bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1410: Clinicopathological characteristics of lung cancer patients with concomitant idiopathic pulmonary fibrosis
Authors: Araki Kota , Shien Kazuhiko , Miyauchi Shunsaku , Miura Akihiro , Takahashi Yuta , Kurihara Eisuke , Ogoshi Yusuke , Namba Kei , Suzawa Ken , Yamamoto Hiromasa , Tomida Shuta , Soh Junichi , Sakaguchi Masakiyo , Toyooka Shinichi 
Published: August 2019

Abstract
Background: Idiopathic interstitial pneumonias (IIPs) are diffuse parenchymal lung disease of unknown etiology. Among IIPs, idiopathic pulmonary fibrosis (IPF) is the most frequent subtype. IPF is characterized by the accumulation of activated fibroblasts and extracellular matrix within the parenchyma. IPF is associated with pathologic and radiologic pattern of usual interstitial pneumonia (UIP). There are several possible underlying mechanisms linking lung cancer and IPF, however, many of them are still unknown. The purpose of this study is to reveal the clinicopathological characteristics of lung cancers patients with concomitant IPF.
Materials and Methods: The clinical and pathological data of lung cancer patients with IPF who underwent surgical resection of lung cancer between 2001 to 2016 at our institution were analyzed. We defined IPF as IIPs with UIP pattern, based on the chest CT scan and pathological findings. Mutations of EGFR (L858R point mutation and exon19 deletion), AKT1, BRAF, EGFR, KRAS, MEK1, NRAS, PIK3CA, and PTEN were analyzed.
Result: A total of 37 patients’ data of lung cancer with concomitant IPF was collected. Two patients had metachronous lung cancers. Thus, we analyzed 39 lung cancers from 37 patients. Based on the radiographic findings, 33 (84.2%) of the available 38 tumors arose from the fibrotic legion, which were mainly observed in peripheral region. The frequency of EGFR mutation was detected in 1 (2.6%) of 39 lung cancers. As control, we had EGFR mutation profile of 583 lung cancer without IPF. For this population, EGFR mutation was found in 164 (28.1%) of 583 cases. There was a significant difference in EGFR mutation between lung cancers with or without IPF (p = 0.0001). Among other examined genes in 16 tumors, one PIK3CA mutation was found.
Conclusion: The lung cancer with IPF mainly arouse from fibrotic lesion. The frequency of EGFR mutation was less common in lung cancers with IPF than those without IPF. Our result suggests that molecular profile of lung cancer with IPF is different from that without IPF.
Citation Format: Kota Araki, Kazuhiko Shien, Shunsaku Miyauchi, Akihiro Miura, Yuta Takahashi, Eisuke Kurihara, Yusuke Ogoshi, Kei Namba, Ken Suzawa, Hiromasa Yamamoto, Shuta Tomida, Junichi Soh, Masakiyo Sakaguchi, Shinichi Toyooka. Clinicopathological characteristics of lung cancer patients with concomitant idiopathic pulmonary fibrosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1410.
Abstract 1420: Novel expansion of CD8+PD1+ spleen cells for therapeutic intent in pancreatic adenocarcinoma cancer
Authors: Cole Kathryn , Ly Quan P. , Cox Jesse L. , Hollingsworth Michael A. , Padussis James C. , Foster Jason M. , Vargas Luciano M. , Talmadge James E. 
Published: August 2019

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with poor prognosis and overall survival. In 2018 it is estimated that there will be 44,333 deaths making PDAC the 3rd cause of cancer related deaths. A distal pancreatomy for PDAC in the body/tail of the pancreas usually includes a splenectomy, with current practice to discard the spleen post-surgery. Spleens can provide a large number of lymphocytes, including CD8+ T-cells with potential to be utilized for adoptive cellular therapy. Our studies have focused on spleen from this patient population, which we posit (and show herein) provides a large number of CD8+PD1+ cells for expansion and the first clinical strategy to expand activated, tumor specific T-cells for subsequent infusion with therapeutic intent. In our studies we used Milteny magnetic bead isolation of CD8+PD1+ T-cells from the spleens of PDAC patients with disease in the distal pancreas. The purity of the cells was 98% with a yield of 79% providing 9x108 CD8+PD1+ cells from an idealized 160 gm spleen. CD8 expansion was undertaken with various growth factor cocktails incorporating combinations of three interleukins (IL); IL-7, IL-15, and IL-21 at varying concentrations. IL-7 supports T-cell survival and proliferation, IL-15 is a potent T-cell growth factor and promotes naïve and memory T-cell survival, and IL-21 limits T-cell exhaustion in response to chronic stimulation. The optimized cocktail incorporated IL-7, IL-15, and IL-21 at 40 ng/mL, which demonstrated maximum T-cell expansion, based on cellularity and cell viability. The predominant T-cell memory phenotype of the CD8+PD1+ cells following expansion was transitional memory (TTM) T-cells that increased from 35.6 ± 4.3 to 52 ± 3%. This memory T-cell phenotype has a high proliferative potential while retaining effector function. Following six days of culture with the three interleukins we observed a 10 fold increase in CD8+PD1+ cells such that 9x109 cells are obtained from the 160 gm spleen. These cells, based on ELISPOT analysis with autologous tumor lysate pulsed dendritic cells retained tumor specificity. In conclusion, CD8+PD1+ cells can be isolated from resected spleen, expanded with retention of tumor specificity and potentially used for adoptive cellular therapy.
Citation Format: Kathryn Cole, Quan P. Ly, Jesse L. Cox, Michael A. Hollingsworth, James C. Padussis, Jason M. Foster, Luciano M. Vargas, James E. Talmadge. Novel expansion of CD8+PD1+ spleen cells for therapeutic intent in pancreatic adenocarcinoma cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1420.
Abstract 1422: Preclinical development of CD37CAR T-cell therapy for treatment of B-cell lymphoma
Authors: Dillard Pierre , Köksal Hakan , Josefsson Sarah , Maggadottir Solrun Melkorka , Pollmann Sylvie , Fåne Anne , Blaker Yngvild Nuvin , Beiske Klaus , Huse Kanutte , Kolstad Ane , Holte Harald , Kvalheim Gunnar , Smeland Erlend Bremertun , Myklebust June , Inderberg Else Marit , Wälchli Sebastien 
Published: August 2019

Abstract
T cells modified to express chimeric antigen receptor (CAR) targeting CD19 have produced remarkable clinical responses in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). CD19CAR T-cell therapy has also demonstrated prominent effects in B-cell non-Hodgkin lymphoma (B-NHL) patients. However, a subset of patients who relapse after CD19CAR T-cell therapy have outgrowth of CD19-negative tumor cells. Hence, development of alternative CARs targeting other B-cell markers represents an unmet medical need for B-ALL and B-NHL. Here, we confirmed previous data by showing that B-NHL overall have high expression of CD37. A second generation CD37CAR was designed and its efficacy in T cells was compared to that of CD19CAR. In vitro assessment of cytotoxicity and T-cell function upon co-culture of the CAR T cells with different target B-cell lymphoma cell lines demonstrated comparable efficacy between the two CARs. In an aggressive B-cell lymphoma xenograft model, CD37CAR T cells were as potent as CD19CAR T cells in controlling tumor growth. In a second xenograft model, using U2932 lymphoma cells containing a CD19-negative subpopulation, CD37CAR T cells efficiently controlled tumors and cured the mice while CD19CAR T cells had limited effect. We further show that, unlike CD19CAR, CD37CAR was not sensitive to antigen masking. Finally, CD37CAR reactivity was restricted to B-lineage cells. Collectively, our results demonstrated that CD37CAR T cells effectively can eradicate B-cell lymphoma tumors also when CD19 antigen expression is lost, and support further clinical testing for patients with relapsed/refractory B-NHL.
Citation Format: Pierre Dillard, Hakan Köksal, Sarah Josefsson, Solrun Melkorka Maggadottir, Sylvie Pollmann, Anne Fåne, Yngvild Nuvin Blaker, Klaus Beiske, Kanutte Huse, Ane Kolstad, Harald Holte, Gunnar Kvalheim, Erlend Bremertun Smeland, June Myklebust, Else Marit Inderberg, Sebastien Wälchli. Preclinical development of CD37CAR T-cell therapy for treatment of B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1422.
Abstract 1431: In vivo CRISPR/Cas9 screen of adoptively transferred T cells reveals novel mediators of T cell exhaustion and immunosuppression
Authors: Park Jin K. , Canner David A. , Herbst Rebecca , Li Amy , Smith Olivia C. , Regev Aviv , Jacks Tyler E. 
Published: August 2019

Abstract
Adoptive cell therapy (ACT) is a form of cancer immunotherapy in which patients receive an infusion of a polyclonal population of autologous CD8+ T cells that can be genetically modified ex vivo to optimize their function against the tumor. Although clinical responses to ACT have been successful for a very limited number of indications (most notably pediatric leukemias), its efficacy in solid tumors is very limited, likely due to immunosuppressive mechanisms constraining efficacy. To date, there have not been systematic approaches to discover novel T cell-intrinsic mediators of exhaustion in the context of ACT. Here, we describe a systematic and unbiased approach to uncover novel regulators of exhaustion in adoptively transferred CD8+ T cells. We report the results of longitudinal RNA sequencing of adoptively transferred cells at various time points post-transfer, revealing the complex transcriptional changes that transferred cells undergo. In addition, we report the results of an in vivo CRISPR/Cas9-mediated genetic screen. Taken together, this integrated approach of longitudinal RNAseq and CRISPR/Cas9 screening has yielded mediators previously uncharacterized in T cells that can be targeted to drastically improve functionality, cytotoxicity, and persistence in the tumor microenvironment.
Note: This abstract was not presented at the meeting.
Citation Format: Jin K. Park, David A. Canner, Rebecca Herbst, Amy Li, Olivia C. Smith, Aviv Regev, Tyler E. Jacks. In vivo CRISPR/Cas9 screen of adoptively transferred T cells reveals novel mediators of T cell exhaustion and immunosuppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1431.
Abstract 1432: Enhanced effector responses of regenerated CAR-T cells derived from genome edited iPSCs
Authors: Ueda Tatsuki , Iriguchi Shoichi , Kawai Yohei , Minagawa Atsutaka , Miyoshi Hiroyuki , Terakura Seitaro , Uemura Yasushi , Woltjen Knut , Kodama Yuzo , Seno Hiroshi , Hitoshi Yasumichi , Nakatsura Tetsuya , Tamada Koji , Kaneko Shin 
Published: August 2019

Abstract
Chimeric antigen receptor (CAR) is an artificial protein that provides HLA-independent antigen specificity to T cells. CAR-T therapy has shown remarkable clinical responses especially in hematologic malignancies. But this therapy requires cell preparation for each patient and it cause some limitations for applicability of CAR-T therapy. We have reported regeneration of T cells from iPSCs (Cell Stem Cell. 2013). Since this technology can provide unlimited number of T cells, CAR-T therapy using iPSCs is thought to broaden its applicability. To target solid tumors, it is important to avoid immunosuppressive factors from tumor microenvironment and to exert sufficient cytotoxicity. Tumor reactive T cells are known to fall into anergy state by continuous antigen stimulations. To overcome immunosuppression in tumor microenvironment, enhancement of TCR signaling by modification of genes related to TCR signal is a promising strategy. Recent studies revealed that the efficacy of CAR-iPS-T cells are not equivalent to primary CAR-T cells. To enhance the efficacy of CAR-iPS-T cells and to produce resistant CAR-T cells to immunosuppression, we focused on TCR signaling pathway. We found that antigen reactivity of CAR-iPS-T cells was insufficient compared with primary CAR-T cells. To overcome the weakness of TCR signal, we disrupted genes negatively related to TCR signal and successfully enhanced TCR signal. As a result, genome edited CAR-iPS-T cells could persist longer in vivo and displayed enhanced tumor suppressive function comparable with primary CAR-T cells. Genome edited iPSCs can be a unlimited cell source of enhanced CAR-T cells. These findings indicate that regenerated CAR-T cells derived from genome edited iPSCs would be a promising CAR-T therapy which would overcome immunosuppressive tumor microenvironment.
Citation Format: Tatsuki Ueda, Shoichi Iriguchi, Yohei Kawai, Atsutaka Minagawa, Hiroyuki Miyoshi, Seitaro Terakura, Yasushi Uemura, Knut Woltjen, Yuzo Kodama, Hiroshi Seno, Yasumichi Hitoshi, Tetsuya Nakatsura, Koji Tamada, Shin Kaneko. Enhanced effector responses of regenerated CAR-T cells derived from genome edited iPSCs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1432.
Abstract 1436: Development of a chimeric antigen receptor against glycosylated annexin A2 on ovarian tumors
Authors: Leong Leonard W. , Cua Simeon , Tan Heng Liang , Choo Andre B. 
Published: August 2019

Abstract
Chimeric antigen receptors (CARs) have been a significant focus of cancer therapeutic investigation in recent years, due to the remarkably effective responses observed in hematological cancers. However, the utility of CAR T cells has yet to be fully exhibited in solid tumours. One of the key challenges facing the treatment of solid tumors with CAR T cells is the dearth of viable antigen targets, which limits the expansion of this therapeutic space.
Here, we describe how the anti-glycan monoclonal antibody 2448, which target annexin A2 on a number of ovarian and breast cancer cell lines, has been successfully reformatted as a CAR T cell construct.
Messenger RNA (mRNA) encoding CAR(2448) was transfected into activated T cells, resulting in cytotoxicity and cytokine release upon co-incubation with target cells expressing annexin A2. While CAR(2448) variants with differing spacer chain lengths all mediated cytotoxicity against target cells compared to untransfected T cells, real-time target cell growth monitoring revealed that the long spacer CAR(2448) mediated higher levels of cytotoxicity, consistent with the membrane-proximal location of the annexin A2 target epitope.
This optimization of CAR spacer length in the in vitro setting, using mRNA transfected T cells and real-time target cell growth monitoring, suggests that several aspects of CAR construction can be optimized in vitro, thereby lowering the threshold for CAR T cell development.
These results suggest the potential for anti-glycan antibodies to be repurposed as CARs, and the development of CAR(2448) is currently being extended to lentiviral vectors for the purpose of developing long-term expressing CAR(2448) T cells, in anticipation of in vivo studies in murine models.
This project was funded by the Agency for Science, Technology, and Research (A*STAR), Singapore and the A*STAR Graduate Academy (A*GA).
Citation Format: Leonard W. Leong, Simeon Cua, Heng Liang Tan, Andre B. Choo. Development of a chimeric antigen receptor against glycosylated annexin A2 on ovarian tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1436.
Abstract 1437: Improving efficacy and accuracy of CAR-T cells for neuroblastoma
Authors: Moghimi Babak , Muthugounder Sakunthala , Asgharzadeh Shahab 
Published: August 2019

Abstract
Background: Anti-disialoganglioside (GD2) specific CAR T-cell therapy has shown limited efficacy in children with recurrent/refractory neuroblastoma (NBL). A recent pre-clinical study demonstrated significant neurotoxicity in mice treated with CAR T-cells bearing a high-affinity anti-GD2 short chain variable fragments (scFv; Richman S et al. 2017). To devise a safe and more efficacious CAR T-cells, we developed a gated CAR T-cell system utilizing the Syn-Notch technology.
Methods: GD2 and CD19 specific Syn-Notch gated systems were constructed by linking corresponding scFv to the Notch core followed by Gal4Vp64. Upon target recognition, Gal4VP64-dependent UAS element would initiate expression of the B7H3-BBZ CAR. Reporter activity of CD19 or GD2 Syn-Notch systems were monitored using flow cytometry after exposure to CD19+ transduced CHLA255 NBL cell line. In vitro cytotoxicity was assessed using DIMSCAN and xCELLigence impedance assays at varying Effector: Target ratios. NSG mice with established metastatic CHLA255(GD2+CD19+) NBL were treated with 1x10^7 transduced and control T cells and monitored for disease burden.
Results and discussion: Jurkat and human primary T cells were successfully transduced with the Syn-Notch system. GD2-Notch-Gal4VP64 and CD19-Notch-Gal4VP64 T-cells effectively activated downstream reporter in exposure to CHLA255(GD2+CD19+) within 6 hours of exposure but not in the presence of NBL cells lacking GD2 or CD19. The GD2 system exhibited greater leakiness than the CD19 counterpart. GD2- Syn-Notch-B7H3-BBZ or CD19- Syn-Notch-B7H3-BBZ CAR T-cells demonstrated statistically significant cytotoxicity against CHLA255(GD2+CD19+) NBL cell line. Preliminary in vivo data also show the anti-tumor effect of these gated CAR systems compared to mock-transduced T-cells.
Conclusions: We have successfully established a novel GD2-B7H3 gated system using the Syn-Notch technology, and demonstrate successful specificity to both antigen targets. This system increases the specificity of CAR T-cells against GD2 and B7H3 positive neuroblastoma tumors and likely minimize GD2-induced toxicity. These gated CARs show great promise for establishing immunotherapies that maximize tumor specificity while minimizing toxicity.
Citation Format: Babak Moghimi, Sakunthala Muthugounder, Shahab Asgharzadeh. Improving efficacy and accuracy of CAR-T cells for neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1437.
Abstract 1442: Chimeric antigen receptor T cell therapy targeting ICAM-1 in gastric cancer
Authors: Jung Minkyu , Zaman Marjan , Vedvyas Ygindra , Zhang Xianglan , McCloskey Jaclyn E. , Yang Yanping , Min Irene M. , Zamegar Raza , Choi Yoon Young , Cheong Jae-Ho , Noh Sung Hoon , Rha Sun Young , Chung Hyun Cheol , Jin Moonsoo M. 
Published: August 2019

Abstract
Introduction:
Despite advances in treatment, gastric cancer (GC) remains among the most fatal malignancies. Intercellular adhesion molecule-1 (ICAM-1) is overexpressed and associated with various cancers, including GC. We developed a third-generation chimeric antigen receptor (CAR) targeting ICAM-1 (ICAM-1-CAR) and investigated ICAM-1 as a immunotherapeutic target for CAR T therapy in GC.
Methods:
We investigated ICAM-1 expression in tissues of curatively resected GC patients (n=134) by immunohistochemical staining to determine its prognostic value. Effector to target assays were performed with ICAM-1-CAR T cells co-cultured with 8 GC cell lines with varying levels of ICAM-1 expression to investigate specific target cell death. We created a firefly luciferase-expressing human GC model in mice to measure tumor growth and killing by whole body bioluminescence imaging. To find the best treatment route and optimal dose of T cells in GC mice model, ICAM-1-CAR was injected via tail vein and intraperitoneal administration (IP) at two different doses, i.e., low dose (1 million CAR T) and high dose (10 million live T cells).
Results:
The ICAM-1 expression was higher in advanced stages (22.2% in stage II vs. 48.8% in stage III, p=0.002) and the patients with high ICAM-1 expression showed significantly poor survival (disease free survival, hazard ration [HR], 4.55, p&lt;0.001; overall survival, HR, 3.89, p&lt;0.001). The efficacy of ICAM-1-CAR T cells in vitro showed a strong correlation with the level of ICAM-1 expression in target cells, i.e., faster killing of GC with higher ICAM-1 expression. ICAM-1-CART facilitated regression of tumor in MKN-28 xenograft IP model. Additionally, the efficacy of ICAM-1-CAR was more prominent in mice treated with high dose of T cell and IP route. Compared to no treatment, ICAM-1CAR via IP led to tumor reduction that persisted for over 80 days and significantly improved survival without toxicity (p=0.049).
Conclusion:
ICAM-1 specific CAR T cells demonstrated significant therapeutic efficacy in vitro and in vivo against preclinical GC models. ICAM-1-CAR T cells may be developed into a promising treatment strategy for patients with ICAM-1 positive GC cancers.
Citation Format: Minkyu Jung, Marjan Zaman, Ygindra Vedvyas, Xianglan Zhang, Jaclyn E. McCloskey, Yanping Yang, Irene M. Min, Raza Zamegar, Yoon Young Choi, Jae-Ho Cheong, Sung Hoon Noh, Sun Young Rha, Hyun Cheol Chung, Moonsoo M. Jin. Chimeric antigen receptor T cell therapy targeting ICAM-1 in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1442.