bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1768: Multiplexed shRNA cassettes targeting orthogonal pathways (FAS/PTPN2/TGFBR) enhance the potency of integrated circuit T cells (ICTs) in multiple solid tumor models
Authors: Gardner Thomas J. , Litterman Adam , Singh Brenal K. , Silva Luisa , Hari Mukund , Zhou Stanley , Tang Colin , Joshi Sahil , Gagnon John , Takacsi-Nagy Oliver , Hall Jason , Pope Hans , Zhang James , Gomez Alma , Chen Jeremy , Mohanty Suchismita , Thomas Vince , Quant Nicholas , Millare Beatriz , Casbon Amy-Jo , Bezman Natalie , Gray-Rupp Levi , Boroughs Angela C. , Haining W. Nicholas 
Published: April 2023

Abstract
T cell exhaustion resulting from chronic antigen stimulation and immunosuppression in the tumor microenvironment (TME) limits CAR T efficacy in the solid tumor setting. We have previously shown that engineering therapeutic T cell products using CRISPR-based gene insertion of a dual shRNA cassette targeting Fas and PTPN2 significantly increased antitumor efficacy of Integrated Circuit T cells (ICTs) in ovarian cancer models. We sought to build on this finding to induce additional gene perturbations that improve the efficacy of ICTs. Transforming growth factor (TGF)-b is an immunosuppressive cytokine that potently inhibits T cell responses and is present at high levels in numerous solid tumors, including renal cell carcinoma (RCC). In order to render ICT cells less susceptible to TGF-b-mediated suppression, we developed a quadruple shRNA cassette that simultaneously targets Fas, PTPN2, and TGFBR. Candidate TGFBR-targeting shRNAs were selected for their ability to reduce surface TGFBR receptor expression and impair proximal (pSMAD) or distal (CD103, PD-1) signaling through TGFBR. While single shRNAs against TGFBR did not rescue ICT cell activity in the presence of TGF-b, likely due to partial knockdown of TGFBR signaling, a cassette encoding two shRNAs against TGFBR restored ICT function to similar levels observed in the absence of TGF-b. The quadruple shRNA cassettes targeting Fas/PTPN2/TGFBR significantly enhanced antitumor activity of ICT cells in multiple xenograft tumor models relative to Fas/PTPN2 cassettes. These results demonstrate the utility of multiplexed shRNA strategies to render therapeutic T cells resistant to orthogonal suppressive pathways in solid tumors.
Citation Format: Thomas J. Gardner, Adam Litterman, Brenal K. Singh, Luisa Silva, Mukund Hari, Stanley Zhou, Colin Tang, Sahil Joshi, John Gagnon, Oliver Takacsi-Nagy, Jason Hall, Hans Pope, James Zhang, Alma Gomez, Jeremy Chen, Suchismita Mohanty, Vince Thomas, Nicholas Quant, Beatriz Millare, Amy-Jo Casbon, Natalie Bezman, Levi Gray-Rupp, Angela C. Boroughs, W. Nicholas Haining. Multiplexed shRNA cassettes targeting orthogonal pathways (FAS/PTPN2/TGFBR) enhance the potency of integrated circuit T cells (ICTs) in multiple solid tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1768.
Abstract 177: Expansion of established patient-derived tumoroids in a novel serum-free, Wnt-free media system
Authors: Paul Colin , Balhouse Brittany , Yankaskas Chris , Salen Shyanne , Djikeng Sybelle , Thakuri Pradip Shahi , Dallas Matt , Kuninger David 
Published: April 2023

Abstract
Tumoroid technology enables culture of patient tissue-derived cancer cells in 3D, with retention of key characteristics from the original patient tumor. However, current tumoroid culture relies on labor-intensive media formulations and culture workflows. To address these issues, we have developed the serum- and conditioned medium-free Gibco™ OncoPro™ Tumoroid Culture Medium to enable derivation and expansion of patient-derived lines from multiple cancer indications. The system has been optimized to retain key patient genotypic and phenotypic characteristics during in vitro culture in a Wnt agonist-free system that can be easily adopted and transferred between labs. To test the applicability of our system with previously established tumoroid/cancer organoid models, we procured publicly available cancer models from the National Cancer Institute Patient-Derived Models Repository (NCI PDMR). Multiple colorectal, lung, pancreas, and head and neck tumoroid models were tested, including tumoroids originally derived in conditioned medium containing Wnt-3A, R-spondin 3, and Noggin. Cells were assessed for survival, growth, and fidelity to starting material in both OncoPro Tumoroid Culture Medium and in PDMR-recommended homebrew media. Growth and morphology of tumoroid cells was monitored and was comparable between culture conditions. To test for genetic stability of cultures over time, the mutational status of organoids expanded in each condition was characterized using targeted NGS. Both SNV allelic frequency and ploidy values were conserved from initial starting material following expansion to cryopreservation-competent banks (&gt;10e6 cells). Gene expression levels across over &gt;20,000 human RefSeq genes were compared between culture methods and showed high (&gt;0.9) correlation, and Wnt-related signaling pathways were not differentially regulated between media types. In select cases, tumoroid cells expanded in each condition were also analyzed by flow cytometry using optimized antibody panels and protocols. Total cell viability and expression of EpCAM, CD45, CD31, smooth muscle actin, vimentin, CDX2, CEACAM, and cytokeratin 7 was nearly identical across culture conditions. Taken together, our approach represents a simple and effective method to expand and maintain patient-derived human cancer organoids in vitro, with no clear adverse effects from moving to a Wnt-free system.
Citation Format: Colin Paul, Brittany Balhouse, Chris Yankaskas, Shyanne Salen, Sybelle Djikeng, Pradip Shahi Thakuri, Matt Dallas, David Kuninger. Expansion of established patient-derived tumoroids in a novel serum-free, Wnt-free media system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 177.
Abstract 1804: Durable eradication of tumors by single injections of a pHLIP-STING agonist
Authors: Engelman Donald M. , Reshetnyak Yana K. , Andreev Oleg A. 
Published: April 2023

Abstract
Purpose: pHLIPs (pH-Low Insertion Peptides) target cell surface acidity resulting from the metabolism of cells in a solid tumor. The acidity causes pHLIPs to insert as transmembrane helices, and attached cargoes can be delivered into targeted cells. STING agonists can trigger an immune response when they are inside cells. pHLIP targeted delivery of a STING agonist (STINGa) effectively triggers cytokine secretion to mobilize the immune system to eradicate tumors while avoiding side effects.
Experimental Procedures: Constructs consisting of a pHLIP peptide (Var3) linked to a STINGa (diABZI) via a self-immolating linker were synthesized and characterized. Activation of the STING pathway by the agent was confirmed in cells. Small (100 mm3) and large (400-700 mm3) tumors were grown in female Balb/c mice following flank injections of CT26 colorectal cancer cells. Randomized groups of mice were injected i.p. or i.v. with pHLIP-STINGa made with L- or D- amino acid pHLIP peptides, STINGa alone, pHLIP alone or vehicle. Tumor size and body weight were then measured 3 times per week. The durability of the response to the agent was tested by a second injection of CT26 cells after 60 days. In separate experiments, the identities of targeted immune and stromal cells, the production of cytokines, the PK, tumor targeting and biodistribution were assessed.
Results and Conclusions: pHLIP extends the lifetime of a STINGa in the blood 6-fold and delivers STINGa to acidic cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), myeloid derived suppressor cells (mMDSCs), and dendritic cells (DCs). The resulting activation of cytokines within the tumor microenvironment (TME) triggers the eradication of small and large CT26 tumors in mice after a single dose of pHLIP-STINGa. The tumor stroma was destroyed, intratumoral hemorrhage developed, and the TME pH increased, which is important for the efficient cytotoxic activity of immune cells. Further, no tumors developed in 20 out of 25 tumor-free mice re-challenged by an additional injection of cancer cells. The therapeutic effect on CT26 tumors was insignificant in nude mice lacking T-cells. Inhibition of MHC-I negative B16F10 melanoma tumor growth was also observed in Balb/c mice. Thus, targeted delivery of the STINGa to the tumor stroma and TAMs activates signaling, potentially resulting in the recruitment and infiltration of both T-cells and NK-cells, which gain access to the tumor core. The cytotoxic activity of immune cells is enhanced, and immune memory is developed.
Citation Format: Donald M. Engelman, Yana K. Reshetnyak, Oleg A. Andreev. Durable eradication of tumors by single injections of a pHLIP-STING agonist [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1804.
Abstract 1806: Modulation of natural killer cell immune response to tumor with novel synthetic tumor -immune cell agonist, NK-TICA(r)
Authors: Dufort Fay , Leitheiser Christopher J. , Ho Kathleen , Ezell Tucker , Rezvaya Alexandra , Brown Peter , Chen Liuhong , Brandish Philip , McDonnell Kevin , Skynner Michael , Keen Nicholas 
Published: April 2023

Abstract
The tumor specific activation of natural killer (NK) cells with Bicycles is an area of active investigation in immune oncology. 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 discover and evaluate a new class of fully synthetic molecules termed NK tumor immune cell agonists (NK-TICA®). The NK-TICA® consists of chemically coupled Bicycles® that bind specifically to the key activating receptor, NKp46, and to tumor antigens, that results in highly potent, antigen-dependent receptor activation and NK cell activation. 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.
Citation Format: Fay Dufort, Christopher J. Leitheiser, Kathleen Ho, Tucker Ezell, Alexandra Rezvaya, Peter Brown, Liuhong Chen, Philip Brandish, Kevin McDonnell, Michael Skynner, Nicholas Keen. Modulation of natural killer cell immune response to tumor with novel synthetic tumor -immune cell agonist, NK-TICA(r) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1806.
Abstract 1834: Cholinergic nerve release of CGRP increases tumor growth in HNSCC by suppressing TILs
Authors: Darragh Laurel B. , Pham Tiffany T. , Knitz Michael M. , Nguyen Alexander , Mukdad Laith A. , Alhiyari Yazeed , John Maie St. , Karam Sana D. 
Published: April 2023

Abstract
Perineural invasion (PNI) and nerve density within the tumor microenvironment (TME) have long been associated with worse outcomes in head and neck squamous cell carcinoma (HNSCC). We investigate how nerves within the tumor microenvironment impact the adaptive immune system and tumor growth. RNA sequencing and proteomics data led us to identify cholinergic nerves as the potential drivers of tumor growth in human and mouse HNSCC. Using three syngeneic orthotopic murine models of HPV-unrelated HNSCC, experimental and pharmacologic manipulation of cholinergic output, and knockout mouse models, we discovered that activation of cholinergic nerves accelerate tumor growth by directly acting on the adaptive immune system. Cholinergic nerve release of calcitonin gene-related peptide (CGRP) directly inhibited CD8 T cell activity in vitro, and blocking cholinergic nerves pharmacologically or genetically increased CD8 T cell activity in vivo. These data support therapeutic translation of cholinergic nerve targeting of CGRP release to enhance antitumor immune response within the HNSCC TME.
Citation Format: Laurel B. Darragh, Tiffany T. Pham, Michael M. Knitz, Alexander Nguyen, Laith A. Mukdad, Yazeed Alhiyari, Maie St. John, Sana D. Karam. Cholinergic nerve release of CGRP increases tumor growth in HNSCC by suppressing TILs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1834.
Abstract 1870: VBI-003, a CD47xEpCAM bispecific antibody as a potential treatment for colorectal and small cell lung cancers
Authors: Wong Oi Kwan , Wang Xinhua , Chen Xiaocheng , Post Leonard 
Published: April 2023

Abstract
CD47/SIRPα axis is an important checkpoint of innate immune system and is often exploited by tumor cells to evade host immune surveillance. In recent years, therapies such as anti-CD47 monoclonal antibodies (mAbs) and SIRPα fusion proteins that target this axis have garnered much attention. Although exciting clinical activities have been observed in hematological cancers, responses in solid tumors are less impressive and often require complex combination strategies.
We previously described a novel CD47xEpCAM bispecific antibody, VBI-003, built on a human IgG1 backbone to harness the power of blocking CD47/SIRPα pathway while preserving the effector functions of IgG1 Fc (J ImmunoTher Cancer 2021;9:doi: 10.1136/jitc-2021-SITC2021.274). The bispecific design aims to improve selectivity so that SIRPα blocking and stable binding occur selectively on tumor cells where both CD47 and EpCAM are present. In vitro studies show that VBI-003 exhibits minimal red blood cell binding and does not cause hemagglutination, in contrast to benchmark CD47 mAb. VBI-003 has potent single agent activity in cell line derived xenograft (CDX) models of gastric and esophageal cancers. Here, we further explored the anti-tumor activities of VBI-003 in areas with great unmet needs such as small cell lung cancers (SCLC) and colorectal cancers (CRC).
Gene expression analysis from public datasets reveals frequent expression of CD47 and EpCAM in SCLC and CRC tumors. Flow cytometry studies confirmed co-expression of CD47 and EpCAM on SCLC and CRC cell lines. Furthermore, in vitro assays showed that VBI-003 has potent EpCAM dependent SIRPα blocking, antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity activities towards SCLC and CRC cell lines. Moreover, VBI-003 demonstrated potent single agent activity in multiple CDX models of SCLC with tumor regression and often outperformed benchmark CD47 mAb. Significant tumor growth inhibition was observed in colorectal cancer models post VBI-003 treatment, with additional activity by combination with standard of care chemotherapies. VBI-003 synergized with irinotecan and outperformed monotherapy groups in CDX models of CRC. In conclusion, VBI-003 has potent single agent activity in SCLC tumor models and combined synergistically with irinotecan in CRC models. Our data support further investigation of VBI-003 as a treatment for CD47 and EpCAM expressing SCLC and CRC.
Citation Format: Oi Kwan Wong, Xinhua Wang, Xiaocheng Chen, Leonard Post. VBI-003, a CD47xEpCAM bispecific antibody as a potential treatment for colorectal and small cell lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1870.
Abstract 1898: Racial/ethnic disparities in stage at diagnosis among women with cervical cancer in Texas: Mediating effects of neighborhood-level socioeconomic deprivation
Authors: Sokale Itunu O. , Oluyomi Abiodun O. , Thrift Aaron P. 
Published: April 2023

Abstract
Background: Although mortality from cervical cancer has declined steadily in the U.S. since the advent of population-based screening in the 1970s, the benefit has not reached all racial/ethnic groups of patients equally. This study examined the underlying role of neighborhood-level socioeconomic disadvantage as a potential mediator of the association between race/ethnicity and being diagnosed with late-stage versus early-stage cervical cancer. Methods: We analyzed Texas Cancer Registry data for cervical cancer cases diagnosed among women aged 18 or older from 2010 to 2018. Cervical cancer cases were categorized as early or late stage at diagnosis. First, we used a stepwise hierarchical logistic regression model to examine the associations between race/ethnicity and stage at diagnosis. Then, we performed causal mediation analyses using the counterfactual framework approach to estimate the direct, indirect (mediated), and total effects, and percent mediated. Results: Of the 9525 women with cervical cancer, 4869 (2200 non-Hispanic White (NHW) (45.2%), 720 non-Hispanic Black (NHB) (14.8%), 1800 Hispanic (37.0%)) had late-stage cervical cancer at diagnosis (overall, 51.1%). Women 65 years or older, NHB, Hispanic, with Medicaid/Medicare, uninsured, and those who reside in more deprived neighborhoods were more likely to present with advanced cervical cancer at diagnosis (p &lt;0.001). Compared to NHW women (11.8%), NHB (28.5%) and Hispanic (34.4%) women were more likely to live in most deprived neighborhoods and had greater odds of late-stage cervical cancer diagnosis (unadjusted odds ratios 1.49 (95% CI 1.31-1.69) and 1.20 (95% CI 1.10-1.31), respectively). In the age-adjusted mediation analysis, 23.1% and 52.2% of the disparity were attributable to higher disadvantages among NHB and Hispanic women, respectively.Conclusions: Results of mediation analyses suggested that area-level deprivation explained some of the racial/ethnic disparities in stage at diagnosis of cervical cancer among NHB and Hispanic women versus NHW women.Impact: These findings can be applied to develop targeted and race-specific interventions to improve early diagnosis and treatment of cervical cancer for cancer care equity.
Citation Format: Itunu O. Sokale, Abiodun O. Oluyomi, Aaron P. Thrift. Racial/ethnic disparities in stage at diagnosis among women with cervical cancer in Texas: Mediating effects of neighborhood-level socioeconomic deprivation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1898.
Abstract 19: Braf(v600e) mutation together with loss of trp53 or pten drives the origination of hairy cell leukemia from b-lymphocyte
Authors: Yap Jiajun , Yuan Jimin , Chen Bin Gao , Ng Wan Hwa , Sim Yuen Rong M. , Goh Kah Chun , Hu Jiancheng 
Published: April 2023

Abstract
Hairy cell leukemia (HCL) is a B-lymphoma induced by BRAF(V600E) mutation. However, introducing BRAF(V600E) in B-lymphocytes fails to induce hematological malignancy, suggesting that BRAF(V600E) needs concurrent mutations for driving HCL ontogeny. To resolve this issue, here we surveyed the human HCL genomic sequence data. Together with previous reports, we speculated that tumor suppressor, Trp53, P27, or pTEN restricted the oncogenicity of BRAF(V600E) in B-lymphocytes, whose loss-of-function facilitates the BRAF(V600E)-driven HCL ontogeny. Using genetic mice models, we demonstrated that indeed BRAF(V600E)KI together with Trp53KO or pTENKO in B-lymphocytes induced chronic lymphoma with pathological features of human HCL. To further understand cellular programs essential for HCL ontogeny, we next profiled the gene expression of leukemic cells isolated from BRAF(V600E)KI and Trp53KO or pTENKO mice, and found that these leukemic cells had similar but different gene expression signatures that resemble that of M2 or M1 macrophages. In addition, we examined the expression signature of transcription factors/regulators required for germinal center reaction and memory B cell versus plasma cell differentiation in these leukemic cells and found that most transcription factors/regulators essential for these programs were severely inhibited, which illustrates why hairy cells are arrested at a transitional stage between activated B cells and memory B cells. Together, our study has uncovered concurrent mutations for HCL ontogeny, revealed the B cell origination of hairy cells as well as molecular basis that underlies unique pathological features of this disease, and hence has important implications in both HCL research and clinic treatment.
Citation Format: Jiajun Yap, Jimin Yuan, Bin Gao Chen, Wan Hwa Ng, Yuen Rong M. Sim, Kah Chun Goh, Jiancheng Hu. Braf(v600e) mutation together with loss of trp53 or pten drives the origination of hairy cell leukemia from b-lymphocyte [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 19.