bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5416: RNA-seq and proteomics to identify response to immunotherapy in advanced melanoma: a Spanish Melanoma Group Study
Authors: Trilla-Fuertes Lucia , Prado-Vazquez Guillermo , Gámez-Pozo Angelo , Lopez-Vacas Rocio , Herrera Maria Isabel Lumbreras , Soriano Virtudes , Garicano Fernando , Lecumberri Maria Jose , Rodriguez Maria , Majem Margarita , Perez Elisabeth , Gonzalez-Cao Maria , Oramas Juana , Magdaleno Alejandra , Fra Joaquin , Martin Alfonso , Corral Monica , Puertolas Teresa , Vara Juan Angel Fresno , Espinosa Enrique 
Published: June 2022

Abstract
Background: Prediction of response to immunotherapy remains an unmet need in the field of advanced melanoma.
Methods: Computational analyses, including probabilistic graphical models, sparse k-means, and consensus cluster, were used to characterize melanoma TCGA samples. The implication of the identified processes in response to immunotherapy was then studied in an independent cohort of 53 patients with advanced melanoma and treated with PD-1 inhibitors. Paraffin samples from this cohort were analyzed using RNA-seq and mass-spectrometry proteomics.
Results: In the TCGA cohort, there were two different layers of information: one related to molecular features of the tumor (based on keratinization, melanogenesis, and extracellular space), and one related to immune status. Therefore, two independent classifications of TCGA melanoma samples were established: molecular and immune. The immune classification distinguished between responders and not responders to immunotherapy in the second cohort (p= 0.0006, HR=6.52). Finally, high-throughput proteomics was used to characterize molecular mechanisms involved in response to immunotherapy, identifying several biological processes and proteins that may be relevant in treatment selection for patients who do not respond.
Conclusions: We established that the immune information was independent of tumor molecular features in melanomas included in the TCGA. An immune classification of these tumors was established. This immune classification predicted response to immunotherapy in a new cohort of patients with advanced melanoma treated with PD-1 inhibitors. Finally, proteomics was used to identify possible targets in those patients who did not respond to immunotherapy.
Citation Format: Lucia Trilla-Fuertes, Guillermo Prado-Vazquez, Angelo Gámez-Pozo, Rocio Lopez-Vacas, Maria Isabel Lumbreras Herrera, Virtudes Soriano, Fernando Garicano, Maria Jose Lecumberri, Maria Rodriguez, Margarita Majem, Elisabeth Perez, Maria Gonzalez-Cao, Juana Oramas, Alejandra Magdaleno, Joaquin Fra, Alfonso Martin, Monica Corral, Teresa Puertolas, Juan Angel Fresno Vara, Enrique Espinosa. RNA-seq and proteomics to identify response to immunotherapy in advanced melanoma: a Spanish Melanoma Group Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5416.
Abstract 5486: ENPP1 inhibitor ZX-8177 enhances anti-tumor activity of conventional therapies by modulating tumor microenvironment
Authors: Li Ying-ying , Peng Zhiyuan , Sun Shuaijun , Guo Kun , Kong Deming , Li Xiaomin , Xie Yuning , Shui Siyu , Wang Yin , Yang Jinfu , Hao Xiaolin Alan , Qin Xiaoli (Shelley) 
Published: June 2022

Abstract
Emerging studies revealed that tumor derived 2’3’-cGAMP could act as an immune transmitter and directly trigger anti-tumor immunity. Damage associated molecular patterns, e.g. damaged genomic DNA, released from injured cancer cells can be converted into 2’, 3’-cGAMP by cGAS. Subsequently, cGAMP triggers STING pathway activation to produce type I interferons (IFNs) and other related innate immunity in the tumor microenvironment. Ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1), a membrane-bound nucleotide hydrolase, has been discovered as the predominant enzyme hydrolyzing 2’3’-cGAMP (Li, et al). Hence, ENPP1 blockade in the tumor milieu is a potential strategy against tumors by improving innate immunity response. In this report, we present a potent ENPP1 inhibitor ZX-8177. ZX-8177 showed an IC50 of 9.5 nM in a biochemical assay and an IC50 of 11 nM in MDA-MB-231 cell-based enzymatic assay. In a functional assay for evaluating efficacy of ZX-8177, the production of IFN-β1 by THP-1 cells was measured after the cells were cultured in the conditioned medium collected from MDA-MB-231 cells treated with or without ZX-8177. The interferon production assay showed an EC50 of 15 pM, suggesting that ZX-8177 effectively facilitated IFN-β1 production via cGAMP-STING axis. In CT-26 syngeneic mouse model, ZX-8177 treatment at 2 mg/kg, BID for 14 days can achieve around 37-60% tumor growth inhibition (TGI). No body weight loss was observed during treatment. Flow cytometry analysis indicated that ZX-8177 treatment resulted in a 2-3-fold increase in tumor-infiltrating NK (CD314+CD335+) cells, cytotoxic CD8 T cells (GranzB+CD8+), and M1-macrophages (CD206-MHCII+); and a decrease in M2-macrophages (CD206+MHCII-) (p&lt; 0.05). Combination of Mitomycin C (0.5 mg/kg, i.p., BIW) and ZX-8177 (2 mg/kg, i.p., BID) in CT-26 model yielded synergistic anti-tumor efficacy (increased &gt;30% TGI). The level of cGAMP in tumor tissue harvested from the combination treatment group was around 2-fold higher than that in the vehicle group. Furthermore, synergistic tumor inhibition of ZX-8177 and anti-PD-L1 antibody was also observed in MC38 mouse model. TGI of anti-PD-L1 antibody vs. combo treatment is 53% vs. 75%, p &lt; 0.05. ZX-8177 has a favorable DMPK and safety pharmacology profile to support it as a clinical candidate for further development.
Citation Format: Ying-ying Li, Zhiyuan Peng, Shuaijun Sun, Kun Guo, Deming Kong, Xiaomin Li, Yuning Xie, Siyu Shui, Yin Wang, Jinfu Yang, Xiaolin Alan Hao, Xiaoli (Shelley) Qin. ENPP1 inhibitor ZX-8177 enhances anti-tumor activity of conventional therapies by modulating tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5486.
Abstract 5489: Utilization of cancer cell line screening and bioinformatic analyses to identify optimal developmental pathways for the novel anticancer agent BOLD-100
Authors: Raha Paromita , Park Brian , Carie Adam , Pankovich Jim , Bazett Mark 
Published: June 2022

Abstract
Cell line screening of unique compounds can provide mechanistic insights and identify optimal drug combination partners. Bioinformatics analysis of cell screen data and correlation to publicly available datasets can support identification of appropriate patient populations for subsequent preclinical and clinical development. BOLD-100 is a first-in-class ruthenium-based anticancer agent currently being tested in a Phase 1b/2a clinical trial in combination with FOLFOX in the treatment of advanced gastrointestinal cancers. BOLD-100 works by altering the unfolded protein response through selective GRP78 inhibition; and inducing reactive oxygen species which causes DNA damage and cell cycle arrest. Collectively, these result in cell death in a range of different cancer types, and in combination with many different classes of anticancer agents. To determine optimal indications for BOLD-100 development, BOLD-100 was tested against 316 cancer cell lines in 72-hour Cell Titer Glo assays with downstream bioinformatic analysis and validation experiments. Multiple cancer types showed preferential response to BOLD-100, including bladder, esophageal, pancreatic, multiple myeloma and ovarian cancers. Subtype analysis identified potential populations of increased responsiveness, including in bladder cancer where BOLD-100 had increased response in luminal and mixed subtypes, as compared to basal subtypes. Utilizing bladder cancer as a case study, subsequent combination testing of BOLD-100 in combination with fluorouracil or cisplatin demonstrated that BOLD-100 enhanced cell death across different bladder cancer cell lines through synergistic interactions with these standard-of-care agents. The pan-cancer response profile of BOLD-100 was compared against 449 other anticancer drug responses that are part of the GDSC database. BOLD-100 displayed limited correlation with existing drugs, suggesting a unique mechanism of action and clinical utility where standard-of-care agents have limited efficacy. Pharmacogenomic analysis of the cell screen data indicated potential pathways and genes of relevance to BOLD-100 response, including increased response in KRAS-mutant cancers. Collectively, BOLD-100 showed a unique sensitivity profile across a panel of over 300 cancer cell lines, identifying multiple potential indications for future development. Subsequent investigations into several cancer types of interest and drug combinations are ongoing.
Citation Format: Paromita Raha, Brian Park, Adam Carie, Jim Pankovich, Mark Bazett. Utilization of cancer cell line screening and bioinformatic analyses to identify optimal developmental pathways for the novel anticancer agent BOLD-100 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5489.
Abstract 5546: Inflamed lymph nodes mark active tumor immune response in colorectal cancer patients
Authors: Shen Dingcheng , Wang Xiaolin , Huang Meijin , Luo Yanxin , Yu Huichuan 
Published: June 2022

Abstract
Background Tumor-infiltrating lymphocytes (TILs) can be used to predict immune response in multiple tumors. Currently, the evaluation of TILs relies on pathological and molecular examine on resected tumor samples. Enlarged regional lymph nodes could be attributed to tumor involvement or local inflammation with active immune response. We therefore aimed to investigate the role of inflamed lymph nodes in distinguishing the hot tumor from cold tumor.
Methods Fresh-frozen tumor samples from pathologically-confirmed node-negative colorectal cancer patients with inflamed nodes (n= 22) and non-inflamed nodes (n= 23) were used to generate the genome-wide DNA methylation profile using Infinium Methylation EPIC BeadChip. The inflamed and non-inflamed nodes were defined as the pathologically-confirmed negative regional lymph nodes with enlarged size (≥ 5mm) and normal size (&lt; 5mm) in radiological imaging, respectively. A MeTIL algorithm that integrates CD3+ T cell-specific differentially methylated positions was constructed and validated by immunohistochemical assay to evaluate TIL-based tumor immune response in bulk tumor samples.
Results The baseline characteristics were balanced between patients with inflamed and non-inflamed nodes. The high abundance of TILs was significantly associated with inflamed nodes (P= 0.025). In addition, we identified a subgroup of superhot tumors characterized by inflamed nodes, enriched TILs and favorable overall survival outcomes (HR 0.53, 95% CI: 0.36-0.97; P = 0.032).
Conclusions Inflamed regional lymph nodes in radiological imaging indicate potential active immune response in tumor. Our findings provide an easily accessible biomarker for cancer immunotherapy.
Citation Format: Dingcheng Shen, Xiaolin Wang, Meijin Huang, Yanxin Luo, Huichuan Yu. Inflamed lymph nodes mark active tumor immune response in colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5546.
Abstract 5557: PMC-309, a highly selective anti-VISTA antibody reverses immunosuppressive TME to immune-supportive TME
Authors: Park Cheon Ho , Byun Sang Soon , An Jin Yong , Han Hyerim , Lee Weon Sup 
Published: June 2022

Abstract
Purpose: We investigated the pharmacology of PMC-309 in ex vivo or in vivo characterization for the development of the preclinical study.
Experimental procedures: Target selectivity: it was measured by SPR assay. Human VISTA expressing CHO k1 cells or CHO k1 mock cells were used in cell binding assay. Target cell analysis: human peripheral blood mononuclear cells (PBMC) containing lymphocyte and myeloid lineage cells were used for target cells analysis with flow cytometry. In vitro T cell activity: human PBMC was employed for the evaluation of T cell activity (IRB #1041107-201703-BR-002-02) and was stimulated with or w/o PMC-309 in the presence of anti-CD3/28 Antibody. In vivo study: MC38 bearing human VISTA knock-in (KI) mice were employed for the assessment of anti-tumor activity of PMC-309. The tumor infiltrated immune cells: Immune cells in the TME were evaluated by immunohistochemistry (IHC) or flow cytometry (FACS) analysis. Statistics: All data were presented as the mean ± SEM and analyzed using one-way ANOVA followed by Dunnett’s multiple comparison tests in Graph pad prism®. ***p&lt;0.001, **p&lt;0.01 and *p&lt;0.05 compared to Control group.
Summary of data: PMC-309 binding to VISTA expressing cells is highly selective and the selectivity is maintained even in the low pH conditions that mimic TME. PMC-309 enhances the secretion of IFN-gamma, TNF-alpha, and IL-2 in Mixed Lymphocyte Reaction (MLR) settings. In addition, PMC-309 promoted monocyte differentiation into M1 macrophage that stimulates proinflammatory cytokine secretion of T cells. For the in vivo study, PMC-309 was intravenously administrated in VISTA-KI mice. The tumor growth rate was suppressed in accompanied by a synergistic effect with an anti-PD1 antibody. The anti-tumor activity was associated with enhanced T cell activation, increased secretion of pro-inflammatory cytokines, and increased penetration of cytotoxic T cells, but lowing immune-suppressive MDSC cells into TME as demonstrated with IHC analysis.
Conclusions: PMC-309 is a fully human anti-VISTA antibody that targets human VISTA specifically. PMC-309 enhanced both T cell activation and monocyte activation when monocytes were cultured with or without T cells by targeting VISTA. PMC-309 increased the number of T cell infiltration while a decrease of MDSCs in the TME. PMC-309 in combination with chemotherapy or other IO drugs could address highly medical unmet needs from patients with drug resistance to currently available IO treatment options.
Citation Format: Cheon Ho Park, Sang Soon Byun, Jin Yong An, Hyerim Han, Weon Sup Lee. PMC-309, a highly selective anti-VISTA antibody reverses immunosuppressive TME to immune-supportive TME [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5557.
Abstract 556: Novel anti-TACI single and dual-targeting CAR T cells overcome BCMA antigen loss in multiple myeloma
Authors: Larson Rebecca C. , Castano Ana , Bouffard Amanda A. , Kann Michael C. , Schmidts Andrea , Gallagher Kathleen M. , Maus Marcela V. 
Published: June 2022

Abstract
Anti-BCMA CAR T cell therapy has had success clinically against multiple myeloma, recently leading to FDA approval. However, the median progression free survival is 8.8 months, suggesting that targeting BCMA alone may not be sufficient. Reports of BCMA-negative relapse have occurred, highlighting the need for therapeutics that can overcome antigen loss. We have generated a novel antibody against a second target in multiple myeloma, transmembrane activator and CAML interactor (TACI). This antibody specifically recognizes TACI-positive cells (with either endogenous or exogenous expression) and has no recognition of non-B cell peripheral blood mononuclear cells. We designed novel second-generation CAR T cells based on the single chain variable fragment (scFv) from this antibody. We observe that anti-TACI CARs are cytotoxic in vitro at comparable levels to anti-BCMA CAR against multiple myeloma cell lines MM1S and RPMI-8226. Anti-TACI CARs are also functional in vivo and expand in peripheral blood of xenograft multiple myeloma models. We generated BCMA-knockout MM1S cells and observe that while anti-BCMA CAR treated mice have outgrowth of tumor, anti-TACI CAR treated animals retain anti-tumor activity. To overcome potential antigen loss of either BCMA or TACI, we designed tandem bispecific CAR T cells based on both single-targeting CAR designs. These BCMA and TACI dual-targeting CARs are functional in vitro and in vivo, even in the context of single antigen loss. We monitor the activation (CD69), exhaustion (PD-1, TIM-3, LAG-3), and memory (CCR7, CD45RA) phenotype over time to investigate the differences of single versus dual-targeting CAR T cells. We also study the ability of these CAR T cells to bind soluble antigen, as well as their binding avidity to tumor cells. We observe that the anti-TACI scFv more proximal to the CD3ζ signaling domain has a stronger effect on CAR functionality than when this scFv is more distal. Our studies provide a potential superior therapeutic option which remains efficacious in the context of BCMA antigen loss.
Citation Format: Rebecca C. Larson, Ana Castano, Amanda A. Bouffard, Michael C. Kann, Andrea Schmidts, Kathleen M. Gallagher, Marcela V. Maus. Novel anti-TACI single and dual-targeting CAR T cells overcome BCMA antigen loss in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 556.
Abstract 5586: Demonstrating restoration of T cell function in exhausted T cells with IKZF3 small molecule inhibitor, Lenalidomide
Authors: Hay Joanne , Acklam Francis , Turner Darryl , Barbour Mark , Singh Preeti , Grant Courtney , Gooding Hayley , McPherson Rhoanne , Rzepecka Justyna 
Published: June 2022

Abstract
CD8+ T cell exhaustion as a result of prolonged antigenic stimulation in the tumour microenvironment is thought to be a major mechanism by which tumours can escape immune surveillance. T cell exhaustion is characterised by co-expression of checkpoint inhibitor molecules such as PD-1, LAG-3 and TIM-3; reduced proliferative capacity; and diminished production of pro-inflammatory cytokines such as IL-2, IFN-γ and TNF-α and treatment with checkpoint inhibitor blockade such as Nivolumab (anti-PD-1) have shown great promise in the treatment of a subset of individuals and tumour types. However, resistance to these approaches is prevalent and there is a need to identify novel targets to provide alternative options for the rescue of T cell exhaustion and cancer treatment for use alone or potentially in combination with checkpoint inhibitor modulation. One such target is IKZF3, a transcription factor that is increased in murine models of T cell exhaustion and reduces IL-2 expression. Previously we presented an in vitro human T cell exhaustion assay whereby in vitro stimulated T cells phenotypically and functionally recapitulate the exhausted T cells found within the tumour microenvironment and now we demonstrate that exhaustion can be partially rescued by treatment with the IKZF3 small molecule inhibitor, Lenalidomide, alone and in combination with checkpoint inhibitor blockade. The use of small molecule inhibitors offers new avenues for reversing T cell exhaustion in cases of checkpoint inhibitor resistance and this platform delivers a robust assay allowing for assessment of small molecules or checkpoint inhibitors both individually and in combination.
Citation Format: Joanne Hay, Francis Acklam, Darryl Turner, Mark Barbour, Preeti Singh, Courtney Grant, Hayley Gooding, Rhoanne McPherson, Justyna Rzepecka. Demonstrating restoration of T cell function in exhausted T cells with IKZF3 small molecule inhibitor, Lenalidomide [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5586.
Abstract 5611: CRB-601: A highly potent and selective integrin αvβ8 blocking antibody with anti-tumoral properties
Authors: Kolodziej Andrew , Haines Eric , Morse Richard , Zhukovsky Eugene 
Published: June 2022

Abstract
TGFβ is a secreted protein produced by tumors that promotes cancer progression primarily via the suppression of both the innate and adaptive immune systems. This makes TGFβ a promising immunotherapeutic target in cancer. It is ubiquitously expressed in a latent (L-TGFβ) form and the latent form has been shown to promote an immune suppressive phenotype within the tumor microenvironment. Integrin αvβ8 specifically binds to L-TGFβ. This interaction is essential for the activation of L-TGFβ-mediated signals in a variety of immune cell types. Interestingly, it has been recently shown that integrin αvβ8-mediated TGFβ activation can active directly through L-TGFβ and does not require the release of active TGFβ (1). Inhibition of integrin αvβ8-mediated TGFβ activation has been shown to block immunosuppressive regulatory T cell differentiation and enhance the recruitment of cytotoxic T cells into the tumor microenvironment (2). Here, we demonstrate by Surface Plasmon Resonance (SPR) that CRB-601, our selective inhibitor of integrin αvβ8 monoclonal antibody candidate, has a high affinity and specificity for the integrin αvβ8 complex. Moreover, in comparison to competitor molecules, such as ADWA-11, CRB-601 substantially blocks TGFβ activation in a reporter cell assay system. Additionally, using syngeneic mouse models, we evaluated the anti-tumoral properties of CRB-601 as a monotherapy, as well as in combination with immune checkpoints therapies. Findings from this study highlight the importance of integrin αvβ8 blockade in mediating the immune landscape within the tumor and leads to an enhanced response to immune checkpoint therapy. In conclusion, CRB-601 is a potent and selective integrin αvβ8 blocking monoclonal antibody that enhances the activity of immune checkpoint inhibitors in vivo and holds promise as a potential combination partner for immunotherapy. Investigational New Drug (IND) enabling studies are currently underway.
References: 1: Campbell MG. et al. (2020) Cyro-EM reveals integrin-mediated TGF-β activation without release from latent TGF-β. Cell 180, 490-501. 2: Mariathasan S. et al. (2018) TGFbeta attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554, 544-48.
Citation Format: Andrew Kolodziej, Eric Haines, Richard Morse, Eugene Zhukovsky. CRB-601: A highly potent and selective integrin αvβ8 blocking antibody with anti-tumoral properties [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5611.