tbuckley/cabot-search huggingface dataset:
Abstract 2882: Coronin 1B overexpression promotes invasion of HPV- HNSCC
Authors: Jessica L. Allen, Elyse L. Walk, Kristen L. Rhodes, Steven M. Markwell, Brenen W. Papenberg, Hong Wu, Marileila Garcia, James E. Bear, Scott A. Weed
Journal: Cancer Research (2021)

Abstract Introduction: Amplification of chromosome 11q13 is the most common DNA aberration in human papilloma virus negative (HPV-) head and neck squamous cell carcinoma. (HSNCC). The 11q13 region encodes various genes known to enhance invasion and drive tumor progression. CORO1B (coronin 1B) flanks the core 11q13 region and is amplified in 7-14% of HNSCC cases. Coronin 1B governs cell motility in fibroblasts by negatively regulating the ability of the Arp 2/3 nucleator cortactin to stabilize the actin cytoskeleton during mesenchymal cell migration. This study seeks to determine the impact of CORO1B amplification and protein overexpression in driving HNSCC progression. Experimental Procedures: Two patient cohorts were used to assess the impact of CORO1B amplification or overexpression on patient outcome. In addition, HNSCC cell lines lacking or overexpressing coronin 1B were assayed for invadopodia function using gelatin degradation assays. Three-dimensional invasion was analyzed using tumor spheroid and organotypic assays. Invasive and cervical lymph node metastatic potential of CORO1B was evaluated using knockdown and overexpression cells in orthotopic tongue models. Data Summary: CORO1B amplification and overexpression in patient tumors correlates with enhanced patient decline. Coronin 1B-null cell lines display decreased invadopodia function, with a 30-60% decrease in extracellular matrix-mimicking gelatin degradation. HNSCC tumor spheroids lacking coronin 1B expression decreased 3D invasion in native collagen I, while overexpression enhanced invasive capabilities in both tumor spheroids and organotypic cultures. Coronin 1B knockdown cells show decreased lymph node metastasis, while mice with tumors overexpression coronin 1B have enhanced lymph node metastasis and decreased survival. CORO1B amplification protein overexpression predict poor overall patient survival. Conclusion: The identification of coronin 1B overexpression as an important mediator in promoting HNSCC invasive processes may define a novel aggressive subset of locoregional involved HNSCC, warranting enhanced clinical intervention. Citation Format: Jessica L. Allen, Elyse L. Walk, Kristen L. Rhodes, Steven M. Markwell, Brenen W. Papenberg, Hong Wu, Marileila Garcia, James E. Bear, Scott A. Weed. Coronin 1B overexpression promotes invasion of HPV- HNSCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2882.
Abstract 1537: CD70 knockout: A novel approach to augment CAR-T cell function
Authors: Mary-Lee Dequeant, Jason Sagert, Demetri Kalaitzidis, Hui Yu, Ashley Porras, Brigid McEwan, Zinkal Padalia, Paul Tetteh, Thao Nguyen, Andrew Dunn, Sarah Spencer, Nicolette Lee, Henia Dar, Daniel Henderson, Sushant Karnik, Pooja Keerthipati, Jonathan A. Terrett
Journal: Cancer Research (2021)

Abstract CD70 and its ligand, CD27, have been described as both activating and suppressing for different cell types including B and T cells. There has been speculation that the CD70/CD27 axis can act in a checkpoint or co-stimulatory manner in certain immuno-oncology settings. Knockout (KO) of CD70 function scored highly in a CRISPR/Cas9 screen of candidate genes for enhanced T cell activity. Deletion of other checkpoint candidates such as PD1, TIM3, LAG3 and TIGIT scored much lower than CD70, both alone and in combination with each other. T cells with CD70 KO showed resistance to exhaustion upon repeated stimulation in culture. CAR-T cells with CD70 KO similarly showed exhaustion resistance, as well as a reduction in apoptosis, increased proliferation, and improved target cell lysis upon sequential rechallenges. CTX130 is an investigational allogeneic CAR-T therapy currently being studied in patients with CD70-expressing tumors, including clear cell renal cell carcinoma and B and T cell malignancies. CTX130 contains KOs of TRAC to avoid GvHD, B2M to protect the product from patient T cells, and CD70 for enhanced CAR-T performance. Comparing CTX130 with and without CD70 KOs shows that CAR-T cells with CD70 KO have increased potency, enhanced ability to withstand multiple tumor challenges in vivo, and increased resistance to overexpression of PDL1 on target cells. Interestingly, while CD70 surface expression may be extremely low or undetectable after manufacturing of CD70-targeted CAR-T cells without CD70 KO, the beneficial properties outlined here are only achievable when the CD70 gene is genetically knocked out. In summary, KO of CD70 confers benefit to CAR-T cells that far exceeds KO of other checkpoint related genes, and this benefit was present regardless of the antigen being targeted. CD70 KO is included in the CTX130 investigational allogeneic CAR-T therapy currently in clinical trials. Citation Format: Mary-Lee Dequeant, Jason Sagert, Demetri Kalaitzidis, Hui Yu, Ashley Porras, Brigid McEwan, Zinkal Padalia, Paul Tetteh, Thao Nguyen, Andrew Dunn, Sarah Spencer, Nicolette Lee, Henia Dar, Daniel Henderson, Sushant Karnik, Pooja Keerthipati, Jonathan A. Terrett. CD70 knockout: A novel approach to augment CAR-T cell function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1537.
Abstract 1224: Discovery of novel BAF inhibitors for the treatment of transcription factor-driven cancers
Authors: Richard C. Centore, Luis M. Soares, Rishi G. Vaswani, Kana Ichikawa, Zhifang Li, Hong Fan, Jeremy Setser, David L. Lahr, Laura Zawadzke, Xueying Chen, Kimberly D. Barnash, Jordana Muwanguzi, Neville Anthony, Gabriel J. Sandoval, Katharine Feldman, Ammar Adam, David Huang, Shawn Schiller, Kevin Wilson, Johannes Voigt, Martin Hentemann, David S. Millan, Ho Man Chan, Steven F. Bellon, Carl P. Decicco, Lan Xu
Journal: Cancer Research (2021)

Abstract The BRG/Brahma-associated factors (BAF) family of chromatin remodeling complexes (also referred to as the mSWI/SNF complex) regulates the chromatin landscape of the genome. Through its ATP-dependent chromatin remodeling activity, BAF regulates the accessibility of gene-control elements, allowing for the binding of transcription factors. Thus, BAF is a major regulator of lineage- and disease-specific transcriptional programs. We have discovered and developed a novel series of compounds that potently and selectively inhibits the ATPase components of the BAF complex, SMARCA4 and SMARCA2 (also called BRG1 and BRM, respectively). Mutational, structural, and biochemical studies demonstrated that these SMARCA4/SMARCA2 inhibitors act through a unique allosteric mechanism. Pharmacologic inhibition of the BAF complex resulted in lineage-specific changes in chromatin accessibility in cancer cell lines from diverse origins. Phenotypic screening of cancer cell lines showed that uveal melanoma and hematological cancer cell lines were exquisitely sensitive to BAF inhibition. In the example of uveal melanoma, BAF inhibition resulted in the loss of accessibility at the binding sites of the SOX10 and MITF transcription factors, two essential proteins in supporting the proliferation and survival of uveal melanoma cells. Enhancer occupancy of SOX10 and MITF was reduced upon BAF inhibition, and subsequently, the melanocytic and pigmentation gene expression program regulated by these master transcription factors was suppressed. Finally, in a mouse xenograft model of uveal melanoma, BAF inhibition was well tolerated and resulted in dose-dependent tumor regression that correlated with pharmacodynamic modulation of BAF-target gene expression. These data provide the foundation for first-in-human studies of BAF ATPase inhibition as a novel therapeutic to treat uveal melanoma. Citation Format: Richard C. Centore, Luis M. Soares, Rishi G. Vaswani, Kana Ichikawa, Zhifang Li, Hong Fan, Jeremy Setser, David L. Lahr, Laura Zawadzke, Xueying Chen, Kimberly D. Barnash, Jordana Muwanguzi, Neville Anthony, Gabriel J. Sandoval, Katharine Feldman, Ammar Adam, David Huang, Shawn Schiller, Kevin Wilson, Johannes Voigt, Martin Hentemann, David S. Millan, Ho Man Chan, Steven F. Bellon, Carl P. Decicco, Lan Xu. Discovery of novel BAF inhibitors for the treatment of transcription factor-driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1224.
Clinically advanced pelvic Squamous Cell Carcinomas (pSCC) in men and women: A Comprehensive Genomic Profiling (CGP) study
Authors: A. Necchi, P. Spiess, D. Mata, G. Bratslavsky, J. Jacob, O. Gjoerup, A. Martini, N. Danziger, D. Lin, B. Decker, E. Sokol, R. Huang, J. Ross
Journal: European Urology (2021)
Abstract 49: Brain penetrant HDAC inhibitor RG2833 induces DIPG cell death and synergizes with lomustine
Authors: Katherine K. Barnett, Orlandi Novak, Charles Eberhart, Eric Raabe
Journal: Cancer Research (2021)

Abstract Diffuse intrinsic pontine glioma (DIPG) is a universally fatal pediatric brain tumor. The pan-histone deacetylase (HDAC) inhibitor panobinostat showed great activity against DIPG in pre-clinical models, but has poor blood brain barrier penetration and demonstrated significant toxicity in clinical trials. RG2833 (RGFP109) is a selective HDAC1/3 inhibitor with established brain penetration. In clinical trials, the Cmax(plasma) of RG2833 was 32uM. RG2833 demonstrated cytotoxicity against temozolomide-resistant glioblastoma and downregulated the NFĸB pathway. Because this pathway is overexpressed in DIPG and may play a role in DIPG cell growth and survival, we hypothesized that RG2833 would kill DIPG cells. Treatment of DIPG cell lines with RG2833 as a single agent inhibits cell growth in the 5 to 10μM range (MTS assay for HSJD007 p=0.0004 10μM vs DMSO, JHH-DIPG1 p=0.001 10μM vs DMSO, SF-7761 p=0.04 10μM vs DMSO, SU-DIPG13 p=0.01 10μM vs DMSO by t-test). RG2833 induces apoptosis by 48 hours as measured by Western blot for cPARP and cleaved caspase 3 immunofluorescence (HSJD007 p&amp;lt;0.003 8μM vs DMSO, JHH-DIPG1 p=0.0026 10μM vs DMSO by t-test). RG2833 also slows cell proliferation as measured by Western blot for phospho-Rb and immunofluorescence for BrdU (HSJD007 p=0.008 8μM vs DMSO, JHH-DIPG1 p=0.0002 10μM vs DMSO by t-test). Western blot confirmed a dose-dependent increase in histone 3 acetylation with RG2833 treatment. We detected increased acetylated p65 and decreased expression of the NFĸB regulated pro-survival genes BCL2, BCL-xL, and XIAP with RG2833 treatment in vitro. Treatment of DIPG flank tumor mouse models with RG2833 alone for 5 days suppressed tumor growth (p&amp;lt; 0.005 by t-test). Combination treatment with RG2833 and lomustine was synergistic against DIPG cell lines in vitro (ZIP synergy scores by SynergyFinder for JHH-DIPG1 17.8 and HSJD007 17.7). We will next assess combination treatment in vitro and in vivo for apoptotic effects. This data indicates that selective HDAC inhibitor RG2833 may be a promising therapeutic candidate for DIPG. Citation Format: Katherine K. Barnett, Orlandi Novak, Charles Eberhart, Eric Raabe. Brain penetrant HDAC inhibitor RG2833 induces DIPG cell death and synergizes with lomustine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 49.
Randomized Phase II Trial of MIBG Versus MIBG, Vincristine, and Irinotecan Versus MIBG and Vorinostat for Patients With Relapsed or Refractory Neuroblastoma: A Report From NANT Consortium
Authors: Steven G. DuBois, M. Meaghan Granger, Susan Groshen, Denice Tsao-Wei, Lingyun Ji, Anasheh Shamirian, Scarlett Czarnecki, Fariba Goodarzian, Rachel Berkovich, Hiroyuki Shimada, Judith G. Villablanca, Kieuhoa T. Vo, Navin Pinto, Yael P. Mosse, John M. Maris, Suzanne Shusterman, Susan L. Cohn, Kelly C. Goldsmith, Brian Weiss, Gregory A. Yanik, Clare J. Twist, Meredith S. Irwin, Daphne A. Haas-Kogan, Julie R. Park, Araz Marachelian, Katherine K. Matthay
Journal: Journal of Clinical Oncology (2021)

I-metaiodobenzylguanidine (MIBG) is an active radiotherapeutic for neuroblastoma. The primary aim of this trial was to identify which of three MIBG regimens was likely associated with the highest true response rate.
Transrectal and transperineal MRI-guided prostate cancer pathways in biopsy-naïve men
Authors: B. Israël, J.J.F.M. Immerzeel, M.M.G. Van Der Leest, G.J. Hannink, P. Zámecnik, J.G.R. Bomers, I.G. Schoots, J.P.A. Van Basten, F.M.J. Debruyne, I.M. Van Oort, J.P.M. Sedelaar, J.O. Barentsz
Journal: European Urology (2021)
有糸分裂の心筋細胞におけるアネキシン6の核シグナリングの、FKBP12とプロテインキナーゼC(PKC)による調整
Authors: Koide M, Obata K, Yazawa S, Yamada A, Somura F, Ishiki R, Yokota M, Tuan Rs
Journal: Circulation (1999)
Abstract LB177: Targeting SIRPα with APX701, a Novel Myeloid Checkpoint Inhibitor
Authors: Ryan Alvarado, Sushma Krishnan, Minu K. Srivastava, Christine Tan, George Huang, Swati Jalgaonkar, Frances R. Bahjat, Erin L. Filbert, Xiaodong Yang
Journal: Cancer Research (2021)

Abstract Therapeutically targeting tumor myeloid cells has emerged as a complementary strategy to existing cancer immunotherapy approaches. The interaction of tumor-expressed CD47 with SIRPα (Signal Regulatory Protein-α, SIRPA) on macrophages, dendritic cells, and neutrophils inhibit key immune effector mechanisms. Targeting the SIRPα-CD47 axis represents a novel approach to enhance anti-tumor immunity by augmenting or reactivating critical tumor clearance mechanisms. While agents that target CD47 have shown promise in clinical trials, they present hematological toxicities and antigen sink issues that narrow their therapeutic application. Our approach targets SIRPα to focus on relevant mechanisms related to myeloid cell activation and increase of tumor cell phagocytosis while simultaneously avoiding the undesired effects of targeting CD47. Furthermore, SIRPγ, a close relative of SIRPα, is expressed on T cells and potentially co-stimulates T cell proliferation and is required for trans-endothelial T cell migration. We sought to develop an anti-SIRPα therapeutic that does not cross-react with SIRPγ and avoids potentially deleterious effects on T cell functions. Here, we describe APX701, a novel anti-SIRPα antibody generated using Apexigen's APXiMAB™ proprietary antibody discovery platform, and its differentiated properties as compared to other approaches targeting the SIRPα-CD47 interaction. APX701 binds to human SIRPα at a unique epitope with high affinity (Kd = 0.95nM) and with no detectable binding to SIRPγ expressed on primary human T cells. APX701 strongly binds to the major SIRPα variants—V1 and V2—and potently blocks their interaction with CD47, thereby allowing therapeutic targeting of SIRPα in a majority of patients. APX701 reverses SIRPα-mediated suppression of macrophage phagocytosis, resulting in potent destruction of a variety of tumor cells both as a single agent and in combination with anti-TAA (tumor associated antigen) antibodies including cetuximab, rituximab, and trastuzumab. Moreover, targeting SIRPα with APX701 does not interfere with T cell function, an effect previously observed following anti-CD47 treatment. Together, these data demonstrate the unique binding profile of APX701 and its ability to potently reactivate myeloid cell-mediated anti-tumor immunity. Our data support the development of APX701, a promising myeloid checkpoint inhibitor, for the treatment of cancer. Citation Format: Ryan Alvarado, Sushma Krishnan, Minu K. Srivastava, Christine Tan, George Huang, Swati Jalgaonkar, Frances R. Bahjat, Erin L. Filbert, Xiaodong Yang. Targeting SIRPα with APX701, a Novel Myeloid Checkpoint Inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB177.
Nephrectomy after complete response to immune checkpoint inhibitors for Metastatic Renal Cell Carcinoma (mRCC): A surgical challenge allowing favorable oncological outcomes
Authors: G. Pignot, A. Thiery-Vuillemin, J. Walz, H. Lang, L. Balssa, L. Geoffrois, L. Leblanc, L. Albiges, K. Bensalah, S. Ladoire, P. Bigot, A. Ingels, C. Saldana, G. Roubaud, T. Piechaud, O. Cassuto, D. Klifa, B. Parier, J.C. Bernhard, G. Malouf, G. Gravis, P. Barthelemy
Journal: European Urology (2021)
Individualized genetic makeup that controls natural killer cell function influences the efficacy of isatuximab immunotherapy in patients with multiple myeloma
Authors: Haibo Sun, Thomas G Martin, John Marra, Denice Kong, Jonathon Keats, Sandrine Macé, Marielle Chiron, Jeffrey L Wolf, Jeffrey M Venstrom, Raja Rajalingam
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Phase IIb clinical trial with isatuximab (Isa)-lenalidomide (Len)-dexamethasone (Dex) showed an improved progression-free survival (PFS) in patients with relapsed or refractory multiple myeloma (RRMM), but the efficacy varied by patient. Antibody-dependent cell-mediated cytotoxicity (ADCC) by natural killer (NK) cells plays a crucial role in arbitrating antitumor activities of therapeutic-antibodies. We tested if patient-specific genetic makeup known to set NK cell functional threshold influence response to Isa-Len-Dex therapy. Methods We characterized 57 patients with RRMM receiving Isa-Len-Dex for polymorphisms of killer-cell immunoglobulin-like receptors (KIR), human leukocyte antigen (HLA) class I, and FCGR3A loci. In vitro ADCC assay, coincubating primary NK cells expressing specific KIR repertoire with multiple myeloma cell lines (MM cells) expressing selected HLA class I ligands, was used to confirm the identified genetic correlatives of clinical response. Results Patients with KIR3DL2+ and its cognate-ligand HLA-A3/11+ had superior PFS than patients missing this combination (HR=0.43; p=0.02), while patients carrying KIR2DL1+ and HLA-C2C2+ compared with to patients missing this pair showed short PFS (HR=3.54; p=0.05). Patients with KIR3DL2+ and HLA-A3/11+ plus high-affinity FCGR3A-158V allele showed the most prolonged PFS (HR=0.35; p=0.007). Consistent with these clinical data, mechanistic experiments demonstrated that NK cells expressing KIR3DL2 trigger greater ADCC when MM cells express HLA-A3/11. Inversely, NK cells expressing KIR2DL1 do not kill if MM cells express the HLA-C2C2 ligand. NK cells expressing high-affinity FCGR3A-158VV-induced greater ADCC compared with those with low-affinity FCGR3A-158FF. Conclusions Our results suggest that KIR3DL2+ and HLA-A3/11+ with FCGR3A-158V markers lead to enhanced Isa-dependent NK-mediated cytolysis against MM cells and results in improved PFS in patients with RRMM treated by Isa-Len-Dex. Moreover, the presence of KIR2DL1+ and HLA-C2C2+ identifies patients who may have a lower response to Isa-Len-Dex therapy linked to a reduced NK-mediated ADCC. These biomarkers could potentially identify, via precision medicine, patients more likely to respond to Isa-Len-Dex immunotherapy. Trial registration number NCT01749969 .
Abstract 2942: Improved LAG-3 humanized knock-in mouse model for assessment of mono- and combination therapy strategies for cancer treatment
Authors: Huilin Li, Xiaofei Zhou, Dirui Li, Veronika Chromikova, Qingcong Lin
Journal: Cancer Research (2021)

Abstract In recent years, immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. One of the potential therapeutic targets that seems increasingly attractive is LAG-3 (Lymphocyte activation gene 3, CD223), a human protein encoded by the LAG3 gene. LAG-3 can be found on activated T cells, NK cells, B cells and plasmacytoid DCs and serves as a negative regulator of immunity. Inhibition of LAG-3 enhances the antitumor effect of specific CD8+ T cells, which is an observation pursued by several pharmaceutical companies with their products in pre-clinical or early clinical development. Therefore, it is clear there is a need for suitable pre-clinical models able to accurately reflect the relevant physiological processes to evaluate the safety and efficacy of LAG3-targeted therapeutics. Biocytogen has generated a humanized LAG-3 mouse model for both in vitro functional validation and in vivo efficacy evaluation of anti-hLAG-3 antibodies. The targeting strategy is that exons 2~7 of mouse Lag3 gene which encode the extracellular domain are replaced by human LAG3 exons 2~7. After an introduction of this modification, human LAG-3 was detectable on Tregs in the mouse spleen and the anti-hLAG-3 antibodies and recombinant human FGL-1 protein associated well to the mouse splenocytes. Basal leukocyte subpopulations, including T/B/NK cells, DC, granulocytes, and monocytes/macrophages, were similar between humanized and wild-type mice. Additionally, anti-human LAG-3 antibodies partially blocked LAG-3/FGL-1 binding. Furthermore, using the MC38 tumor model, we show robust efficacy of anti-human LAG-3 antibodies in inhibiting tumor growth in vivo.In summary, LAG-3 humanized mice are a useful tool for in vivo efficacy evaluation of anti-human LAG-3 antibodies. Moreover, Biocytogen has also generated PD-1/PD-L1/LAG3 multi-gene humanized mice, in which blood cell composition, morphology and the levels of ALT, AST and other indicators were comparable to wild-type mice. This model is ideal to assess an increased therapeutic benefit in cancer treatment provided by combination therapies. Indeed, in our hands using the MC38 tumor model, the combination of anti-LAG-3 antibodies with anti-PD-1 (or anti-PD-L1) antibodies shows synergistic inhibitory effects , demonstrating that the PD-1/PD-L1/LAG3 humanized mice represent a powerful tool for preclinical assessment of in vivo efficacy of future therapeutics. Citation Format: Huilin Li, Xiaofei Zhou, Dirui Li, Veronika Chromikova, Qingcong Lin. Improved LAG-3 humanized knock-in mouse model for assessment of mono- and combination therapy strategies for cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2942.