bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 342: Development and characterization of a novel anti-CLDN6 antibody drug conjugate for the treatment of CLDN6 positive cancers
Authors: McDermott Martina S. , Gong Ke Wei , O'Brien Neil A. , Conklin Dylan , Hoffstrom Benjamin , Lu Ming , Zhang Jun , Luo Tong , Jia Weiping , Hong Jenny J. , Chau Kevin , Davenport Simon , Press Michael F. , Handly-Santana Abram , Brugge Joan S. , Drapkin Ronny , Glaspy John A. , Presta Leonard , Slamon Dennis J. 
Published: June 2022

Abstract
Background: Claudin 6 (CLDN6), a member of the claudin family of tight junction proteins, is expressed at high levels in multiple human malignancies including ovarian and endometrial cancers. Conversely it has little or no expression in normal tissues. This expression profile makes CLDN6 an ideal target for development of potential therapeutic antibody-drug conjugates (ADCs). This study describes the generation and preclinical characterization of an anti-CLDN6 ADC consisting of a humanized anti-CLDN6 monoclonal antibody coupled to MMAE via a cleavable linker.
Materials and Methods: A fully humanized anti-CLDN6 antibody was initially characterized for binding affinity, selectivity/specificity, internalization characteristics and in vivo efficacy. It was then conjugated to MMAE resulting in the potential therapeutic anti-CLDN6 ADC. The anti-tumor efficacy of the ADC was next assessed for anti-tumor efficacy in CLDN6 positive (CLDN6+) and negative (CLDN6-) xenografts and patient-derived xenograft (PDX) models of specific cancers including ovarian and endometrial cancer.
Results: Selective binding of the ADC to CLDN6, without cross reactivity to other CLDN family members CLDN3, CLDN4 and CLDN9, was confirmed in human cancer cell lines and cells engineered to overexpress each protein. The ADC was also shown to rapidly internalize in CLDN6+ cells. Robust tumor regressions following treatment with the ADC were observed in CLDN6+ xenografts that were sustained beyond the treatment window. Conversely, there was limited to no activity of the ADC in CLDN6- xenografts models. In addition, the prevalence of CLDN6 expression in human ovarian and endometrial cancers was assessed by IHC in tissue microarrays and found to be 28% (ovarian epithelial carcinomas) and 11% (endometrial carcinomas), respectively.
Discussion: Overall, these data suggest that our anti-CLDN6 ADC may be a promising treatment for patients with CLDN6+ tumors and it is currently in Phase I clinical testing.
Citation Format: Martina S. McDermott, Ke Wei Gong, Neil A. O'Brien, Dylan Conklin, Benjamin Hoffstrom, Ming Lu, Jun Zhang, Tong Luo, Weiping Jia, Jenny J. Hong, Kevin Chau, Simon Davenport, Michael F. Press, Abram Handly-Santana, Joan S. Brugge, Ronny Drapkin, John A. Glaspy, Leonard Presta, Dennis J. Slamon. Development and characterization of a novel anti-CLDN6 antibody drug conjugate for the treatment of CLDN6 positive 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 342.
Abstract 345: Development of a novel and direct peptide Helicon࣪ inhibitor of β-catenin-TCF interaction with in vivo validation of transcriptional modulation and anti-tumor activity
Authors: Si Yaguang , White Brian , Cappucci Sarah , Ramirez Jessica , Ponthier Charles , Visness Erica , Ling Kevin , Du Peicheng , Choi Minjung , Thomson Ty , Alfaro-Lopez Josue , Beerepoot Pieter , Agarwal Sorabh , Ortet Paula , Lech Miroslaw , Li Zhi , Olokpa Voké , Jewett Ivan , La Daniel , Yu Lihua , McGee John , Tremblay Martin , Hurov Jonathan , Verdine Greg 
Published: June 2022

Abstract
Wnt pathway mutations can be found in nearly all colorectal cancers and a significant number of cancers of the liver, breast, prostate, endometrium and lung, among others. β-catenin is a key signaling hub in the Wnt pathway. Activated nuclear β-catenin forms a complex with TCF/LEF (T-cell factor/lymphoid enhancer binding factor) and drives the transcription of genes essential for cancer cell proliferation, survival, and metabolism. Blocking the β-catenin-TCF/LEF interaction offers an attractive therapeutic strategy to treat a large population of patients with WNT pathway mutations. However, β-catenin is considered as an “undruggable” target because it lacks tractable hydrophobic pockets for small-molecule binding. To address this challenge, we have successfully discovered and developed Helicon࣪ peptides targeting the β-catenin-TCF/LEF interaction. Using this novel modality, linear peptides are locked in a helical structure via a proprietary tethering technology to yield macrocyclic stapled peptides.
Our helicons exhibit picomolar β-catenin binding affinity and nanomolar anti-proliferative cell-based activity. Cells treated with lead helicons followed by unbiased RNAseq GSEA indicate that the WNT/β-catenin pathways represent the top downregulated transcriptional signatures after treatment. Furthermore, PRISM cell line screening of more than 900 cell lines reveals that the most sensitive lines are enriched with APC and CTNNB1 mutations. Mechanistically, helicon treatment reduces nuclear β-catenin and alters the levels of cyclin D2/D3 and p27 in the sensitive lines. In vivo, our helicons display favorable pharmacokinetic properties, broad tissue distribution, and potent anti-tumor effects. Taken together, our data demonstrate β-catenin-targeting Helicon࣪ peptides have the potential to become the next-generation class of therapeutics to treat cancers with defined genetic mutations.
Citation Format: Yaguang Si, Brian White, Sarah Cappucci, Jessica Ramirez, Charles Ponthier, Erica Visness, Kevin Ling, Peicheng Du, Minjung Choi, Ty Thomson, Josue Alfaro-Lopez, Pieter Beerepoot, Sorabh Agarwal, Paula Ortet, Miroslaw Lech, Zhi Li, Voké Olokpa, Ivan Jewett, Daniel La, Lihua Yu, John McGee, Martin Tremblay, Jonathan Hurov, Greg Verdine. Development of a novel and direct peptide Helicon࣪ inhibitor of β-catenin-TCF interaction with in vivo validation of transcriptional modulation and 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 345.
Abstract 3495: A novel Mediterranean dietary intervention for prostate cancer
Authors: Cass Samuel , Wargo Jennifer , Pettaway Curtis , Pisters Louis , Davis John , Chapin Brian , Ward John , Daniel Carrie , Gregg Justin 
Published: June 2022

Abstract
Active surveillance (AS) is a safe management strategy for men with low-risk prostate cancer; however, nearly 35% of men on AS will undergo definitive treatment within 4 years, most commonly due to disease progression. Determining a non-invasive means of limiting disease progression would allow men to avoid quality of life issues associated with radical prostate treatment. Some modifiable factors, such as obesity and lipid levels, are associated with prostate cancer risk, though no behavioral intervention has been shown to affect prostate cancer outcomes. Using a prospective study of men on active surveillance, our group recently demonstrated that higher quality diets were associated with a significantly lower risk of disease progression. The Mediterranean diet (MD) specifically may be beneficial for men with localized prostate cancer (PCa) on active surveillance (AS) because of its anti-inflammatory, antilipidemic, and chemopreventive properties. Furthermore, recent evidence supports that dietary interventions can induce modulation of the gut microbiome, and consequently, immune function and inflammatory pathways, which warrants further investigation of the microbiome’s role in the context of prostate cancer. Here, we describe a novel dietary intervention among a group of men with localized prostate cancer who are electing to undergo prostatectomy for prostate cancer treatment. The intervention is a feeding study involving the provision of an isocaloric, high quality diet based on the lipid-lowering and anti-inflammatory parameters of the Mediterranean diet, including a strong focus on fiber-rich plant foods and healthy sources of mono and poly-unsaturated fatty acids. The primary outcome in this pilot study is the feasibility of a neoadjuvant dietary intervention. Secondary outcomes include studying the effects of the diet on metabolic parameters, the fecal microbiome, and changes in circulating metabolites shown to be associated with progression on active surveillance. Furthermore, by focusing on African-American and non-Hispanic White males, this study may provide insights into the key differences in inflammatory, immune and microbiome signatures, which may underly the prominent cancer-racial disparity seen in African-American men. Therefore, this study will gain preliminary data needed to inform further dietary interventions that may impact risk of progression in select men with prostate cancer enrolled on active surveillance.
Citation Format: Samuel Cass, Jennifer Wargo, Curtis Pettaway, Louis Pisters, John Davis, Brian Chapin, John Ward, Carrie Daniel, Justin Gregg. A novel Mediterranean dietary intervention for prostate cancer [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 3495.
Abstract 3504: QL415, a tumor targeted IL-15 fusion protein stimulating both lymphoid and myeloid immune cells for optimal anti-tumor immune response
Authors: Tang Irene , Schwimmer Lauren , Jin Monica , Gu Shenda , Prior Wei Wei , Capacio Arianne , Tran Hieu V. , Chan Allan , McClain Anna , Chen Shihao , Cao Chuanzeng , Wu Xiaoran , Xu Yanling , Guan Dongmei , Chen Xi , Su Xianli 
Published: June 2022

Abstract
Cytokines are potent stimulators of the immune system and have long been investigated and used as therapeutics to treat cancer. However, free cytokines have short half-life and the lack of tumor targeting often results in systemic toxicity. IL-15 is a stimulatory cytokine that shares the common beta and gamma receptors with IL-2. In contrast to IL-2, IL-15 is more selective for NK and effector memory T cells, with less proliferative effect on Tregs, making it a more preferred therapeutic candidate for cancer. QL415 is an anti-PD-L1 x IL-15 fusion protein designed to enhance tumor accumulation and prolong blood circulation, thereby widening the therapeutic window. IL-15 and IL-15 receptor alpha sushi domain are covalently linked to the C-terminus of our proprietary PD-L1 antibody. Fc-mediated effector functions were ablated using mutations in the CH2 domain, to prevent depletion of effector immune cells. In vitro studies showed QL415 to be highly potent in promoting proliferation and pSTAT5 signaling of IL-15 -responding NK92 and M07e cells. QL415 selectively induced proliferation of NK and CD8+ T cells from human PBMC in vitro and mouse CD8+ and NK1.1 cells in vivo. In a MC38 mouse colon cancer model expressing human PD-L1, QL401 was highly effective in suppressing tumor growth, in contrast to PD-L1 monoclonal antibody or a non-targeted IL-15 control. Follow up tumor rechallenge study showed protective memory against cognate MC38 but not B16F10. In a separate MC38 tumor model using a mouse surrogate molecule of QL415, immunophenotyping of antigen presenting cells offered preliminary evidence of enrichment of conventional dendritic cells 1 in the tumor draining lymph nodes. Therefore, QL415 not only directly stimulates effector immune cells, but also indirectly through antigen presenting cells, promotes robust anti-tumor response. In non-human primates, Q415 was tolerated up to 1.5 mg/kg, well above the effective therapeutic dose. In light of these favorable preclinical efficacy and safety results, a phase 1 dose escalation and expansion study has been initiated to evaluate the safety, tolerability, and early efficacy of QL415.
Citation Format: Irene Tang, Lauren Schwimmer, Monica Jin, Shenda Gu, Wei Wei Prior, Arianne Capacio, Hieu V. Tran, Allan Chan, Anna McClain, Shihao Chen, Chuanzeng Cao, Xiaoran Wu, Yanling Xu, Dongmei Guan, Xi Chen, Xianli Su. QL415, a tumor targeted IL-15 fusion protein stimulating both lymphoid and myeloid immune cells for optimal anti-tumor immune response [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 3504.
Abstract 3531: Sensitizing immune unresponsive colorectal cancers to immune checkpoint inhibitors through MAVS overexpression
Authors: Hwang Bin-Jin , Tsao Li-Chung , Acharya Chaitanya , Trotter Timothy , Agarwal Pankaj , Wang Tao , Wei Junping , Yang Xiao-Yi , Lei Gang-jun , Osada Takuya , Lyerly Herbert Kim , Morse Michael A. , Hartman Zachary 
Published: June 2022

Abstract
Background: The majority of colorectal carcinomas (CRCs) are insensitive to anti-PD-1/PD-L1 immune checkpoint inhibitor (ICI) antibodies. While there are many causes for ICI insensitivity, recent studies suggest that the suppression of innate immunity through a loss of innate immune adaptor expression could be a root cause of this insensitivity and an important factor in the evolution of tumor immunosuppression.
Methods: We interrogated mitochondrial antiviral signaling gene (MAVS) expression through bioinformatics analyses of multiple datasets to validate its suppression in clinical samples. We then engineered MAVS expressing tumor cells and tested its ability to elicit innate and adaptive anti-tumor immunity using both in vitro and in vivo approaches, which we then confirmed using MAVS expressing viral vectors. Finally, we observed that MAVS stimulated PD-L1expression in different types of tumor cells and then assessed the combination of PD-L1 ICI antibodies with MAVS tumor expression in vivo.
Results: MAVS was significantly downregulated in CRCs, but its re-expression could stimulate broad cellular interferon-related responses, in both murine and patient-derived CRCs. In vivo, local MAVS expression elicited significant anti-tumor responses in both immune-sensitive and insensitive CRC models, through the stimulation of an interferon responsive axis that elicited tumor antigen-specific adaptive immunity. Critically, we found that tumor-intrinsic MAVS expression triggered systemic adaptive immune responses that enabled abscopal CD8+ T cell cytotoxicity against distant CRCs. As MAVS also induced PD-L1 expression, we further found synergistic anti-tumor responses in combination with anti-PD-L1 ICIs.
Conclusion: These data demonstrate that intratumoral MAVS expression results in local and systemic tumor antigen-specific T cell responses, which could be combined with PD-L1 ICI to permit effective anti-tumor immunotherapy in ICI resistant cancers. We are further exploring to overcome the ICI insensitivity of other types of solid tumor, with MAVS-delivery strategies other than viral vectors.
Citation Format: Bin-Jin Hwang, Li-Chung Tsao, Chaitanya Acharya, Timothy Trotter, Pankaj Agarwal, Tao Wang, Junping Wei, Xiao-Yi Yang, Gang-jun Lei, Takuya Osada, Herbert Kim Lyerly, Michael A. Morse, Zachary Hartman. Sensitizing immune unresponsive colorectal cancers to immune checkpoint inhibitors through MAVS overexpression [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 3531.
Abstract 3538: A CTLA-4 targeted ETB for Treg depletion shows favorable preclinical efficacy and safety
Authors: Sarkar Asis , Martin Rebecca , Byrne Lauren R. , Howard Caleigh , Khanna Swati , Rabia Lilia A. , Adhikari Diana , Sousares Michaela M. , Aldana Alvaro , Robinson Garrett L. , Zhao Jay , Moore Chris B. , Iberg Aimee 
Published: June 2022

Abstract
CTLA-4-targeted engineered toxin bodies (ETBs) are designed to deplete immune-suppressive regulatory T cells (Tregs) in the tumor microenvironment (TME) directly and in a manner independent of Fc-mediated effector functions, offering a unique approach to CTLA-4 targeted therapy that may show efficacy where blocking antibodies have failed. ETBs are large molecule proteins consisting of an antibody fragment genetically fused to a proprietary de-immunized (DI) form of the Shiga-like toxin-1 subunit A (SLTA). Once engaged to the specific cell surface target of interest, ETBs internalize, route to the cytosol, and permanently inactivate ribosomes through an irreversible enzymatic process. This results in cell death via apoptotic mechanisms.
Here we describe the preclinical characterization of a candidate CTLA-4-targeted ETB. The candidate ETB kills gain-of-function model cell lines that express CTLA-4 at levels observed on primary human tumor Tregs. Notably, the potency of the candidate ETB is limited when CTLA-4 is expressed at low levels, thereby allowing a mechanism to spare CD8+ cytotoxic T lymphocytes (CTLs) and effector CD4+ T cells from targeted depletion. The candidate ETB binds CTLA-4 with high affinity utilizing a unique biparatopic binding domain. Using in vitro systems, we show that the candidate ETB can block CTLA-4:B7 interactions and repress Treg-mediated T-cell suppression. In a syngeneic mouse pharmacodynamic model, the candidate ETB depletes tumor-resident Tregs and increases the CD8:Treg ratio in the TME. A toxicological study in naive NHP demonstrate that the candidate ETB, which is cross-reactive to NHP, is well-tolerated at 450 mcg/kg (highest dose tested) administered intravenously once weekly for 4-weeks and does not significantly alter the CTLA-4 low/null peripheral T cell populations. Overall, the candidate ETB is a unique CTLA-4 targeting modality that is designed to deplete Tregs selectively and directly in the tumor, spare CD8+ CTLs, and represents an alternative treatment option to traditional blocking antibodies. Development activities are underway to support the upcoming IND application.
Citation Format: Asis Sarkar, Rebecca Martin, Lauren R. Byrne, Caleigh Howard, Swati Khanna, Lilia A. Rabia, Diana Adhikari, Michaela M. Sousares, Alvaro Aldana, Garrett L. Robinson, Jay Zhao, Chris B. Moore, Aimee Iberg. A CTLA-4 targeted ETB for Treg depletion shows favorable preclinical efficacy and safety [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 3538.
Abstract 3558: A novel and versatile cytokine empowered DNA vaccine platform with superior immune activating potential
Authors: Beraas Audun , Dillard Pierre , Wong Judith Jing , Wold Christian Winther , Solbakken Eirik , Oslen Linn Guro , Heim Joel Benjamin , Chellappa Stalin , Fredriksen Agnete , Pedersen Mikkel Wandahl , Granum Stine 
Published: June 2022

Abstract
Immunotherapy, in particular Immune Checkpoint Blockade (ICB) has been regarded as the next standard of care for many solid tumor indications. Yet, a significant proportion of patients do not respond to therapy. More specifically, failure of ICB has been linked to the absence of an anti-tumor immune response that can be boosted or revitalized. Cancer vaccines that are designed to elicit such response by educating the host immune system to recognize tumor antigens, are therefore considered a key next generation therapeutic modality for the treatment of human cancers.
Various vaccine platforms have been developed over the years, but recent advances in delivery technologies combined with the intrinsic qualities of the DNA matrix have positioned DNA vaccines as a safe and flexible alternative to other types of vaccine technologies. Vaccibody is developing DNA vaccines that allows specific targeting of tumors antigens to Antigen Presenting Cells (APCs), thus maximizing the elicited immune response.
Here we present a second-generation version of our DNA platform in which our vaccibody molecule can be co-expressed with immune-stimulatory proteins from one plasmid using a multicistronic design. Compared to the vaccibody molecule alone the simultaneous expression of selected immune stimulatory cytokines was shown to boost the overall immune response almost 3-fold to drive a potent anti-tumor response.
These data demonstrate the flexibility and potential of DNA vaccines as well as the advantages of combining an APC targeted delivery of tumor specific antigens together with a local production of immune stimulatory proteins.
Citation Format: Audun Beraas, Pierre Dillard, Judith Jing Wong, Christian Winther Wold, Eirik Solbakken, Linn Guro Oslen, Joel Benjamin Heim, Stalin Chellappa, Agnete Fredriksen, Mikkel Wandahl Pedersen, Stine Granum. A novel and versatile cytokine empowered DNA vaccine platform with superior immune activating potential [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 3558.
Abstract 3563: CD8+ T cell-mediated tumor rejection by an Adeno-associated virus-like particle (AAVLP) vaccine
Authors: Neukirch Lasse , Schmidt Patrick , Zörnig Inka , Jäger Dirk , Uhrig-Schmidt Silke 
Published: June 2022

Abstract
The utilization of adeno-associated viruses (AAVs) as vaccines has primarily been focused on the induction of antibody responses. Displaying antigens derived from HER2 or HPV on the AAV capsid surface lead to strong humoral immune responses. However, the potential of AAVs as T cell inducing vaccines has been poorly investigated. Model antigens have been inserted into the capsid of AAVs to analyze T cell responses, but these studies rather focused on preventing vector immunity for an improved tolerance of gene therapies. By using this as a starting point, we set out to test AAVs as T cell inducing vaccines with the prospect of targeting cancer neoantigens. In first experiments, the general properties of the vaccination strategy were estimated by displaying the ovalbumin-derived model antigen SIINFEKL on the surface of adeno-associated virus-like particles (AAVLPs). Upon injection of the AAVLP-SIINFEKL vaccine, mice developed strong CD8+ T cell responses against the displayed antigen. Highest immune responses were achieved by subcutaneous hock injection of AAVLPs, adjuvanted by Montanide ISA 51 VG. SIINFEKL-specific T cell responses peaked around three weeks after vaccination, whereas a memory subset remained present for long term. The anti-tumor efficacy of the vaccine was shown by injecting SIINFEKL-expressing B16F10 melanoma cells subcutaneously into mice, in which the tumor was completely rejected after vaccination. Interestingly, the induction of CD8+ T cell responses and the tumor protection depended on the presence of CD4+ T cells. Accordingly, T helper epitopes were identified in the AAVLP capsid sequence. In addition to the initial tests, a set of murine neoantigens, derived from B16F10 cells, were displayed on AAVLPs. In direct comparison to a peptide vaccine, which did not have an effect on tumor growth, the AAVLP vaccine had a significant impact on the tumor growth rate. In conclusion, AAVLPs show promising effects as T cell vaccines. The vaccination strategy can be used to induce cytotoxic T cell responses in general and anti-tumor effects in particular. AAV capsid-specific helper epitopes is one inherent advantage, since the AAVLP vaccine delivers immune stimulation within the viral particle itself. Thus, antigen-displaying AAVLPs could be an alternative to current gold standards in the field of neoantigen vaccines and have a prospect for future clinical applications.
Citation Format: Lasse Neukirch, Patrick Schmidt, Inka Zörnig, Dirk Jäger, Silke Uhrig-Schmidt. CD8+ T cell-mediated tumor rejection by an Adeno-associated virus-like particle (AAVLP) vaccine [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 3563.