bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4185: Targeting variant of CEACAM5 and CEACAM6 using NEO-201 and IL-15 in gynecologic cancers
Authors: Morelli Maria Pia , Fantini Massimo , Tsang Kwong Y. , Arlen Phillip , Fauceglia Paulette , Hernandez Lidia , Korrapati Soumya , Edmonson Elijah , Cole Christopher , Annunziata Christina M. 
Published: June 2022

Abstract
Background: Uterine and ovarian cancers express glycosylated forms of CEACAMs 5 and 6 that regulate interactions with the tumor microenvironment. NEO-201 is a novel monoclonal antibody that binds a glycosylated variant of these CEACAMs that is upregulated in cancer compared to normal uterine or ovarian epithelia. Previous work has shown that NEO-201 induced cancer cell death predominantly by antibody-dependent cellular cytotoxicity (ADCC) that can be enhanced by the addition of IL-15.
Methods: NEO-201 target expression was assessed on uterine and ovarian cancer cell lines, as well as a tissue microarray of primary uterine cancer samples. Cell lines were profiled with DNA and RNA sequencing. Chromium-release assays were performed to quantify ADCC without and with varying concentrations of IL-15 and varying target to effector ratios. In vivomodeling was performed using ovarian cancer cell line OV90, and mice were treated with NEO-201, with PBMC or NK cells, with or without IL-15.
Results: NEO-201 target antigen was highly expressed in uterine cancer cell line ACI158 and ovarian cancer cell line OV90. The antigen was expressed in primary uterine cancer samples as well. IL-15 consistently increased the in vitro killing of both cell lines and was further enhanced with the use of NK cells compared to PBMC. These findings were replicated in the in vivo mouse model, where mice survived longest with the combination of NEO-201, IL-15 and NK cells.
Conclusions: The ADCC activity of NEO-201 monoclonal antibody was enhanced with the addition of IL-15, especially in the presence of purified NK cells. NEO-201 with IL-15 shows promising results as a potential treatment for biomarker-selected gynecologic cancers.
Citation Format: Maria Pia Morelli, Massimo Fantini, Kwong Y. Tsang, Phillip Arlen, Paulette Fauceglia, Lidia Hernandez, Soumya Korrapati, Elijah Edmonson, Christopher Cole, Christina M. Annunziata. Targeting variant of CEACAM5 and CEACAM6 using NEO-201 and IL-15 in gynecologic cancers [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 4185.
Abstract 419: The development of BRPF1 degraders as a potential treatment for acute myeloid leukemia
Authors: Glynn Daniel Joseph , Crampton Rosie , Pesnot Thomas , Scott Andrew , Nassoy Anne-Chloe , Kirk Ralph , Narducci Daniele , Nelson Gary , Ongiri Lynette , Begum Habiba , Rao Vincent , Bingham Matilda , McPherson Rhoanne , Turner Darryl 
Published: June 2022

Abstract
Acetylation of histones and additional nuclear proteins is a key mechanism in the regulation of gene expression. Aberrant acetylation has been linked to a wide range of diseases including cancer, inflammation, and neurodevelopmental disorders. Histone acetylation is introduced by histone acetyltransferases complexes (HATs), where substrate specificity is dramatically enhanced by scaffolding proteins that activate and target them to specific chromatin sites. A protein of interest with both epigenetic acetyl reader and scaffolding function is the protein Bromodomain and PHD finger-containing protein 1 (BRPF1). The Protein contains domains of two plant homeodomain (PHD) fingers separated by a zinc knuckle (PZP domain), a bromodomain, and a proline-tryptophan-tryptophan-proline (PWWP) Tudor domain. Native BRPF1 complexes can contain either MOZ/MORF or HBO1 as the catalytic MYST-family acetyltransferase subunit and the stable complex with Moz-Tif2 is known to lead to the development of human acute myeloid leukemia (AML). Given this, we chose to pursue the development of BRPF1 degraders to probe cancer disease biology especially in AML, where new therapies are required to overcome several unmet needs such as less-toxic treatments and relapsed/refractory disease paradigms. Here we present the design and synthesis of a range of BRPF1 degraders in highly desirable physicochemical space utilizing in-silico modeling. The prepared degraders which utilize multiple E3 ligases were then screened against cell lines harboring Mixed-lineage leukemia (MLL) translocations specifically the THP-1 cell line. In addition to this, we investigated the ability of the compounds to effectively degrade the target and suitability of our degraders for potential in-vivo exposure through a panel of routine ADMET assays.
Citation Format: Daniel Joseph Glynn, Rosie Crampton, Thomas Pesnot, Andrew Scott, Anne-Chloe Nassoy, Ralph Kirk, Daniele Narducci, Gary Nelson, Lynette Ongiri, Habiba Begum, Vincent Rao, Matilda Bingham, Rhoanne McPherson, Darryl Turner. The development of BRPF1 degraders as a potential treatment for acute myeloid leukemia [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 419.
Abstract 4199: rhIL-7-hyFc (efineptakinalpha; NT-I7) enhances the anti-tumor response when combined with hIL-2/TCB2c complex
Authors: Baek Seungtae , Im Sun-Kyoung , Lee Minji , Ji Mankyu , Kim Miyoung , Kim Daeun , Lee Jun Young , Choi Donghoon 
Published: June 2022

Abstract
rhIL-7-hyFc (efineptakin-alfa; NT-I7) is a potent T cell amplifier, with a homodimeric interleukin-7 (IL-7) fused to the hybridizing IgD/IgG4 immunoglobulin domain. Previous work has shown that in mice, NT-I7 dramatically increases tumor-infiltrating CD8+ T cells while reducing the frequency of PD-1+ CD8+ T cells in the tumor. There is also significant expansion of Central Memory (CM)-phenotype CD8+ T cells (CD62L+CD44+) in the tumor and tumor draining lymph node. Here, we investigated the anti-tumor effect of NT-I7 in combination with a T cell activator, SLC-3010 (hIL-2/TCB2c complex), in MC38 tumor-bearing mice. Because TCB2 is an antibody specific for IL-2 that blocks interaction of IL-2 and IL-2Rα (CD25), SLC-3010 can selectively activate T cells while disfavoring Treg activation. Mice were administered a single dose of NT-I7 or SLC-3010 via intramuscular or intravenous injection, respectively. The combination of NT-I7 with SLC-3010 enhanced the anti-tumor response with increased number and frequency of CD8+ T cells as well as granzyme B expression in the tumor. The number of CD8+ T cells peaked at day 4 and day 7 by SLC-3010 and NT-I7, respectively. The number of Tregs in the tumor was slightly increased by NT-I7 and SLC-3010, but it was not statistically significant. Interestingly, NT-I7, but not SLC-3010, increased the frequency of PD-1+TCF-1+TOX- stem-like CD8+ T cells in the draining lymph node. Meanwhile, SLC-3010 significantly increased the number of PD-1+ CD8+ T cells in the tumor. Our data suggests that NT-I7 can be applied in combination with other immunotherapies such as IL-2 to enhance the anti-tumor response.
Citation Format: Seungtae Baek, Sun-Kyoung Im, Minji Lee, Mankyu Ji, Miyoung Kim, Daeun Kim, Jun Young Lee, Donghoon Choi. rhIL-7-hyFc (efineptakinalpha; NT-I7) enhances the anti-tumor response when combined with hIL-2/TCB2c complex [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 4199.
Abstract 4205: Staged anti-PD-1 therapy with intratumoral recombinant calreticulin improves anti-tumor immunity and survival in glioblastoma mouse models
Authors: Taori Suchet , Noffsinger Breanna , Miller Charlotte A. , Xiao Aizhen , Manigat Laryssa , Zhong Qing , Harris Tajie , Purow Benjamin 
Published: June 2022

Abstract
Background: Glioblastoma (GBM), the most common and lethal primary brain tumor, has a median survival of a mere 15 months and leads to approximately 12,000 deaths in the US annually. Targeted and combinatorial-based clinical trial therapies have shown poor efficacy in GBM treatment, partly due to the restrictive nature of the blood-brain barrier, an immunosuppressive tumor microenvironment, GBM’s heterogeneity and adaptability, and GBM’s ability to metastasize and invade critical regions of the brain. However, promising recent literature has indicated that neoadjuvant anti-PD-1 checkpoint-inhibition immunotherapy - i.e., starting it right before surgery for recurrence - improves survival outcomes in human GBM patients.
Results: Here, we demonstrate a proposed mechanism of action wherein localized intratumoral danger-associated molecular pattern (DAMP, a known immunogenic driver) injection of calreticulin - used to mimic natural DAMP release from necrotic cells during surgery - combined with neoadjuvant anti-PD-1 immunotherapy leads to better survival outcomes in both orthotopic mouse CT2A and CT2A-Luc GBM models. This survival benefit is also seen in a more aggressive (larger tumor inoculation size) orthotopic CT2A-Luc GBM model. Flow cytometry indicates increased microglia cell counts and activation marker expression, and increased myeloid activation marker expression in mice brains treated with our combination immunotherapy in a CT2A GBM model. Additionally, in vivo treatment with our combination immunotherapy led to increases in the local T and NK cell numbers, the CD8:CD4 ratio, and the proliferation of CD4 T cells in mice brains of a CT2A GBM model. In vitro results suggest that co-culture with CT2A cells increased PD-1 expression in macrophages and microglia and that our combination treatment of calreticulin and anti-PD-1 immunotherapy reduces the viability of mouse GBM cells when mixed with macrophages.
Significance: This project paves the path for a novel immunotherapeutic approach to tackle GBM and other cancers. Future studies could incorporate relevant DAMP’s into nanoparticles for sustained release after intratumoral injection and possibly viral delivery of DAMP’s that are constitutively secreted, thereby prolonging an anticipated immune response.
Citation Format: Suchet Taori, Breanna Noffsinger, Charlotte A. Miller, Aizhen Xiao, Laryssa Manigat, Qing Zhong, Tajie Harris, Benjamin Purow. Staged anti-PD-1 therapy with intratumoral recombinant calreticulin improves anti-tumor immunity and survival in glioblastoma mouse models [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 4205.
Abstract 4217: MEKi in combination with anti-OX40 generates metabolically fit effector CD8+ T cells, enhances stem cell-like memory CD8+ T cells, and leads to strong anti-tumor activity
Authors: Gaur Pankaj , Verma Vivek , Elayyan Mays Alreem , Ramlaoui Zainab , Barry Simon T. , Valge-Archer Viia E. , Smith Paul D. , Gupta Seema , Khleif Samir N. 
Published: June 2022

Abstract
In the tumor microenvironment (TME), T cell exhaustion and short persistence of effector cells are crucial factors that limit the efficacy of endogenously generated or adoptively transferred effector cells. Regenerative stem-cell memory CD62LhiCD44lowSca1+ CD8+ CD8+ T cells (TSCM) persist longer and produce cells with more vital effector functions. OX40, a member of TNFRSF4, has been shown to promote the expansion and proliferation of activated effector T cells, leading to the generation of robust anti-tumor responses and immune memory. However, treatment with anti-OX40 as a single therapeutic modality has not generated desirable clinical outcomes. A combination of immune modulators has been found to enhance the therapeutic efficacy synergistically. Recently, we reported that inhibition of MEK1/2 using selumetinib (AZD6244) leads to a significant increase in the numbers of CD8+ TSCM cells with self-renewability, enhanced multipotency and proliferative capacity, leading to potent anti-tumor effects. Therefore, here we combined selumetinib with anti-OX40 to investigate if enhanced immune-mediated anti-tumor responses could be obtained. Using three mouse tumor models (TC1, B16, and CT26), we found that combination of MEKi with anti-OX40 enhances the anti-tumor activity by increasing the expansion of total and antigen-specific CD8+ T cells in the TME. These CD8+ T cells have higher functional activity as seen by increased Granzyme B and INF-γ production. We also found similar results after adoptive cell therapy (ACT) where infusion of MEKi-treated cells in B16 tumor-bearing mice synergized with anti-OX40 agonist treatment. Interestingly, anti-OX40 treatment of MEKi-treated CD8+ T cells enhanced the metabolic fitness as demonstrated by low mitochondrial potential and enhanced Oxygen Consumption Rates (OCR), Spare Respiratory Capacity (SRC), and Extra-cellular Acidification Rates (ECAR) compared to anti-OX40 treatment alone. Furthermore, OX40 agonist significantly enhanced the longevity of MEKi-induced CD8+ TSCM cells. In summary, our data provide a novel strategy to utilize MEKi to enhance the efficacy of ACT and combination immunotherapy using anti-OX40 agonist.
Citation Format: Pankaj Gaur, Vivek Verma, Mays Alreem Elayyan, Zainab Ramlaoui, Simon T. Barry, Viia E. Valge-Archer, Paul D. Smith, Seema Gupta, Samir N. Khleif. MEKi in combination with anti-OX40 generates metabolically fit effector CD8+ T cells, enhances stem cell-like memory CD8+ T cells, and leads to strong anti-tumor activity [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 4217.
Abstract 4223: Cis-activation of PD-1+ effector T cells with dual-targeting immunocytokines generated using a novel chemical conjugation platform
Authors: Carralot Jean-Philippe , Ruiz Matilde Arévalo , Tam Robert , Armentani Eric , Pattabiraman Vijaya R. , Kreft Bertolt 
Published: June 2022

Abstract
Immunocytokines (IC) provide the opportunity for targeted delivery of cytokines as payloads to tissues and cells to improve safety and efficacy of cytokine-based therapies. ICs have gained significant interest in recent years and several antibody-cytokine fusion proteins have entered clinical trials. Compared to recombinant fusion proteins, we have developed an entirely different approach to IC generation based on the site-specific, chemical conjugation of synthetic cytokines to antibodies. Bright Peak generates enhanced and conjugatable cytokines using a novel protein engineering platform based on solid-phase peptide synthesis and subsequent chemical ligation of protein segments. Our synthetic cytokines can then be readily chemically conjugated to specific lysine residues in the Fc region of an existing IgG1, IgG2 or IgG4 antibody without the need for prior antibody engineering. Chemical conjugation of cytokine payloads is rapid, enabling the flexible generation of ICs based on different antibodies and payloads within weeks. We applied our technology to more than 10 antibodies and found that neither antigen binding nor payload potency and selectivity are affected by chemical conjugation. Importantly, binding of the Fc domain of ICs to Fc gamma receptors or FcRn is not significantly affected. We are initially focusing on the development of PD-1-targeted ICs to achieve dual-targeting of PD-1+ effector T cells (cis-signaling). Using several anti-PD-1 antibodies and various synthetic IL-2 variants as payloads, we created ICs with different drug-antibody ratios and explored alternative conjugation sites within the Fc region. Resulting PD-1/IL-2 ICs are highly active showing significantly enhanced potency due to avidity resulting from binding of the cytokine to PD-1+ effector T cells in cis. Our PD-1/IL-2 ICs induce strong pharmacodynamic effects in vivo, and we are currently optimizing the pharmacological profiles of PD-1-targeted ICs for clinical application. In addition, we are actively exploring cis-signaling ICs targeting different surface receptors and immune cells.
Citation Format: Jean-Philippe Carralot, Matilde Arévalo Ruiz, Robert Tam, Eric Armentani, Vijaya R. Pattabiraman, Bertolt Kreft. Cis-activation of PD-1+ effector T cells with dual-targeting immunocytokines generated using a novel chemical conjugation platform [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 4223.
Abstract 4230: Modeling the cDC1 ex vivo and in vitro: Development and comparison of a conventional dendritic cell culture system for industry
Authors: Goodfield Laura L. , Lahdenranta Johanna , Scott Heather , Ashworth Tamera , Luus Lia , Licht Anna F. , McDonnell Kevin , Brandish Phil , Keen Nicholas 
Published: June 2022

Abstract
Conventional dendritic cells (cDC) are innate immune cells specialized in antigen sampling and subsequent cross-presentation to immune cells and are critical for an effective anti-tumor immune response. While crucial to immunity against intracellular pathogens, viruses, and tumors, cDC type I (cDC1) are a relatively rare population and constitute about 0.05% of cells in the blood. Using these rare cells in screening assays can be a challenge, as very small proportions are found in peripheral human blood and since they are difficult to isolate with high viability and purity. Existing methods to generate acceptable numbers of cDC1s require a feeder cell line, which is not accessible to many laboratories.
Using a systematic approach, we developed a scalable differentiation system to generate a mixed culture containing cDC1 cells from CD34+ hematopoietic stem cells isolated from cord blood that does not require feeder cells. This culture of cells has been phenotypically and functionally characterized to express high levels of CD141 and Clec9a, as well as responsiveness to various activating stimuli including poly (I:C). Cells derived from this culture method express similar levels of CD141 and Clec9a compared to those observed in peripheral blood of healthy donors. Our effort to find a less laborious, more efficient system includes comparison to cDC1 responses from an in vitro differentiation system to cDC1s isolated from humanized mouse bone marrow, with evaluation of both surface marker phenotype and responsiveness to activating stimuli. We also compared the responses of these cells to monocyte derived dendritic cells that express CD141 and Clec9a. These data demonstrate that the HSC-derived cDC1 cultures provide a comparison of unique dendritic cells that may be utilized for screening assays in an industry setting.
Citation Format: Laura L. Goodfield, Johanna Lahdenranta, Heather Scott, Tamera Ashworth, Lia Luus, Anna F. Licht, Kevin McDonnell, Phil Brandish, Nicholas Keen. Modeling the cDC1 ex vivo and in vitro: Development and comparison of a conventional dendritic cell culture system for industry [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 4230.
Abstract 4233: Generation of a Bicycle NK-TICA™, a novel NK cell engaging molecule designed to induce targeted tumor cytotoxicity
Authors: Dufort Fay J. , Leitheiser Christopher J. , Mudd Gemma , Kristensson Julia , Rezvaya Alexandra , Gaynor Katie , Uhlenbroich Sandra , Urbonas Liudvikas , Scott Heather , Chen Liuhong , Harrison Helen , Skynner Michael , McDonnell Kevin , Brandish Philip E. , Keen Nicholas 
Published: June 2022

Abstract
The tumor specific activation of natural killer (NK) cells is an area of active investigation in immune oncology, but to date has relied on complex biologic modalities (e.g., antibodies, fusion proteins, or cell therapies). NK cells are highly responsive immune cells that can detect and eliminate tumor cells and bridge innate to adaptive immune responses. Bicycles® are small (ca.1.5kDa), chemically synthetic, structurally constrained peptides discovered via phage display and optimized using structure-driven design and medicinal chemistry approaches. We have applied the Bicycle platform technology to identify Bicycles® that bind specifically to the key activating receptor, NKp46. When chemically coupled to tumor antigen binding Bicycles, this results in highly potent, antigen-dependent receptor activation and NK cell activation. We term this new class of fully synthetic molecules NK-TICAs and we will describe herein their discovery and evaluation.We demonstrate potent, selective binding of our Bicycles to receptor-expressing cells and the capability of the bifunctional molecule to induce NK cell function in vitro. With Bicycle’s novel NK-TICA™ compound, we demonstrate the engagement of NK cells, the specific activation and function of NK cells, and enhanced tumor cytotoxicity in a tumor target- and dose-dependent manner.In conclusion, NK-TICAs drive NK cell-mediated tumor cell killing and cytokine production in vitro and as such have the potential to catalyze the development of durable anti-tumor immunity in tumor types not well served by current therapies. We hypothesize that utilization of Bicycle NK-TICA™ as a multifunctional immune cell engager will promote the modulation of NK cells, as well as the infiltration and anti-tumor activity of NK cells in solid tumors. The data presented here provide initial proof of concept for the application of our Bicycle technology to drive NK cell-mediated tumor immunity.
Citation Format: Fay J. Dufort, Christopher J. Leitheiser, Gemma Mudd, Julia Kristensson, Alexandra Rezvaya, Katie Gaynor, Sandra Uhlenbroich, Liudvikas Urbonas, Heather Scott, Liuhong Chen, Helen Harrison, Michael Skynner, Kevin McDonnell, Philip E. Brandish, Nicholas Keen. Generation of a Bicycle NK-TICA™, a novel NK cell engaging molecule designed to induce targeted tumor cytotoxicity [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 4233.
Abstract 4238: A novel immunotherapy approach by inhibiting nanotube-mediated mitochondrial trafficking between cancer cells and T cells
Authors: Saha Tanmoy , Jaybalan Ruparoshni , Jang HaeLin , Sengupta Shiladitya 
Published: June 2022

Abstract
Trafficking of mitochondria from immune cells to cancer cells via physical nanotubes is a new mechanism by which cancer cells undergo immune evasion. This results in depletion of T cell, which can limit the efficacy of classical immune checkpoint inhibitors. Here we introduce a novel pharmacological inhibitor that inhibits nanotube-mediated mitochondria transfer from immune cell to cancer cell. Our preliminary study implicates the exocyst complex in the nanotube assembly. We performed molecular dynamic simulations to identify the potential inhibitors for the exocyst proteins. We have identified a drug candidate, TS-1, which successfully inhibits the mitochondria transfer from immune cell to cancer cell. Currently we are exploring the modification of the structural component to increase the inhibitory potential of the drug. TS-1-loaded liposome significantly inhibited tumor growth in a 4T1 metastatic breast cancer mouse model. We observed considerable increase in intratumoral T cell population with treatment. Furthermore, the use of TS-1 in combination with an anti-PD1 inhibitor resulted in effective tumor reduction in the 4T1 model, which typically responds poorly to anti-PD1 therapy alone.
Conclusion: Taken together, the inhibition of nanotube-mediated mitochondrial hijacking from immune cells emerges as an approach for the development of next generation of immunotherapy agents.
Citation Format: Tanmoy Saha, Ruparoshni Jaybalan, HaeLin Jang, Shiladitya Sengupta. A novel immunotherapy approach by inhibiting nanotube-mediated mitochondrial trafficking between cancer cells and T cells [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 4238.