bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1425: Chimeric antigen receptors based on T cell receptor-like antibodies
Authors: Wu Ling , Brzostek Joanna , Sankaran Shvetha , Tan Triscilla , Chan Conrad , Yap Jiawei , Lai Junyun , MacAry Paul , Gascoigne Nicholas 
Published: August 2019

Abstract
T cells are essential in adaptive immunity and play an indispensable role to eliminate abnormal or virus infected cells. By merging antibody technology and cell engineering, T cells equipped with a chimeric antigen receptor (CAR) can be redirected to the target in a non-MHC restricted fashion. Within the past few years, clinical trials using CAR T cells engineered to recognize B cell cancers have shown high rates of response (70%-90%) and durability of response that are unprecedented in acute and chronic leukaemia. However, severe toxicity has been observed due to massive, and to some extent nonspecific, T cell activation. Although CARs have been improved and investigated heavily, the extent to which a CAR is similar to its parental TCR extra- or intracellularly, and whether critical elements involved in normal TCR signalling are kept or rewired in CAR signalling, are unclear. A better understanding of these questions would greatly facilitate improvements in CAR technology and its usefulness in clinical practice. A CAR targeting a peptide-MHC complex (using an Fv from an antibody that recognizes MHC-peptide: in other words, a TCR-like Ab) mimics the process of TCR recognition and takes advantage of CAR technologies developed so far. It is thus an excellent study object to compare TCR and CAR signalling. Well-built research methods on TCR can be transferred immediately to TCR-like CAR, while the knowledge and findings generated through the studies of TCR-like CAR can in turn renew our perceptions on TCR.
TCR-like antibodies targeting the EBV epitopes LMP1125-133, LMP2A426-434 or EBNA1562-570, were engineered as CARs. We find that conformation change, if any, upon ligand binding is not enough to activate downstream TCR signalling, but oligomerization is a crucial factor. Although CAR with a TCR-like specificity can recruit CD8 co-receptor to the immunological synapse, it is dispensable for activation of the T cell. Furthermore, the activation kinetics of CAR and TCR are distinctly different. TCR shows a pulse-like activation, whereas CAR shows an activation that gradually plateaus and remains steady. These unique properties of CAR identified in our study demonstrate that CAR signalling properties may be amenable to modifications leading to better specificity and activity in vivo. Our long-term goal is that the TCR-like CAR can be used to combat EBV induced Nasopharyngeal Carcinoma.
Citation Format: Ling Wu, Joanna Brzostek, Shvetha Sankaran, Triscilla Tan, Conrad Chan, Jiawei Yap, Junyun Lai, Paul MacAry, Nicholas Gascoigne. Chimeric antigen receptors based on T cell receptor-like antibodies [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 1425.
Abstract 1426: Expansion of CD8+PD-1+ T cells restored TCR repertoire as a prognostic marker to adoptive T cell immunotherapy of advanced pancreatic cancer
Authors: Qiao Guoliang 
Published: August 2019

Abstract
Purpose: We have previously reported the clinical benefits of autologous adoptive T cell immunotherapy in advanced pancreatic cancer (APC). We therefore aimed to further identify the core functional population of CD8+ T cells which exerted on the aberrant TCR repertoire and subsequently contribute to favorable prognosis after adoptive T cell therapy(ACT).
Experimental Design: PBMC from APC patients (n=25) treated on a protocol of S-1 plus adoptive T cell immunotherapy were expanded ex vivo with a cytokine cocktail. The different fractions of CD8+PD-1+, CD8+LAG-3+, CD8+TIM-3+ and CD8+4-1BB+ T cells from time dependent segment were quantitated and expression of co-inhibitory molecules and biological functions on tumor killing and comparative analysis TCR repertoire from each patient were measured. The multivariate Cox hazards regression analysis was performed to identify the key T cell subset that affected the TCR repertoire recovery and subsequently associated with clinical outcome.
Results: The CD3+, CD3+CD4+, and CD3+CD8+ T cells within the expanded cell product reached peak levels by day 15. CD8+ T cells exhibited enhanced expression of PD-1, LAG-3, and TIM-3, but not 4-1BB, after ex vivo expansion. Survival analysis showed that patients with a ratio of post/pre CD8+PD-1+ T cells &gt; 2 had significantly favorable progressive-free survival (PFS) (median PFS time 180 days vs 85 days, P=0.002) and overall survival (OS) (median OS time 238 days versus 142 days, P=0.024). The sorted CD8+PD-1+ T cells displayed enhanced anti-tumor activity, and increased IFN-γ secretion after co-culture with autologous tumor cell lines. TCR repertoire diversity simultaneously rose during the ex vivo expansion and was associated with an increase in CD8+ T cells and decline in CD8+/CD28- T cells. Moreover, an increased TCR diversity was associated with significantly favorable PFS (median PFS time 166 days vs 79 days, P=0.043) and OS (median OS time 216 days versus 112 days, P=0.031) and was associated with the extent of expansion of the CD8+PD-1+ T cells (r2=0.464, P=0.001). Cox proportional hazards analysis showed that post/pre CD8+PD-1+ T cells after expansion ex vivo was an independent prognostic marker associated with both OS(P=0.009) and PFS(P=0.012).
Conclusion: CD8+PD-1+ T cells, after ex vivo expansion over 15 days, are tumor-reactive. The extent of CD8+PD-1+ T cell expansion could restore TCR repertoire and was an independent prognostic factor associated with clinical outcomes in APC patients treated with ACT.
Citation Format: Guoliang Qiao. Expansion of CD8+PD-1+ T cells restored TCR repertoire as a prognostic marker to adoptive T cell immunotherapy of advanced pancreatic 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 1426.
Abstract 143: Immune landscape in lung adenocarcinoma drawn by single-cell RNA sequencing
Authors: KU Bo Mi , Kim Nayoung , Lee Kyung Young , Sun Jong-Mu , Lee Se-hoon , Ahn Jin Seok , Park Keunchil , Kim Hong Kwan , Lee Hae-Ock , Ahn Myung-Ju 
Published: August 2019

Abstract
Immune cells in the tumor microenvironment from an ecosystem that modulates cancer progression. However, the exact nature and dynamics of tumor microenvironment in lung cancer remain largely unknown. To depict the baseline landscape of the composition of tumor microenvironment at different stages, we conduceted single-cell RNA sequencing of 58 samples from 43 lung adenocarcinoma patients. Here, we analyzed 11 early-stage lung tumor and normal pairs that had been resected before systemic therapy, 11 late-stage lung tumor biopsy, and 5 metastatic pleural-effusion or 10 metastatic brain tumor samples and revealed differential immune profiles encompassing lymphoid and myeloid compartment. In normal lung, large numbers of macrophages and T cells consistently comprised the immune cell repertoire across patients. In paired cancer tissues, decrease in macrophage but increase in B cell proportions were evident indicating the activation of humoral immunity. In addition, diverse effector T cell populations mark the cancer tissues both at the primary and metastatic sites, corroborating the activation of cellular adaptive immunity. These data provide valuable insight of tumor-driven immune changes in lung cancer.
Citation Format: Bo Mi KU, Nayoung Kim, Kyung Young Lee, Jong-Mu Sun, Se-hoon Lee, Jin Seok Ahn, Keunchil Park, Hong Kwan Kim, Hae-Ock Lee, Myung-Ju Ahn. Immune landscape in lung adenocarcinoma drawn by single-cell RNA sequencing [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 143.
Abstract 1433: NeoTCR-P1, a novel neoepitope-specific adoptive cell therapy, consists of T cells with ‘younger’ phenotypes that rapidly proliferate and kill target cells upon recognition of cognate antigen
Authors: Sennino Barbara , Conroy Andrew , Purandare Bhamini , Litterman Adam , Jacoby Kyle , Moot Robert , Lu William , Nguyen Diana , Urbinati Fabrizia , Foy Susan , Hunter Theresa , Dalmas Olivier , Bethune Michael , Park Tim , Peng Songming , Franzusoff Alex , Mandl Stefanie 
Published: August 2019

Abstract
Clinical benefit observed with immuno-oncology trials often depends on the unleashing of a pre-existing intrinsic T cell immune response in each cancer patient. The targets of these intrinsic T cells are commonly ascribed to recognition of patient-specific neoantigens that arose from cancer mutations.
PACT Pharma has developed the ability to selectively capture neoantigen-specific CD8+ T cells from peripheral blood of the patient. Leveraging this technology, PACT Pharma is developing personalized, autologous neo-epitope specific TCR-engineered T cell therapies for the eradication of solid tumors.
Briefly, using PACT's proprietary TCR isolation technology neoepitope-specific TCRs are cloned and autologous CD8+ and CD4+ T cells from the same patient with cancer are precision genome engineered (using a DNA-mediated (non-viral) method) to express the neoTCR. NeoTCR expressing T cells are then expanded in a manner that preserves a “younger” T cell phenotypes, resulting in a NeoTCR-P1 product in which the majority of the T cells exhibit T memory stem cell and T central memory phenotypes.
Upon cognate antigen encounter, NeoTCR-P1 rapidly differentiate into potent effector T cells. Engineered NeoTCR-P1 cells rapidly expand, secrete effector molecules such as perforin and granzyme B, and cytokines such as interferon-gamma (IFN-γ), IL-2 and TNF-alpha (TNF-α). Single cell secretome analysis demonstrates that NeoTCR-P1 cells are highly polyfunctional (secretion of two or more cytokines or effector proteins). These results demonstrate that PACT’s autologous ex vivo engineered NeoTCR-P1 T cells represent a highly personalized adoptive T cell therapy with potential to provide significant clinical benefit to subjects with solid tumors.
Citation Format: Barbara Sennino, Andrew Conroy, Bhamini Purandare, Adam Litterman, Kyle Jacoby, Robert Moot, William Lu, Diana Nguyen, Fabrizia Urbinati, Susan Foy, Theresa Hunter, Olivier Dalmas, Michael Bethune, Tim Park, Songming Peng, Alex Franzusoff, Stefanie Mandl. NeoTCR-P1, a novel neoepitope-specific adoptive cell therapy, consists of T cells with ‘younger’ phenotypes that rapidly proliferate and kill target cells upon recognition of cognate antigen [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 1433.
Abstract 1439: Identification and characterization of neoantigen specific T cells
Authors: Naradikian Martin S. , Montero Leslie , Hall Samantha , Bahmanof Milad , Thota Rukman , Sternberg Luise , Lane Jerome , Kosaloglu-Yalcin Zeynep , Lanka Manasa , Miller Aaron , Peters Bjoern , Cohen Ezra , Schoenberger Stephen 
Published: August 2019

Abstract
Neoantigens (NeoAg) offer attractive therapeutic targets for directing a patient’s immune response to the immunogenic subset of mutations expressed exclusively by their cancer cells. Despite the specificity with which NeoAg enable tumor recognition, the majority of approaches for their identification rely on purely predictive methods such as calculating the ability of mutated peptides to bind to a patient’s set of HLA molecules, and have met with limited success in revealing natural targets present on tumor cells. We have developed a novel HLA-agnostic functional approach to NeoAg identification which combines genomic sequencing with bioinformatic analysis to nominate mutations for subsequent functional analysis using patient’s own T cells in an effort to identify natural responses generated under physiologic conditions. Using this, we identified a missense mutation (V205&gt;I) in the ribosomal protein RPS2 that is recognized by CD8+ T cells from tumor-infiltrating lymphocytes (TIL) of a metastatic HPV-16+ Head and Neck Squamous Cell Carcinoma (HNSCC) lesion. We then performed adoptive cellular therapy (ACT) using either unseparated TIL or those enriched for RPS2 V205&gt;I-specific CD8+ T cells and found the latter to be superior in controlling outgrowth of tumor of a PDX cell line generated from this lesion in NSG mice. Finally, we used single-cell transcriptomics to isolate the genes encoding the RPS2-specific TCR and show that it recognizes the mutated peptide bound to HLA-B*07.02 as well as the tumor cell line expressing the RPS2 protein. These results demonstrate that high-affinity NeoAg-specific T cell responses can be identified in cancer patients, that ACT of these cells can control tumor growth, and that the relevant TCR can be isolated for use in TCR engineering-based immunotherapy.
Citation Format: Martin S. Naradikian, Leslie Montero, Samantha Hall, Milad Bahmanof, Rukman Thota, Luise Sternberg, Jerome Lane, Zeynep Kosaloglu-Yalcin, Manasa Lanka, Aaron Miller, Bjoern Peters, Ezra Cohen, Stephen Schoenberger. Identification and characterization of neoantigen specific T cells [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 1439.
Abstract 1447: Predicting immunogenic neoepitopes with biology-aware machine learning
Authors: Mazzocco Giovanni , Niemiec Iga , Myronov Oleksandr , Kowalczyk Edyta , Kaczmarczyk Jan , Sanecka-Duin Anna , Stepniak Piotr 
Published: August 2019

Abstract
Introduction: The purpose of this study is to present a novel method for neoepitope prediction, along with extensive benchmarks to existing solutions and identification of the most predictive constituent biological features. The accurate prediction of neoepitope immunogenicity represents an invaluable tool for the design of personalized cancer vaccines with effective treatment outcomes. The effectiveness of the host’s adaptive immune response against cancer relies on the correct HLA-mediated neoepitope presentation and the recognition by specific CD8+ clones. Cancer immunotherapies act by boosting the activity of these effector T-cells.
Methods: The proposed AI-driven bioinformatics solution allows to perform an accurate prediction of HLA I-restricted neoepitope immunogenicity by including several analytical modules simulating biological processes leading to the activation of CD8+ T-cells. These modules can be flexibly composed on the basis of the data available and include: (i) selection of potential neoepitope based on cancer NGS data, (ii) expression of neoepitope-associated genes, (iii) similarity to self, (iv) prediction of neoepitope-HLA binding affinity and stability, (v) effect of post-translational modification on neoepitope presentation and TCR recognition, (vi) prediction of neoepitope:TCR recognition probability based on neoepitope-HLA:TCR structural-derived features and TCR CDR3 sequence similarities. The model was trained on a curated dataset joining records of multiple studies containing neoepitopes experimentally validated for their ability to elicit adaptive immune response.
Results: We present the results of a benchmarking study where we compare the performance of widely used methods for the assessment of neoepitope immunogenicity along with our solution. We investigate the predictive power of each analytical module to determine the individual information gain and determine the most informative ones. All the methods included in the benchmarking study were tested using the dataset provided by Chowell et al. 2015. As the metric for performance evaluation we use ROC AUC and the overall percentage of correctly detected immunogenic neoepitopes (precision).
Conclusion: The results present the utility of the compared methods for personalized cancer vaccine design and the importance of modules related to biological processes underlying the neoepitope presentation and immunogenicity.
Citation Format: Giovanni Mazzocco, Iga Niemiec, Oleksandr Myronov, Edyta Kowalczyk, Jan Kaczmarczyk, Anna Sanecka-Duin, Piotr Stepniak. Predicting immunogenic neoepitopes with biology-aware machine learning [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 1447.
Abstract 1461: mRNA therapeutics against cancers and infectious diseases
Authors: Arya Smriti , Lin Qiubin , Zhou Nan , Huang Jiandong 
Published: August 2019

Abstract
In vitro transcribed (IVT) mRNA is forming a new basis of drug delivery as it can be synthetically engineered to express the desired protein in lesser time and be more specific than the other 2 types of antigens. Using DNA (coding for proto-oncogenes) for immunization poses a risk for host cell transformation into a malignant one and hence proto-oncogenes would express for a longer time. Therefore, mRNA was considered for cancer immunotherapy as it does not integrate into the host cell's genome, so no question of insertional mutagenesis arises. Our main aim is to develop a stable mRNA system working both in vitro and in vivo and then use this system to develop mRNA vaccines. The stability of IVT mRNA can be increased by changing the 3' and 5' UTRs, adding a 5'cap and 3' poly-A tail which could even increase their half-life to a few days. For creating a stable mRNA working system in vitro, EGFP-2A gene was cloned along with the AdsA (Staphylococcus aureusgene important for infection) in a vector backbone with TMV 3’UTR and 5’UTR. The mRNA created in vitro was with modified uridine and cap 1 structure and transfected to the mammalian cell lines. This transfection was further enhanced by using liposome created in the lab (using some cationic and helper lipids in different ratios) by film rehydration method. The expression of luciferase mRNA was then detected in mice by live imaging indicating that the mRNA system is stable in vivo. Further, to direct the mRNA encoded antigens to MHC1 and MHC2 pathways they were tagged with a htPA secretion tag and MHC1 targeting signal along with a 3XFLAG tag. We tried various mode of injections with AdsA mRNA to have a profile of ELISPOT with differently exposed mRNA (in vivo in mice). Now we are focussing on some neo antigens for tumor to be used as. Avaccine in the form of mRNA.
Citation Format: Smriti Arya, Qiubin Lin, Nan Zhou, Jiandong Huang. mRNA therapeutics against cancers and infectious diseases [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 1461.
Abstract 1471: Short hairpin RNA-expressing oncolytic adenovirus-mediated inhibition of PDL1 significantly suppresses human cancer cell growth
Authors: Sheng Jipo , Wang Xue , Dong Xiaoming , Fu Jin , Kang Sanmao , Hu Fang 
Published: August 2019

Abstract
In cancer immunotherapy, it is known that aberrant expression of immune checkpoint proteins in tumor cells and their resulting immunosuppression in surrounding tumor microenviroment and even in whole immune system represent the crucial limiting factors toward successful cancer treatment. Multiple studies evidenced that oncolytic viruses carrying biological molecule including cytokines, shRNAs and miRNAs relieve or attenuate immunosuppression, and may be a promising way toward curing tumor. In this study we generated an oncolytic adenovirus with expression of shRNA targeting human PDL1. The adenovirus exhibited proliferation activity more than two orders of magnitude higher in human cancer cells than in human normal primary cells. Western blot showed significantly decreased expressing levels of PDL1 protein in human cancer cells upon infection of the PDL1 shRNA expressing-oncolytic virus. FACS assay also showed decreased expression levels of PDL1 on the cell membrane after the infection of same viruses. In vivo experiments in two different genetic backgrounds mouse model &lt;NOD-SCID mice and BALBC nude mice&gt; demonstrated that the PDL1 shRNA expressing adenoviruses lysed the majority of the tumor cells derived from HCT116 colorectal cancer cells that were subcutaneously inoculated. Moreover, the adenoviruses downregulated PDL1 expression levels within the HCT116 colon cell-derived tumor cells, remarkably attenuated immunosuppression surrounding the HCT116 tumor. Consisted with these observations, TIL cell counts in the tumors derived from mice with shRNA expressing oncolytic adenovirus treatment were significantly higher than that from mice in other control groups. The growth of HCT116 colon cell-derived tumor in mice with oncolytic adenovirus treatment was greatly inhibited for a longer period compared with that in mice in other control groups. The oncolytic adenovirus described in this study features highly selective amplification in human tumor cells versus normal cells and inhibition of PDL1 expression in tumor cells, therefore it may be important toward developing novel method for cancer therapy.
Citation Format: Jipo Sheng, Xue Wang, Xiaoming Dong, Jin Fu, Sanmao Kang, Fang Hu. Short hairpin RNA-expressing oncolytic adenovirus-mediated inhibition of PDL1 significantly suppresses human cancer cell growth [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 1471.
Abstract 1491: Immune resistance emerges from tumor-initiating stem cells
Authors: Miao Yuxuan 
Published: August 2019

Abstract
The remarkable capacity of the long-lived stem cells-like population to self-renew, initiate and propagate a tumor placed these cancer stem cells (CSC) at the root of tumorigenesis. Many unique molecular features of stem cells endow these key population with specialized properties to drive tumor formation. However, in order to achieve these functions, the neoplastic stem cells must first overcome the immune barrier. Although it has long been postulated that, as the core of a tumor, CSCs must be superior at evading the immune detection, direct evidence is still lacking to demonstrate this stem cell trait. Another important feature of CSCs is that these cells are programed to resist traditional cancer treatments, including chemotherapy and radiation. Yet, it is still unexplored how CSCs react to the immunotherapy, which just start to revolutionize the cancer treatments. In order to address these fascinating questions, we have designed a spontaneous skin squamous cell carcinoma (SCC) mouse model that can be effectively targeted by adoptive cell transfer (ACT)-based immunotherapy, without losing the targeted tumor antigen. Employing this model, we have lineage traced the fate of tumor-initiating stem cells during and after ACT treatment. In this study, we will present data demonstrating that a subset of TGFβ-responding CSCs, residing at the tumor-stromal interface, are always able to survive from the injected CD8+ T cell treatment and give rise to the relapsed tumor. Furthermore, the extensive profiling of ACT surviving stem cells revealed that multiple immune resistant pathways are highly up-regulated in these stem cells. In addition, TGFβ appears to orchestrate these immune resistant processes in the tumor-initiating stem cells. This study highlights CSCs as the core to mediate immune evasion.
Citation Format: Yuxuan Miao. Immune resistance emerges from tumor-initiating stem cells [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 1491.