tbuckley/cabot-search huggingface dataset:
Abstract 4044: Potentiated antitumor activity of poly-γ-glutamic acid combined with anti PD-L1 blockade on murine models of colorectal cancer
Authors: Jae-Pyung Jang, Chan-Hee Yoo, Kyung-Soo Hahm, Do Young Lee, Young-Chul Park, Jae Chul Choi
Journal: Cancer Research (2024)

Abstract Objective: Immune checkpoint inhibitors(ICIs) have been shown to be key role in cancer therapy. Especially, antibodies targeting programmed cell death ligand1(PD-L1) promoted T cells to activate immune response against cancer cells. However, the current ICIs still have insignificant to motivate effective antitumor immunity by blocking PD-1/PD-L1 pathway and the regulatory network of PD-L1 by cytokines in the tumor microenvironment remains to be uncovered. Previously, we have reported the anti-cancer effects of combination treatment with a natural product, poly-γ-glutamic acid(γ-PGA), and PD-1 blockade. Now, we show that combination therapy with anti PD-L1 and γ-PGA can overcome the limits of ICIs and enhance anticancer effect in murine colorectal cancer. Design: In vivo efficacy studies were performed by intraperitoneal injection of antibody targeting PD-L1 and oral administration of γ-PGA in C57BL/6 model transplanted with mouse tumor cell lines. Systemic changes in immunophenotype was measured by tumor volume size and body weight. The splenocyte was isolated from mice and the populations of myeloid-driven suppressor cells(MDSCs) and CD4/CD8 T cells were analyzed by FACS. Also, the significant cytokines activated by T- cell, IFN-γ and IL-2, were measured by ELISA. Results and Conclusions: In murine model of colorectal cancer, γ-PGA and anti PD-L1 blockade combination therapy significantly improved anti-tumor activity compared with single agents. In addition, tumoral infiltration of CD8+ T cells and IFN-γ productions were increased by γ-PGA, and its antitumoral activity was attenuated by antibody-mediated depletion of these cells, indicating that g-PGA suppressed tumor growth in a CD8 T cell-dependent manner. Therefore, our results suggest that γ-PGA promote ICI-mediated antitumor responses by the transformation of "cold tumors" into “hot tumors” Citation Format: Jae-Pyung Jang, Chan-Hee Yoo, Kyung-Soo Hahm, Do Young Lee, Young-Chul Park, Jae Chul Choi. Potentiated antitumor activity of poly-γ-glutamic acid combined with anti PD-L1 blockade on murine models of colorectal 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 4044.
Abstract 2464: Defective NMD promotes aberrant intron retention in clear cell renal cell carcinoma
Authors: Mi Zhou, Gilbert Giri, William Y. Kim, Daniel Dominguez
Journal: Cancer Research (2024)

Abstract Clear cell renal cell carcinoma (ccRCC) is the 8th most common cancer in the United States, constituting 75% of all kidney cancer cases. Clear cell RCC (ccRCC) along with melanoma has traditionally been viewed as an immunotherapy responsive disease with a storied history of immunotherapy treatments including high dose interleukin 2 (IL2), interferon, and allogeneic stem cell transplant. Indeed, RCC was one of the first tumor types to garner FDA approval for PD1 immune checkpoint inhibition (ICI). However, unlike melanoma, most RCC tumors do not have a high tumor mutational burden (TMB) to potentially explain their immunotherapy responsiveness. We and others have sought to explain this unanswered question and have demonstrated that non-canonical tumor associated antigens like endogenous retroviruses (ERVs) may in part explain ICI response in RCC. We have noted that ccRCC tumors have the highest level of retained introns (RI) across all TCGA tumors, that RI levels are secondary to suppressed non-sense mediated decay (NMD) activity, and that one can subset ccRCC into RI-high and normal-like tumors. Moreover, we have found that mTOR signaling plays a key role in regulating NMD and intron retention and that mTOR inhibition can promote intron retention. We hypothesized that these aberrantly retained introns could serve as a rich source of highly foreign, tumor associated neoantigens and that of retained intron neoantigens, the ones not observed in normal tissue would be the most immunogenic. We derived a so called “Neo-RI-antigen burden” that represents the burden of retained intron neoantigens not found in normal tissues and demonstrate that the Neo-RI-antigen burden of complete responders is numerically higher than those with partial response or progressive disease in a dataset of immunotherapy treated melanoma patients. Our work suggests the possibility of using NMD-targeting drugs as a potential therapeutic in combination with ICI to enhance the overall treatment response. Citation Format: Mi Zhou, Gilbert Giri, William Y. Kim, Daniel Dominguez. Defective NMD promotes aberrant intron retention in clear cell renal cell carcinoma [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 2464.
Abstract 539: LN18-MRTX1719R cell line, a useful cell model for the discovery of the new PRMT5 inhibitors
Authors: Yao Tang, Liping Wang, Guoqian Wang, Jinying Ning, Feng Hao
Journal: Cancer Research (2024)

Abstract In recent years, the PRMT5-MTA complex has emerged as a "synthetic lethal" novel target for the treatment of MTAP (methylthioadenosine phosphorylase)-deficient cancers. Kryukov et al. first reported the "synthetic lethal" effect of inhibiting PRMT5 in MTAP-deficient tumors, and they identified MTAP as the synthetic lethal partner of PRMT5 in 2016. MTAP is a tumor suppressor gene frequently lost in various cancers, including pancreatic cancer, non-small cell lung cancer, and mesothelioma. Furthermore, the loss of MTAP leads to the accumulation of MTA in cancer cells, which competes with PRMT5's co-factor SAM for binding and forms the PRMT5-MTA complex. Cancer cells lacking MTAP show enhanced sensitivity to PRMT5 loss. Therefore, this complex has emerged as a potential therapeutic target, particularly for the treatment of MTAP-deficient cancers. MRTX1719 is a highly effective selective inhibitor of the PRMT5-MTA complex, capable of selectively inhibiting PRMT5 activity in MTAP-deficient cells. As the most promising candidate drug, MRTX1719 is undergoing Phase I/II clinical evaluation for patients with MTAP-deficient cancers. Drug resistance is an inevitable problem with small molecule inhibitors. Currently, the mechanism of resistance to MRTX1719 is not clear, as MTAP/CDKN2A loss is an early driver event in most cancers. To further explore the resistance mechanism of MRTX1719, our group used the MTAP-deficient LN-18 cell line and induced mutagenesis using the mutagen ENU. We then used a drug low-concentration gradient method to establish the LN-18-MRTX1719R-resistant cell line. Specifically, LN-18 cells were treated with increasing doses of MRTX1719 for 6 months, and mixed clones that tolerated MRTX1719 were selected. Subsequently, single clones were selected, and a stable MRTX1719-resistant clone was obtained, named LN-18-MRTX1719R. Cell proliferation inhibition assay showed that the IC50 of LN-18-MRTX1719R was over 1000nM, which is 100-fold more resistant than the parental LN-18 cells (9.87 nM). We explored the resistance mechanisms using RNA-Seq and WES methods. The resistance to MRTX1719 of the LN-18-MRTX1719R cell line was highly stable after 20 cell passages. The LN-18-MRTX1719R cell line can be a useful cell line mode in the development of future PRMT5·MTA inhibitors. Citation Format: Yao Tang, Liping Wang, Guoqian Wang, Jinying Ning, Feng Hao. LN18-MRTX1719R cell line, a useful cell model for the discovery of the new PRMT5 inhibitors [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 539.
Abstract 2474: Antitumoral efficacy of ASKG812, a Smartkine® based bifunctional PD-1-eIL-2 molecule, through enhancing T effector cis agonism
Authors: Chunxiao Yu, Kurt Shanebeck, Shiguang Yu, Jeanine Ruiz, Shichang Li, Stone D.-H Shi, Hong Ma, Yuefeng Lu
Journal: Cancer Research (2024)

Abstract Cytokines are potent molecules, yet their broad application as therapeutics has been significantly hampered due to short PK, severe systemic toxicity, and narrow therapeutic window. To improve the developability of cytokines, AskGene has invented a proprietary cytokine platform (Smartkine®) to achieve its overarching objective of modulating immune reactions at a disease site in a selective and controlled manner. Several antibody-cytokine fusion molecules using the SmartKine® platform have been moving into preclinical and clinical development. ASKG812 is a unique fusion molecule composed of anti-PD-1 antibody and engineered IL-2 (eIL-2). The eIL-2 moiety also comprises a specific mask such that the eIL-2 molecule binding biases towards PD-1+ T effector cells in a cis agonism manner for improved efficacy and therapeutic window. In ex vivo human PBMC assays, we demonstrated that ASKG812 significantly reduced activity in PD-1− T and NK cells, and enhanced activity in PD-1+ T cells judged by levels of pSTAT5, Ki67 and Granzyme B. In a cytotoxicity assay, ASKG812 can efficiently induce PBMC-mediated killing of MDA-MB-231 tumor cells in a dose-dependent manner. Moreover, in both anti-PD-1 therapy responsive and non-responsive syngeneic mouse tumor models, ASKG812 showed robust efficacy; without noticeable toxicity compared to a reference anti-PD-1-IL-2v fusion molecule. In conclusion, these findings provide the basis for the development of this new generation of PD-1 cis-targeted IL-2R agonists with enhanced therapeutic potential for the clinical treatment of cancer. Citation Format: Chunxiao Yu, Kurt Shanebeck, Shiguang Yu, Jeanine Ruiz, Shichang Li, Stone D.-H Shi, Hong Ma, Yuefeng Lu. Antitumoral efficacy of ASKG812, a Smartkine® based bifunctional PD-1-eIL-2 molecule, through enhancing T effector cis agonism [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 2474.
Abstract 6705: A novel tri-specific T cell engager targeting the intracellular oncoprotein WT1
Authors: Shan Gao, Liu Yang, Jun Du, Wenqing Jiang, Lei Fang
Journal: Cancer Research (2024)

Abstract Background: Wilms' tumor gene 1 (WT1) is considered an oncogenic factor, with high expression observed in several hematological malignancies and solid tumors. However, its expression is rarely found in normal adult tissue. WT1 can be degraded by the proteasome, processed and presented on the cell surface as major histocompatibility complex (MHC) I epitopes and recognized by T cell receptors (TCR). Here, we described the development of WT1-TOPAbody, a novel tri-specific T cell engager (TCE), that activated T cells by both CD3 and 4-1BB signaling upon recognition of WT1 in the context of HLA-A02, leading to superior anti-tumor efficacy. Materials and Methods: WT1-TOPAbody was evaluated for its antigen binding activity and target specificity by a series protein/peptide and cell-based assays. In vitro cytotoxicity and T cell activation mediated by WT1-TOPAbody was further assessed in a panel of WT1+ tumor cell lines in coculture with effector cells. Anti-tumor activity was investigated in a humanized syngeneic mice model bearing WT1/HLA-A02 expressing tumors. Safety assessment including cytokine release assay (CRA) and preliminary CMC developability was also performed. Results: WT1-TOPAbody exhibited superior binding affinity to the WT1/HLA-A02 complex while displaying lower binding to off-target peptides and CD34+ HSC from healthy donor than clinical benchmark WT1-CD3 bispecific antibody, RG-6007. WT1-TOPAbody effectively induced tumor lysis in multiple WT1+ tumors including leukemia, ovarian, breast, and colon cancer cells. Moreover, serial killing of tumor cells were observed in WT1-TOPAbody treated T cells, accompanied by lower exhaustion markers expressed, suggesting a prolonged anti-tumor inhibition effect of WT1-TOPAbody. In a humanized CD3e/4-1BB/HLA-A2.1 mouse model, WT1-TOPAbody significantly inhibited tumor growth in a dose-dependent manner and the efficacy was superior than that of the benchmark. Additionally, IL-6 release was minimal in PBMC upon treatment of the antibody, indicating a reduced risk of inducing cytokine release syndrome (CRS). Drug developability assessment indicated that the leading WT1-TOPAbody was a reasonably developable molecule to be taken forward. Conclusion: WT1-TOPAbody is a differentiated WT1/HLA-A02 targeted T cell engagers that displayed potent and durable anti-tumor activity. These results collectively support the potential of WT1-TOPAbody as a novel therapeutic agent against WT1/HLA-A02+ cancers and warrant its further development. Citation Format: Shan Gao, Liu Yang, Jun Du, Wenqing Jiang, Lei Fang. A novel tri-specific T cell engager targeting the intracellular oncoprotein WT1 [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 6705.
Abstract 3490: Unveiling sex differences in lung adenocarcinoma through multi-omics integrative protein signaling networks
Authors: Chen Chen, Enakshi Saha, Dawn L. DeMeo, John Quackenbush, Camila M. Lopes-Ramos
Journal: Cancer Research (2024)

Abstract Sex differences in lung adenocarcinoma (LUAD) are evident in incidence rates, prognostic outcomes, and therapy responses, yet the underlying molecular mechanisms driving these disparities remain underexplored. In this study, we conducted a comprehensive proteogenomic analysis encompassing 38 females and 73 males with LUAD from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) dataset. Employing Transcription Inference using Gene Expression and Regulatory data (TIGER), we inferred sex-differentially activated transcription factors (TFs) from The Cancer Genome Atlas (TCGA) LUAD gene expression data and identified sex-differentially activated kinases using CPTAC protein phosphorylation data. We further constructed a comprehensive kinase-TF signaling network by integrating these sex-differentially activated kinases with TFs, identifying all paths shorter than 3 in the protein interaction networks to highlight druggable pathways. Our analyses revealed that many proteins exhibit not only sex-biased abundance but also sex-biased phosphorylation and acetylation. Furthermore, these sex-biased proteins were associated with critical biological pathways including cell proliferation, immune response, and metabolism. Using kinase-TF signaling networks, we found substantial sex bias in the activities of clinically actionable TFs and kinases, including the glucocorticoid receptor (NR3C1), AR, AURKA, CDK6, and MAPK14. Leveraging the PRISM cancer cell line screening database, we identified several small-molecule drugs, such as glucocorticoid receptor agonists and aurora kinase inhibitors, potentially exhibiting sex-specific efficacy as LUAD therapeutics. Our findings showed that the activity of some clinically relevant TFs and kinases differ by sex in LUAD, underscoring the need to consider sex as a biological variable and the utility of multi-omics integrative protein signaling networks in advancing our understanding of cancer biology and the development of sex-aware therapeutics. Citation Format: Chen Chen, Enakshi Saha, Dawn L. DeMeo, John Quackenbush, Camila M. Lopes-Ramos. Unveiling sex differences in lung adenocarcinoma through multi-omics integrative protein signaling networks [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 3490.
Abstract 6690: Gut microbial metabolite butyrate facilitates antitumor efficacy of telomerase-specific oncolytic adenovirus via MHC-I and cGAS-STING pathway activation
Authors: Masaki Sakamoto
Journal: Cancer Research (2024)

Abstract Introduction: Gut microbiota has been reported to have a potential to modulate tumor sensitivity to chemo- or immuno-therapies although the underlying mechanism is still unclear. Oncolytic virotherapy is a promising antitumor treatment that selectively induces oncolytic cell death in tumor cells. We have previously developed OBP-702, a telomerase-specific oncolytic adenovirus armed with the p53 tumor suppressor gene, highlighting potent antitumor effects across different cancer types. To explore the potential of gut microbial metabolites, particularly butyrate, in augmenting the antitumor efficacy of oncolytic virotherapy. Materials and Methods: We assessed the synergistic antitumor effects of butyrate and OBP-702 in cytotoxic assay using two human (HCT116, SW48) and two murine (CT26, MC38) colorectal cancer cell lines in vitro, and the in vivo antitumor effects in subcutaneous tumor models using HCT116 and CT26. We explored underlying mechanisms of the synergistic effects, focusing on the influences of butylate on viral infectivity via Coxsackie-Adenovirus Receptor (CAR) and integrins, and antitumor immunity via tumor MHC-I expression and CD8-positive T cells. Results: Butyrate and OBP-702 showed potent synergistic effects in all four cell lines in vitro, and the combination suppressed tumor growth significantly in HCT116 and CT26 subcutaneous tumors compared to each monotherapy. These synergistic effects were produced by butyrate increasing the potential of OBP-702 by enhancing viral infection efficiency via upregulating expressions of CAR and integrins on tumor cells. Butyrate also increased MHC-I expression on tumor cells by activating the cGAS-STING pathway, leading to increased CXCL10 expression, which led to activation of antitumor immunity through recruitment of CD8-positive T cells in tumor tissues. The synergistic effects of butyrate and OBP-702 were proved in an orthotopic colorectal tumor model with liver metastases using CT26 cells expressing luciferase, in which this combination not only reduced tumor growth, but also improved survival by activating antitumor immunity via CD8-positive T cells. Conclusion: Butyrate and OBP-702 showed synergistic antitumor effects via activation of systemic antitumor immunity in addition to direct effects of butyrate on viral cytotoxic potential, which provides valuable insights into the development of innovative cancer treatment strategies. Citation Format: Masaki Sakamoto. Gut microbial metabolite butyrate facilitates antitumor efficacy of telomerase-specific oncolytic adenovirus via MHC-I and cGAS-STING pathway activation [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 6690.
Abstract 4014: Humanized mouse model to assess PBMC donor derived autologous CD19 CAR Ts for efficacy against Raji tumors and related cytokine release
Authors: Senthil Ramalingam, Danying Cai, Lindsay Shopland, James G. Keck
Journal: Cancer Research (2024)

Abstract Immuno-oncology cell therapies engage the immune system to treat cancer. In recent years, adoptive T-cell therapy with CD19-specific chimeric antigen receptors (CARs) has shown promise for treatment of various malignancies, including acute lymphoblastic leukemia. However, CAR-T-cell therapies have been hampered by various adverse events, including cytokine release syndrome (CRS). To predict and minimize CRS effects from CAR-T therapies, a human immune preclinical murine model that combines efficacy and toxicity readouts is essential. Here, we describe the development of PBMC humanized mouse model based on the NSG-MHC I/II-DKO strain to study autologous CD19 CAR-T treatment related tumor growth inhibition and CRS in vivo. Three different PBMC donors were used to generate CAR-T (CD28-Cd3z) directed against a CD19 epitome. Our preliminary data demonstrate that CD19 CAR-T treatment stimulated dynamic and PBMC donor dependent cytokine release with IFN-g, IL-10, IL-4, IL-2, IL-6 and TNF. Our model showed elevation of shared proinflammatory cytokines (IFN-g, IL-10, IL-2 and TNF) observed in humans after CD19 CAR-T treatment. Currently, we are evaluating our PBMC based cytokine release model in CD19 CAR-T cells tumor control study. Our results to date indicate that PBMC-engrafted NSG-MHC I/II-DKO mouse models are vital platforms to screen adoptive T-cell therapy for potential CRS. Citation Format: Senthil Ramalingam, Danying Cai, Lindsay Shopland, James G. Keck. Humanized mouse model to assess PBMC donor derived autologous CD19 CAR Ts for efficacy against Raji tumors and related cytokine release [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 4014.
Abstract 6685: Control of melanoma development by <i>B. rodentium</i> in germ free mice
Authors: Ximena Diaz Olea, Kristin Beede, Andrei Osterman, David Scott, Christopher Petucci, Daniel Kelly, Amanda Ramer-Tait, Ze’ev A. Ronai
Journal: Cancer Research (2024)

Abstract Growing evidence supports the importance of the gut microbiota in controlling tumor development, often via activation of anti-tumor immunity. Earlier studies from our laboratory identified 11 bacterial strains that were sufficient to inhibit melanoma development by inducing anti-tumor immunity in germ-free mice. Of these, three were predominant at the time of tumor collection. We thus set out to address whether fewer bacterial strains may be sufficient for melanoma growth inhibition. Here, we demonstrate that the administration of one bacterial strain, B. rodentium, was sufficient to attenuate melanoma growth in gnotobiotic mice. In all cases, gnotobiotic mice were also administered the altered Schadler flora (ASF), a mixture of 8 bacterial strains that are provided to establish minimal flora in these mice. RNAseq-based gene expression studies identified enrichment of immune-related genes, suggesting enhanced anti-tumor immunity. Metabolomic analysis identified reduced levels of tryptophane and isoleucine, which were implicated in control of immune system function. These findings point to a mechanism which may provide novel means to alter anti-tumor immunity and limit melanoma growth. Citation Format: Ximena Diaz Olea, Kristin Beede, Andrei Osterman, David Scott, Christopher Petucci, Daniel Kelly, Amanda Ramer-Tait, Ze’ev A. Ronai. Control of melanoma development by B. rodentium in germ free mice [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 6685.