bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 891: CRISPR-Cas9-gRNA RNP mediated gene knockout of TGFBR2 and CISH enhances CD19-CAR NK cell function and provides resistance to TGFβ
Authors: Guo Chao , Chan Ivan H. , Buren Luxuan , Fan Yanying , Aronov Alexander , Trager James B. 
Published: September 2020

Abstract
Natural killer (NK) cells, known for their ability to kill tumor cells, represent a promising ‘off the shelf' therapeutic for cell-based cancer immunotherapy. One of the major challenges with NK cell-based therapies includes their lack of persistence and expansion after adoptive transfer. In addition, the presence of inhibitory signals within the tumor microenvironment and mediated by tumor cells also contributes to the poor infiltration and activation of NK cells at the tumor site. To improve NK cell function, we developed an optimized CRISPR-Cas9 system utilizing electroporation of CRISPR-gRNA ribonucleoproteins (RNPs) to disrupt important regulatory genes to enhance and/or protect primary human NK cell function. This method allowed efficient knockout of the TGFBR2 and CISH genes in NK cells, genes that have a functional impact on NK cells. FACS and Amplicon NGS Sequencing data confirmed both genes were successfully disrupted. Furthermore, we were able to transduce and expand CRISPR/Cas9 edited NK cells to express a CD19-CAR construct and membrane bound IL-15. Cytotoxicity assays demonstrated that TGFBR2 knockout CD19-CAR NK cells were resistant to TGFβ inhibition of cytotoxicity. We also showed that CISH gene-edited CD19-CAR NK cells have significantly improved proliferation, survival, cytokine production, and cancer cell cytotoxicity. In summary, this data demonstrates that this platform enables effective primary human NK cell gene knockout to enhance NK function and provide resistance to tumor microenvironment inhibition.
Citation Format: Chao Guo, Ivan H. Chan, Luxuan Buren, Yanying Fan, Alexander Aronov, James B. Trager. CRISPR-Cas9-gRNA RNP mediated gene knockout of TGFBR2 and CISH enhances CD19-CAR NK cell function and provides resistance to TGFβ [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 891.
Abstract 955: Long-term gemcitabine treatment reshapes the pancreatic tumor microenvironment and sensitizes murine carcinoma to combination immunotherapy
Authors: Principe Daniel R. , Narbutis Matthew , Kumar Sandeep , Park Alex , Viswakarma Navin , Dorman Matthew J. , Kamath Suneel D. , Grippo Paul , Fishel Melissa L. , Hwang Rosa F. , Thummuri Dinesh , Underwood Patrick W. , Munshi Hidayatullah G. , Trevino Jose G. , Rana Ajay 
Published: September 2020

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death with a median survival time of 6-12 months. As most patients present with disseminated disease, the majority are offered palliative chemotherapy. With no approved treatment modalities for patients who progress on chemotherapy, we explored the effects of long-term Gemcitabine on the tumor microenvironment in order to identify potential therapeutic options in chemo-refractory PDAC. Using a combination of mouse models, patient-derived xenografts, primary and established cell lines, we first evaluated chemotherapy-induced alterations in the tumor secretome and immune surface proteins by high throughput proteomic arrays. In addition to enhancing antigen presentation and immune checkpoint expression, Gemcitabine consistently increased the synthesis of CCL/CXCL chemokines and TGFβ-associated signals. These secreted factors altered the composition of the tumor stroma, conferring Gemcitabine-resistance to cancer-associated fibroblasts in vitroand further enhancingTGFβ1 biosynthesis. We therefore combined Gemcitabine with anti-PD-1 in transgenic models of murine PDAC, which failed to alter disease course unless mice also underwent genetic or pharmacologic ablation of TGFβ signaling. In the setting of TGFβ signal deficiency, Gemcitabine and anti-PD-1 led to a robust CD8+ T-cell response and decrease in tumor burden, markedly enhancing overall survival. These results suggest that Gemcitabine may prime PDAC tumors for immune checkpoint inhibition by enhancing antigen presentation, but requires the inhibition of an immunosuppressive cytokine barrier. Given the current lack of third line treatment options, this approach warrants consideration in the clinical management of Gemcitabine-refractory PDAC.
Citation Format: Daniel R. Principe, Matthew Narbutis, Sandeep Kumar, Alex Park, Navin Viswakarma, Matthew J. Dorman, Suneel D. Kamath, Paul Grippo, Melissa L. Fishel, Rosa F. Hwang, Dinesh Thummuri, Patrick W. Underwood, Hidayatullah G. Munshi, Jose G. Trevino, Ajay Rana. Long-term gemcitabine treatment reshapes the pancreatic tumor microenvironment and sensitizes murine carcinoma to combination immunotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 955.
Abstract 958: PARP-inhibition induces cancer immunogenic cell death in response to high levels of interferon-gamma in the tumor microenvironment
Authors: Kinjyo Ichiko , Adams Sarah F. 
Published: September 2020

Abstract
Background: We recently demonstrated that treatment with poly(ADP-ribose) polymerase (PARP) inhibitors sensitize BRCA1-deficient ovarian cancers to immune checkpoint blockade in preclinical models. The extended survival in response to this combination was associated with a significant increase in IFNg producing effector T cells in the tumor environment. In vitro experiments identified a significant interaction between PARP-inhibition and IFNg that promoted tumor cytotoxicity in a caspase-independent manner. We hypothesized that IFNg engages immunogenic cell death mechanisms in response to PARP-inhibition to promote immune-mediated tumor clearance.
Methods: To distinguish cell death mechanisms in vitro, we exposed ovarian cancer cells to a PARP-inhibitor (10 microg/ml) and IFNg (2 ng/ml). Calreticulin translocation to the cell membrane and the release of high-mobility group protein 1 (HMGB-1) were assessed as characteristic features of immunogenic cell death. Innate cell activation was evaluated by analysis of dendritic cells in draining lymph nodes after vaccination. Evidence of immunogenicity was confirmed in vivo with vaccination studies.
Results: Tumor cells treated with a PARP-inhibitor in combination with IFNg, but not the cells exposed to the PARP-inhibitor alone, demonstrated calreticulin translocation and HMGB-1 release. In vivo, vaccination using cells treated with both the PARP-inhibitor and IFNg protected animals from intraperitoneal tumor challenge. Vaccinated mice also rejected secondary and tertiary tumor challenges demonstrating durable protective memory. Vaccinated tumor cells were phagocytosed by DCs in draining lymph nodes and induced co-stimulatory ligand and MHC expression. Adoptive transfer of splenocytes from vaccinated animals confirmed that this protective effect was T cell-mediated.
Conclusions: These results identify a novel mechanism by which PARP-inhibition drives immunogenic cell death in response to IFNg in the ovarian tumor environment. These effects can be leveraged to enhance tumor clearance in combination with immune therapy, and may present a strategy to circumvent adaptive treatment resistance associated with high levels of IFNg in the tumor microenvironment.
Citation Format: Ichiko Kinjyo, Sarah F. Adams. PARP-inhibition induces cancer immunogenic cell death in response to high levels of interferon-gamma in the tumor microenvironment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 958.
Abstract 978: Monocyte-derived macrophages contribute to the inflammation-induced survival of experimental micrometastases in the lung
Authors: Arif Arif A. , Freeman Spencer A. , Atif Jawairia , Dean Pamela , Gilmour Megan , Blanchet Marie-Renee , Wiegand Kimberly , McNagny Kelly M. , Underhill Michael , Gold Michael , Johnson Pauline , Roskelley Calvin D. 
Published: September 2020

Abstract
Circulating tumor cells become fully metastatic if they are able to extravasate from the microvasculature and move into microenvironmental niches that facilitate their survival within distant site organs. To determine if inflammation promotes this process in the lungs, inflammatory asthma, hypersensitivity pneumonitis, or bleomycin-induced injury were initiated prior to the intravenous introduction of low malignant potential B16F0 melanoma cells. All three conditions increased end-stage metastatic burden without increasing the initial tumor cell extravasation from the lung microvasculature. There was, however, an increase in the number and size of early micrometastatic lesions within the lung interstitia that were visible 96 hr after melanoma cell introduction. There was also an increase in tumor cell survival within these early lesions located in the inflamed lungs that was associated with the presence of nearby newly recruited CD11c+CD11b+ monocyte-derived macrophages (MoDM). Adoptive transfer experiments indicated that these MoDM cells facilitated B16F0 cell metastasis in the absence of inflammation. Additionally, a factor, or factors, secreted by MoDM promoted B16F0 cell survival under stress-inducing condition. Taken together, these findings demonstrate that inflammation-induced monocyte-derived macrophages act as a modifier of the post-extravasation microenvironment that appears to facilitate the early emergence of distant site metastasis.
Citation Format: Arif A. Arif, Spencer A. Freeman, Jawairia Atif, Pamela Dean, Megan Gilmour, Marie-Renee Blanchet, Kimberly Wiegand, Kelly M. McNagny, Michael Underhill, Michael Gold, Pauline Johnson, Calvin D. Roskelley. Monocyte-derived macrophages contribute to the inflammation-induced survival of experimental micrometastases in the lung [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 978.
Abstract 996: Reversing tumor induced immune suppression: Role of the secretory autophagy pathway
Authors: Howard Marissa Ashton 
Published: September 2020

Abstract
The goal is to reverse cancer immune evasion at the level of the sentinel lymph node. Reduced expansion of CD8+Tcells and other innate immune effector cells in the cancer draining SLN is associated with progression and resistance to checkpoint inhibitors. Cancer derived extracellular vesicles (EVs) that are PD-L1 positive suppress immune recognition at the level of the SNL. Experimental goal: To remodel the SNL to overcome cancer EV-associated immune suppression and induce immune rejection of the tumor. We developed three methodologies for this project a) Collection of draining lymph fluid to characterize extracellular vesicles (EVs) shed by 4T1 syngeneic breast tumors growing in the mammary fat pad. b) Chromatographic separation and characterization of the repertoire of EVs shed by tumors into the tumor microenvironment interstitial space using western blotting, mass spectrometry, and electron microscopy. c) Nanoparticle delivery of purified classes of EVs to the tumor draining SNL in combination with cytokine chemoattractants for innate immune cells. Results: Murine and human breast cancer cell lines shed classic exosomes and autophagosomes. The latter are shed extracellularly by the activation of the secretory autophagy pathway. The classic exosomes(exosome marker positive) contained PD-L1. In contrast the LC3 I/II P62 positive double membrane extracellular autophagosomes contained mitochondrial components (mitophagy). SLN immune cell populations could be massively remodeled by introducing hydrogel nanoparticles that affinity release chemoattractants locally in the subcapsular sinus. Nanoparticles could also be used to deliver concentrated packages of EVs of different classes to the SLN. Introduction of the autophagosome containing EV population to the SLN augmented tumor growth, angiogenesis, and metastasis, even when cytokine induction was used to remodel the SLN. In marked contrast, introduction of the PD-L1 positive exosomes to the SLN in combination with nanoparticle release of T-cell and dendritic cell chemoattractants, induced immune rejection of the syngeneic breast cancer, reducing tumor growth and blocking metastasis. The findings demonstrate that different classes of EVs have opposite effects on cancer immune evasion at the level of the SLN and that immune suppression can be reversed by SLN remodeling to augment dendritic and CD8 T cells.
Citation Format: Marissa Ashton Howard. Reversing tumor induced immune suppression: Role of the secretory autophagy pathway [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 996.
Abstract CT123: Phase I study of a B cell-based and monocyte-based immunotherapeutic vaccine, BVAC-C, in human papillomavirus type 16- or 18-positive recurrent cervical cancer
Authors: Choi Chel Hun , Choi Hyun Jin , Lee Jeong-Won , Kang Eun-Suk , Cho Duck , Park Byung Kwan , Kim Yong-Man , Kim Dae-Yeon , Seo Hyungseok , Park Myunghwan , Kim Wuhyun , Choi Ki-Young , Oh Taegwon , Kang Chang-Yuil , Kim Byoung-Gie 
Published: September 2020

Abstract
BVAC-C is a B cell-based and monocyte-based immuno-therapeutic vaccine transfected with a recombinant human papillomavirus (HPV) 16/18 E6/E7 gene and loaded with alpha-galactosyl ceramide, which is a natural killer T cell ligand. This phase I study sought to determine the tolerability and immunogenicity of BVAC-C in platinum-resistant recurrent cervical cancer patients. Patients with HPV 16-positive or 18-positive recurrent or persistent cervical cancer who had received at least one prior platinum-based combination chemotherapy were enrolled. BVAC-C was injected intravenously three times every four weeks, and dose escalation was planned in a three-patient cohort design at doses of 1×107, 4×107, or 1×108 cells/dose. Eleven patients were enrolled, and six (55%) patients had received two or more lines of platinum-based chemotherapy prior to enrollment. Treatment-related adverse events (TRAEs) were observed in 21 cycles. Most TRAEs were mild fever (n = 6.55%) or myalgia (n = 4.36%). No dose-limiting toxicities occurred. The overall response rate was 11% among nine patients evaluable, and the duration of response was 10 months. Five patients (56%) achieved a stable disease for 4.2-11 months as their best overall response. The median progression-free survival in all patients was 6.8 months (95% CI, 3.2 to infinite months), and the overall survival rate at 6 and 12 months was 89% (95% CI, 71 to 100%) and 65% (95% CI, 39 to 100%), respectively. BVAC-C induced the activation of natural killer T cells, natural killer cells, and HPV 16/18 E6/E7-specific T cells upon vaccination in all patients evaluated. BVAC-C was well tolerated and demonstrated a durable anti-tumor activity with an immune response in HPV 16-positive or 18-positive recurrent cervical carcinoma patients. A Phase 2 efficacy trial is currently underway.
Citation Format: Chel Hun Choi, Hyun Jin Choi, Jeong-Won Lee, Eun-Suk Kang, Duck Cho, Byung Kwan Park, Yong-Man Kim, Dae-Yeon Kim, Hyungseok Seo, Myunghwan Park, Wuhyun Kim, Ki-Young Choi, Taegwon Oh, Chang-Yuil Kang, Byoung-Gie Kim. Phase I study of a B cell-based and monocyte-based immunotherapeutic vaccine, BVAC-C, in human papillomavirus type 16- or 18-positive recurrent cervical cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT123.
Abstract CT137: A pilot pharmacokinetic study of VAL413 in patients with recurrent pediatric solid tumors
Authors: Geller James I. , Brown Dennis , Bacha Jeffrey , Sankar Neil , Kanekal Sarath , Leggas Mark , Wagner Lars 
Published: September 2020

Abstract
Background: Ewing's sarcoma (EWS) is the second most common malignant bone tumor affecting children, adolescents and young adults. Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer. IRN-IV is also widely used off-label as salvage therapy for patients with recurrent EWS, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, and medulloblastoma. Prior adult and pediatric trials demonstrate that the combination of intravenous irinotecan and temozolomide has significant antitumor activity in advanced EWS. Recently, commercially available intravenous irinotecan has been administered orally (IRN-IVPO) in pediatric patients to reduce intravenous administration-related side effects, improve convenience and reduce clinic time and costs. Unfortunately, the taste of the iv preparation can be limiting, leading to poor compliance especially in pediatric patients. Development of an advanced formulation to improve tolerability and patient compliance is an important unmet need. Methods: VAL-413 is novel formulation developed to improve tolerability of oral irinotecan for the treatment of cancer. This study (USIND#135675) aims to establish the recommended phase II dose of VAL-413 when given in combination with temozolomide. Secondary objectives include characterization of the pharmacokinetics of VAL-413 vs. conventional irinotecan given orally (IRN-IVPO), evaluating palatability of VAL-413, assessing the toxicity profile of VAL-413 in combination with temozolomide, and assessment of tumor response. Up to 20 patients &gt= 1 to &lt= 30 years of age with recurrent pediatric solid tumors will be enrolled at two different dose levels of VAL-413 in combination with fixed-dose temozolomide using a standard 3 + 3 design. During the first cycle of treatment, each patient will receive 4 daily doses of VAL-413 and one daily dose of IRN-IVPO, together with 5 days of concurrent temozolomide. During all subsequent cycles, only VAL-413 will be given with temozolomide in 5-day courses administered every 21 days. Up to 17 cycles of treatment may be administered on this study. This study design will test the hypothesis that VAL-413 will not have significant pharmacokinetic differences from IRN-IVPO using intra-patient comparison of pharmacokinetic profiles. The evaluation of two dose levels will help to formally define a recommended Phase II dose for further studies. Toxicity will be evaluated based on CTCAEv5 and tumor response based on RECISTv1.1.
Citation Format: James I. Geller, Dennis Brown, Jeffrey Bacha, Neil Sankar, Sarath Kanekal, Mark Leggas, Lars Wagner. A pilot pharmacokinetic study of VAL413 in patients with recurrent pediatric solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT137.
Abstract CT144: PD-1-CD28-enhanced receptor and anti-CD19 CAR-modified tumor-infiltrating T lymphocytes produce potential anti-tumor ability in solid tumors
Authors: Chen Xinfeng , Zhao Xuan , Wang Liping , Gu Weiyue , Zhang Yi 
Published: September 2020

Abstract
Purpose: Limited expansion ability and cytotoxic function are major problems of using tumor-infiltrating lymphocytes (TILs) in vivo. We sought to determine whether adoptive transfer of autologous modified TILs mediates regression of advanced tumors.
Experimental Design: First, anti-tumor effects of switching PD-1 to CD28 signaling and anti-CD19 CAR-modified NY-ESO-1-TCR T cells (hereafter “PD-1-CD28 TCR-T” and “Anti-CD19 CAR-TCR-T” cells, respectively) were tested in vitro and in vivo. Furthermore, the safety and anti-tumor ability of S-TILs (TILs modified by transducing with anti-CD19 CAR and PD-1-CD28 vectors) were evaluated in vivo. PD-1-CD28 TCR-T cells produced formidable anti-tumor ability overcoming PD-1/PD-L1 signaling in vivo.
Results: Anti-CD19 CAR-TCR-T cells stimulated with CD19+ B cells exhibited powerful expansion and anti-tumor ability in vitro and in vivo. Three patients with refractory solid tumors received S-TIL infusion. There was no treatment-related mortality, and none of the patients experienced severe side effects. One patient with melanoma achieved a partial response and two patients with colon or kidney cancer achieved long-term stable disease following S-TIL therapy.
Conclusions: To our knowledge, this is the first report describing the safety and efficacy of adoptive transfer of autologous S-TILs to control disease in patients with advanced cancers, suggesting that S-TILs may be a promising alternative therapy for cancer treatment.
Citation Format: Xinfeng Chen, Xuan Zhao, Liping Wang, Weiyue Gu, Yi Zhang. PD-1-CD28-enhanced receptor and anti-CD19 CAR-modified tumor-infiltrating T lymphocytes produce potential anti-tumor ability in solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT144.
Abstract CT205: Phase 2 study to evaluate the safety, pharmacokinetics, and clinical activity of the PI3K / mTOR inhibitor paxalisib (GDC-0084) in glioblastoma (GBM) with unmethylated O6-methylguanine-methyltransferase (MGMT) promotor status
Authors: Wen Patrick Y. , de Groot John , Battiste James D. , Goldlust Samuel A. , Garner James S. , Simpson Jeremy A. , Kijlstra Jelle , Olivero Alan , Cloughesy Timothy 
Published: September 2020

Abstract
Introduction: Paxalisib (previously GDC-0084) is a potent, oral, selective, brain-penetrant, small molecule inhibitor of class I phosphoinositide 3-kinase and mammalian target of rapamycin. The PI3K pathway is upregulated in ~85% of GBM cases and paxalisib has shown efficacy in preclinical models. A phase I study (NCT01547546) investigated paxalisib dosed once daily in 47 patients with recurrent high-grade gliomas and established a maximum tolerated dose (MTD) of 45mg once daily. The current phase II study (NCT03522298) aims to explore the safety, tolerability, and clinical activity of paxalisib in newly diagnosed GBM and an unmethylated MGMT promotor following surgery and temozolomide chemoradiation per Stupp regimen. Methods: This study has a 2-part design: an open-label, dose-escalation phase to assess the safety, tolerability and MTD (Part 1), followed by an expansion cohort (Part 2) at the MTD. Dose-escalation started at 60mg and progressed in 15mg increments using a 3+3 design. Part 2 recruits 20 patients who are randomised to administration in fed or fasted states. Results: Part 1 is complete. Nine patients were recruited and an MTD of 60mg was determined. DLTs were hyperglycemia and oral mucositis, with toxicity and patterns of AEs consistent with prior experience and other PI3K-targeting agents. For eight response-evaluable patients in Part 1, the median progression-free survival (PFS) was 8.4 months, and 25% of patients remained progression free after 15 months of follow-up. Part 2 is ongoing.
Citation Format: Patrick Y. Wen, John de Groot, James D. Battiste, Samuel A. Goldlust, James S. Garner, Jeremy A. Simpson, Jelle Kijlstra, Alan Olivero, Timothy Cloughesy. Phase 2 study to evaluate the safety, pharmacokinetics, and clinical activity of the PI3K / mTOR inhibitor paxalisib (GDC-0084) in glioblastoma (GBM) with unmethylated O6-methylguanine-methyltransferase (MGMT) promotor status [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT205.