested in IPSC-derived iT and iNK cells for off-the-shelf allogeneic cell therapy to expand patient access beyond CD19 CAR-T cell therapies. Ref: 1. Nat Med. 2018;24(1):20-28. doi: 10.1038/nm.4441. 2. Blood. 2018;132(suppl 1). Abstract 27 Citation Format: Jill M. Carton, John Wheeler, Chris Dower, Liam Campion, Hillary J. Millar, Marilda Beqiri, Barry Morse, Buddha Gurung, Rebecca Genovese, Steven DeLuca, Charles Dominick, Michael Naso, Hy Levitsky. The discovery of a novel CD19xCD22 dual-targeting CAR for the development of an IPSC-derived cell therapy [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 36.
Abstract 3993: A tunable safety switch for solid tumor CAR T-cell therapy
Authors: Kyohei Misawa, Meriem Taleb, Srijita Banerjee, William-Ray Vista, Navin K. Chintala, Prasad S. Adusumilli
Journal: Cancer Research (2024)

Abstract On-target off-tumor toxicity, cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS) are severe immune-related adverse events (irAEs) that are frequently associated with Chimeric Antigen Receptor (CAR) T-cell therapy. Current efforts to manage such therapy-related toxicities involve incorporation of an inducible suicide agent within CAR constructs, such as iCaspase-9 or herpes simplex virus type 1 thymidine kinase that can be selectively activated to produce toxic effects within CAR T cells and attenuate their activity. However, while activation of these agents helps to mitigate or overcome such unwarranted toxicities, the therapeutic benefit of CAR T cells anti-tumor activity is also compromised. Therefore, to continue maintenance of CAR T cells’ therapeutic function while minimizing irAEs, an ideal safety switch should 1) rapidly inhibit the activation and proliferation of CAR T cells exposed to the target antigen, 2) reversibly inhibit activity without inducing CAR T cell elimination and 3) be clinically translatable for safe application in patients. Our laboratory investigated one such safety switch to inhibit CAR T-cell activity while maintaining their therapeutic function. We showed that incorporating a mutant variant of c-KIT D816V (KITv) in the intracellular domain of mesothelin-targeting second-generation CAR T cells (M28z-KITv) improved efficacy in solid tumors with low antigen, or an immunosuppressive environment. Herein, we evaluate the use of Dasatinib, a clinically available multitarget (BCR, SRC, c-KIT) tyrosine kinase inhibitor (TKI), as a tunable safety switch to reversibly inhibit M28z-KITv CAR T-cell functional activity. In cohorts of mice established with lung adenocarcinoma, daily administration of Dasatinib starting on day 1 or day 3 after CAR T-cell administration stabilized tumor growth, which otherwise continued to regress in untreated mice, indicating inhibition of CAR T-cell functional activity. Upon discontinuation of Dasatinib, tumors regressed, indicating reversal of CAR T-cell functional activity. In an experiment conducted to investigate functional persistence of CAR T cells upon long-term exposure to Dasatinib (1 month), we noted uninhibited activity of CAR T cells to rechallenged tumors. Dasatinib, thus may act as a tunable safety switch to regulate M28z-KITv CAR T-cell activity without compromising its therapeutic function. Citation Format: Kyohei Misawa, Meriem Taleb, Srijita Banerjee, William-Ray Vista, Navin K. Chintala, Prasad S. Adusumilli. A tunable safety switch for solid tumor CAR T-cell therapy [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 3993.
Abstract 3545: Atlas of therapeutic targets: Evolution of druggable proteome
Authors: Ivan Babic, Elmar Nurmemmedov
Journal: Cancer Research (2024)

Abstract Selection of therapeutic targets and modalities is of fundamental importance in drug discovery, as it can have a direct impact on the economics of drug discovery as well as its success rate. With the advancement of chem-bio and proteomics methods together with advent of artificial intelligence, the scope of the druggable proteome is expanding. The choice of drug targets gains further importance as we link it to potential clinical efficacy and safety, genetic variation and patient populations. Drug targets are often selected based on inadequate understanding of target biology, tractability by existing toolbox of therapeutic modalities and insufficient insight into possible clinical outcome. We have developed an “Atlas of Therapeutic Targets”, an interactive resource that provides classification of drug target families with linked information on clinical and investigational drugs. The atlas also provides key insights and score for tractability of targets with various therapeutic modalities. Particularly, our scoring system grades the targets on dimensions such as ligandability, involvement in protein-protein complexes, structural disorder, hotspot analysis and cross-referencing with known targets, thus yielding a total tractability score of 1-10. Dissection of targets based on such dimensions, enables critical evaluation therapeutic modalities as well tools and methodologies needed for their conversion into successful drug discovery programs. We curate 900+ human drug targets, analysis of which indicates the continued dominance of privileged target families across disease areas, but also the growth of novel first-in-class mechanisms. This atlas will be available as a resource for the wide drug discovery community. Citation Format: Ivan Babic, Elmar Nurmemmedov. Atlas of therapeutic targets: Evolution of druggable proteome [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 3545.
Abstract 6993: SLC1A4 is associated with metabolic reprogramming in triple-negative breast cancer
Authors: Soo Young Park, Da Sol Kim, Hayeon Kim, Min Ji Song, Han Suk Ryu
Journal: Cancer Research (2024)

Abstract The solute carrier protein (SLC) family is transporters as integral membrane proteins that transport solutes in an ATP-independent manner. The SLC1 family consists of five high-affinity glutamate transporters and two neutral amino acid transporters, among which SLC1A4 transports the neutral amino acids and is known to participate in various biological processes, including metabolism and tumorigenesis. However, the relationship between SLC1A4 and breast cancer remains unclear. Here, we aimed to verify the role of SLC1A4 in triple-negative breast cancer (TNBC). To reveal the characteristics of SLC1A4 in TNBC cell lines, five cell lines (HCC38/OE, HCC1395/OE, HCC1937/OE, MDA-MB-468/KD, and Hs578T/KD) that regulate gene expression of SLC1A4 were established using a lentiviral system. The two major energy-producing pathways, glycolysis and oxidative phosphorylation, were measured according to SLC1A4 gene expression. In addition, cell proliferation, cell migration, and cell invasion ability were confirmed upon overexpression or knock-down of SLC1A4. To confirm cancer stem cell function according to SLC1A4 gene expression, ALDH activity and sphere formation ability were evaluated. To ensure transcript changes due to SLC1A4 expression, RNA sequencing was performed. Anti-cancer drug (cisplatin, carboplatin, paclitaxel, and doxorubicin) sensitivity was also tested. The result showed that energy production efficiency was significantly reduced in cells where SLC1A4 expression was suppressed. In addition, in cells overexpressing the SLC1A4 gene, the presence of SLC1A4 was confirmed to increase cell proliferation, migration, and invasion ability significantly. Transcriptome analysis results showed notable changes in genes related to signaling receptor binding. Regarding material transport, to investigate whether there was a change in amino acid uptake ability according to SLC1A4 gene expression, no difference was observed. In the drug responses, doxorubicin showed a significant sensitive response in the absence of SLC1A4 gene expression. Taken together, SLC1A4 is a potential oncogene that not only induces rapid proliferation, aggressive invasion, and migration through metabolic reprogramming but also contributes to increasing cancer stem cell capabilities. In addition, it shows the sensitive response to ADR when SLC1A4 is low or absent, so it can be used as a treatment strategy for TNBC. Citation Format: Soo Young Park, Da Sol Kim, Hayeon Kim, Min Ji Song, Han Suk Ryu. SLC1A4 is associated with metabolic reprogramming in triple-negative breast 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 6993.
Abstract 1860: The smallest antibody class: Cow ultralong CDR3 knobs as a new class of biomolecule for therapeutics and diagnostics
Authors: Vaughn Smider
Journal: Cancer Research (2024)

Abstract Engineered antibodies, including bispecifics and ADCs, are now a major drug class for oncology and other therapeutic areas. There are two fundamental antibody fragments: the Fv (heavy and light chain variable region fragments, derived from most species), and VHH (heavy chain ‘only’ V regions, derived from camelids and sharks). Cows produce antibodies with an unusually long VH CDR3 region, which can be up to seventy amino acids in length and is comprised of a β-ribbon “stalk” and disulfide-bonded “knob” minidomain which sits atop the stalk. The knob region is highly diverse and can bind cryptic epitopes with high affinity. We recently developed the technology to produce knob domains independently of the antibody, and at ~5 kDa are the smallest functional antibody fragment (https://doi.org/10.1073/pnas.2303455120). The high stability and small size could enable improved tissue penetration and development of novel therapeutics, including knob-drug conjugates or extremely small bispecific molecules. Citation Format: Vaughn Smider. The smallest antibody class: Cow ultralong CDR3 knobs as a new class of biomolecule for therapeutics and diagnostics [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 1860.
Abstract 7: Ginsenoside Rb1 delays the senescence of CD8+ T cells to expand T cells with superior antitumor immunity
Authors: Chunhong Ma, Xue Sheng, Chunyang Li
Journal: Cancer Research (2024)

Abstract Background and Objective: Immunosenescence represents a distinct state of T cell dysfunction in the TME, and plays crucial role in many age-related diseases including tumor. Senescent cell removal by senolytic agents or therapies that inhibit the SASP have demonstrated benefit in both preclinical and clinical models of geriatric decline and chronic diseases. Here, we aimed to screen anti-aging compounds to delay T-cell senescence in TME, and explore novel strategies of reversing tumor induced T-cell senescence to restore antitumor immunity. Methods and Results: Using in vitro senescence inducing system, we screened ginsenoside Rb1 from 22 anti-aging compounds as the compound that had the most effective activity to reduce CD8+ T cell senescence, displayed as decreased β-gal, p16, and p21. Further analysis showed that ginsenoside Rb1 promoted anti-CD3/CD28-induced TCR signaling and the secretion of effector cytokines IFN-γ, TNF-α and IL -2 in OTI T cells. Intriguingly, ginsenoside Rb1 treatment significantly increased TCF-1 in CD8+ T cells, and ginsenoside Rb1 treated OT-I T cells significantly inhibited tumor growth. Moreover, ginsenoside Rb1 greatly enhanced the efficiency of CD19-CART cells to kill Namalwa tumor cells. Conclusion: Ginsenoside Rb1 delays T cell senescence and enhances T cell antitumor activity. This data provides a new insight into T cell based antitumor therapy. Citation Format: Chunhong Ma, Xue Sheng, Chunyang Li. Ginsenoside Rb1 delays the senescence of CD8+ T cells to expand T cells with superior antitumor immunity [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 7.
Abstract 1855: Proteomics driven biomarker discovery for high-grade serous ovarian carcinoma from archived tissue specimens
Authors: Anjana Shenoy, Gali Arad, Dimitri Kovalerchik, Amit Manor, Nitzan Simchi, Dina Daitchman, Kirill Pevzner, Eran Seger
Journal: Cancer Research (2024)

Abstract High-Grade Serous Ovarian Carcinoma (HGSOC) is a highly aggressive and heterogeneous cancer with variable treatment responses. Current treatment strategies, including surgical resection and chemotherapy, are often ineffective due to a lack of molecular markers to predict drug sensitivity and patient prognosis. Mass spectrometry-based proteomics analysis is a powerful tool for biomarker discovery, but it is restricted by the availability and quality of archived clinical specimens. In this study, we developed a proteomics-based biomarker discovery pipeline that optimizes the extraction and sample preparation from archived tissue specimens of HGSOC patients. Macrodissection of the tumor rich tissue areas of interest ensured sample purity and statistical power for comparative analysis. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we conducted a comprehensive, global proteomics analysis of FF tissue specimens from 25 HGSOC patients to associate proteomic profiles with patient outcomes. Combining high-resolution mass spectrometry proteomics of clinical samples with advanced computational tools for clinical data mining, we were able to identify pathways associated with HGSOC that hold clinical significance. Our unique biomarker discovery platform provides a novel strategy for detecting cancer vulnerabilities from archived tissue samples and identifying proteomic biomarkers linked with treatment response and patient prognosis beyond BRCA mutation status. Citation Format: Anjana Shenoy, Gali Arad, Dimitri Kovalerchik, Amit Manor, Nitzan Simchi, Dina Daitchman, Kirill Pevzner, Eran Seger. Proteomics driven biomarker discovery for high-grade serous ovarian carcinoma from archived tissue specimens [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 1855.
Abstract 186: Tumor exosome-macrophage interactions: The role of tumor-associated glycans and scavenger receptor class A
Authors: Fariba Jousheghany, Emily S. Blitz, Samir V. Jenkins, Steven R. Post, Vinay Raj, Rajshekar A. Kore, Azemat Jamshidi-Parsian, Robert J. Griffin, Thomas J. Kelly, Behjatolah Monzavi-Karbassi
Journal: Cancer Research (2024)

Abstract Introduction: Increased macrophage infiltration and polarization towards a breast tumor-supportive phenotype have been linked to therapy resistance, immune suppression, and poor patient prognosis. Despite their importance, the specific interactions that drive tumor-associated macrophage (TAM) polarization remain poorly understood. The class A scavenger receptor (SR-A) is a pattern-recognition receptor expressed by macrophages, and the accumulation of SR-A-expressing TAMs has been correlated with poor patient outcomes. Our preliminary data show that SR-A binds to tumor-associated glycans (TAGs) on the surface of breast cancer cells. However, how macrophages bind tumor cell ligands in the tumor microenvironment (TME) is not clear. Tumor-derived exosomes (TDEs) are secreted extracellular vesicles that resemble the tumor cell membrane, carrying cargo that may mediate an immune response within the TME. In this study, we investigated whether TDE glycans represent tumor cell-surface TAGs and whether TDEs interact with macrophages through SR-A. Methods: TDEs were isolated from the murine breast cancer cell line (E0771) by ultracentrifugation of the cell culture medium and then sized and counted using nanoparticle tracking analysis and electron microscopy. The glycans present on the tumor cell surface and TDEs were characterized using plant lectins in flow cytometry and sandwich ELISAs. The isolated TDEs were then fluorescently labeled, and their binding to the murine macrophage cell line Raw 264.7 was assayed by flow cytometry and fluorescence microscopy. Results: SR-A binds strongly to breast cancer cell lines, and a significant portion of the binding depends on the presence of cell surface N-linked glycans. Lectins reactive with sialylated and fucosylated terminal structures showed differential binding to tumor cells and TDEs. We observed that the glycan profiles of E0771 cells and exosomes isolated from E0771 cultures were similar. Our results indicate that TDEs interact with Raw 264.7 cells, and the interaction is mediated by SR-A. Conclusions: TDEs released in the TME can potentially interact with TAMs through SR-A. The glycan profile of TDEs is representative of host cells and may contribute to SR-A-mediated interaction with TAMs. Citation Format: Fariba Jousheghany, Emily S. Blitz, Samir V. Jenkins, Steven R. Post, Vinay Raj, Rajshekar A. Kore, Azemat Jamshidi-Parsian, Robert J. Griffin, Thomas J. Kelly, Behjatolah Monzavi-Karbassi. Tumor exosome-macrophage interactions: The role of tumor-associated glycans and scavenger receptor class A [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 186.
Abstract 2531: rs822336 as a predictive biomarker for anti-PD-1/PD-L1 immunotherapy in advanced NSCLC: Unraveling molecular mechanisms
Authors: Giovanna Polcaro, Luigi Liguori, Valentina Manzo, Annalisa Chianese, Giuliana Donadio, Alessandro Caputo, Giosuè Scognamiglio, Federica Dell'Annunziata, Maddalena Langella, Graziamaria Corbi, Alessandro Ottaiano, Marco Cascella, Francesco Perri, Margot De Marco, Jessica Dal Col, Valentina Pagliara, Pio Zeppa, Amelia Filippelli, Gianluigi Franci, Fabrizio Dal Piaz, Valeria Conti, Stefano Pepe, Francesco Sabbatino
Journal: Cancer Research (2024)

Abstract Efficient predictive biomarkers are needed for immune checkpoint inhibitor (ICI)-based immunotherapy in non-small-cell lung cancer (NSCLC). So far, testing the predictive value of single nucleotide polymorphisms (SNPs) in programmed cell death 1 (PD-1) or its ligand 1 (PD-L1) has shown contrasting results. Here, we aimed to validate the predictive value of PD-L1 SNPs in advanced NSCLC patients treated with ICIs as well as to define the molecular mechanisms underlying the role of identified SNP candidate. rs822336 SNP efficiently predicted response to anti-PD-1/PD-L1-based immunotherapy in advanced NSCLC patients as compared to rs2282055 and rs4143815 SNPs. rs822336 SNP mapped on promoter/enhancer region of PD-L1, differentially affecting the induction of PD-L1 expression in human NSCLC cell lines. The induction of PD-L1 expression by rs822336 SNP was predicted by allele-specificity binding of two identified transcription factors: C/EBPβ and NFIC. As a result, silencing of C/EBPβ and NFIC differentially modulated the induction of PD-L1 expression in human NSCLC cell lines carrying different rs822336 genotypes. In addition, binding microarray validated the allele- specificity binding of C/EBPβ and NFIC to PD-L1 promoter/enhancer region based on rs822336 genotype in human NSCLC cell lines. Lastly, the induction of PD-L1 expression by rs822336 genotype differentially affected the susceptibility to anti-PD-1 monoclonal antibody nivolumab of human NSCLC cell lines co-cultured with HLA class I antigen matched PBMC. These results have clinical relevance since identified rs822336 SNP and the induction of PD-L1 expression as novel biomarkers for predicting ICI-based immunotherapy in NSCLC patients. Citation Format: Giovanna Polcaro, Luigi Liguori, Valentina Manzo, Annalisa Chianese, Giuliana Donadio, Alessandro Caputo, Giosuè Scognamiglio, Federica Dell'Annunziata, Maddalena Langella, Graziamaria Corbi, Alessandro Ottaiano, Marco Cascella, Francesco Perri, Margot De Marco, Jessica Dal Col, Valentina Pagliara, Pio Zeppa, Amelia Filippelli, Gianluigi Franci, Fabrizio Dal Piaz, Valeria Conti, Stefano Pepe, Francesco Sabbatino. rs822336 as a predictive biomarker for anti-PD-1/PD-L1 immunotherapy in advanced NSCLC: Unraveling molecular mechanisms [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 2531.