bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PR04: Decoding tumor microenvironment to enhance NSCLC targeted therapy
Authors: Hu Haichuan , Sequist Lecia , Piotrowska Zofia , Mulvey Hillary , Noeen Sundus , Hare Patricia , Kodack David , Hata Aaron , Niederst Matt , Benes Cyril , Engelman Jeff 
Published: February 2019

Abstract
Background: Tyrosine kinase inhibitors (TKI) have yielded promising responses in non-small cell lung cancer (NSCLC) with EGFR mutations and ALK translocations. However, these and other targeted therapies are limited by intrinsic and acquired drug resistance. The previous study from our group investigated tumor autonomous resistance mechanisms by developing patient-derived cancer models (PDCs). In this study, we aimed to decipher the nonautonomous resistance mechanisms via tumor microenvironment by developing patient-derived fibroblast (PDF) models.
Method: Cancer-associated fibroblast cell lines are established directly from individual EGFR mutant NSCLC biopsies. These cell lines, as representative of each patient’s tumor microenvironment, are further subjected to functional analysis. An imaging-based high-throughput platform is developed to screen for nonautonomous resistance by co-culturing PDC and PDF models in vitro. In the parallel, two independent approaches are performed to further identify mechanisms underlying the nonautonomous resistance. These include a drug screen to determine the pathway maintaining the cancer cells’ survival, and a secretomic analysis on the PDFs to identify the plausible cytokine(s) responsible for the resistance.
Result: By co-culturing screening, nonautonomous resistance can be found in a wide spectrum of models. The subsequent drug screen reveals both a canonical HGF-dependent and novel HGF-independent mechanisms contributing to EGFR TKI resistance. Both of these can be explained by the PDF’s variable cytokine secretion and can be overcome by specific therapeutic combinations. Moreover, the microenvironment-driven EGFR TKI resistance has also been validated in vivo. The prevalence of the identified cytokine is further tested in clinical specimens.
Conclusion: PDFs provide a new avenue to explore nonautonomous resistance for targeted therapy. Applying this approach, we identified both the canonical HGF-dependent and novel HGF-independent mechanisms that putatively confer EGFR TKI resistance. Taking EGFR TKI therapy as a paradigm, these findings will be valuable to optimize targeted therapy and to inform the design of personalized pharmaceutical interventions.
This abstract is also being presented as Poster B25.
Citation Format: Haichuan Hu, Lecia Sequist, Zofia Piotrowska, Hillary Mulvey, Sundus Noeen, Patricia Hare, David Kodack, Aaron Hata, Matt Niederst, Cyril Benes, Jeff Engelman. Decoding tumor microenvironment to enhance NSCLC targeted therapy [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr PR04.
Abstract A009: Forty-three week follow-up of a phase 1a clinical trial of a PSA, IL-2, GM-CSF containing prostate cancer therapeutic vaccine in PSA defined biochemical recurrent prostate cancer patients
Authors: Head Jonathan F. , Daniels Gregory A. , McKinney Michelle , Wang-Rodriguez Jessica 
Published: February 2019

Abstract
While progress has occurred in both cellular and immune checkpoint therapy, the benefit of therapeutic cancer vaccines has been difficult to demonstrate. Prostate cancer may be an exception with the modest activity of Sipuleucel T. We have developed a potentially low cost and easy to administer therapeutic vaccine with the combination of tumor antigen (PSA) and biologic adjuvants (IL2 and GM-CSF). This study is a phase 1a clinical trial of a PSA/IL-2/GM-CSF vaccine in biochemically recurrent hormone-naïve and hormone-independent prostate cancer patients. Major inclusion criteria include adenocarcinoma of the prostate, rising serum PSA and no measurable disease. Phase 1a examines the rate of serious adverse events (SAEs) and dose limiting adverse events (DLAEs) in an initial course of 6 vaccinations (“induction vaccination”). Twenty patients enrolled and nineteen patients completed all six intradermal injections (one patient received 5 vaccines, missed week 11 vaccine) of the PSA/IL-2/GM-CSF vaccine at weeks 1, 2, 3, 7, 11 and 15. None of the patients vaccinated in the phase 1a portion had an SAE or DLAE with the most common AE relating to grade 1 injection site reactions. Fifteen of the 18 patients who received vaccines had immune responses to PSA as demonstrated in a lymphocyte blastogenesis assay by week 31. Interestingly, after vaccination 14 of 20 patients had an increase in the doubling time of their serum PSA, suggesting a slowing of the growth of the prostate cancer. Five of 20 patients have progressed (3 PSA progression and 2 radiologic progression) at 43 weeks’ follow-up.
Citation Format: Jonathan F. Head, Gregory A. Daniels, Michelle McKinney, Jessica Wang-Rodriguez. Forty-three week follow-up of a phase 1a clinical trial of a PSA, IL-2, GM-CSF containing prostate cancer therapeutic vaccine in PSA defined biochemical recurrent prostate cancer patients [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A009.
Abstract A030: Identification of α-fetoprotein-specific T-cell receptors for hepatocellular carcinoma immunotherapy
Authors: He Yukai , Zhu Wei , Peng Yibing , Wang Lan , Hong Yuan , Wu Juan , Celis Esteban 
Published: February 2019

Abstract
Hepatocellular carcinoma (HCC) is the major form of liver cancer for which there is no effective therapy. Genetic modification with T-cell receptors (TCR) specific for HCC-associated antigens, such as α-fetoprotein (AFP), can potentially redirect human T-cells to specifically recognize and kill HCC tumor cells to achieve antitumor effects. In this study, by using lentivector and peptide immunization, we identified a population of CD8-T-cells in HLA-A2 transgenic AAD mice that recognized AFP158 epitope on human HCC cells. Adoptive transfer of the AFP158-specific mouse CD8-T-cells eradicated HepG2 tumor xenografts as large as 2cm in diameter in immunocompromised NSG mice. We then established T-cell hybridoma clones from the AFP158-specific mouse CD8-T-cells and identified three sets of paired TCR genes out of 5 hybridomas. Expression of the murine TCR genes redirected primary human T-cells to bind HLA-A2/AFP158 tetramer. The TCR gene-engineered human T-cells (TCR-T) also specifically recognized HLA-A2+AFP+ HepG2 HCC tumor cells and produced effector cytokines. Importantly, the TCR-T-cells could specifically kill HLA-A2+AFP+ HepG2 tumor cells without significant toxicity to normal primary hepatocytes in vitro. Adoptive transfer of the AFP-specific human TCR-T-cells could eradicate HepG2 tumors in NSG mice. Conclusion: We have identified novel AFP-specific murine TCR genes that can redirect human T-cells to specifically recognize and kill HCC tumor cells, and those AFP158-specific TCRs have a great potential to engineer a patient’s autologous T-cells to treat HCC tumors.
Citation Format: Yukai He, Wei Zhu, Yibing Peng, Lan Wang, Yuan Hong, Juan Wu, Esteban Celis. Identification of α-fetoprotein-specific T-cell receptors for hepatocellular carcinoma immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A030.
Abstract A032: Chimeric antigen receptor (CAR) targeted epitope determines optimal CAR spacer length for therapy against medulloblastoma
Authors: Johnson Adam J. , Chang Cindy A. , Baldwin Michael L. , Yokoyama Jason K. , Jensen Michael C.M. 
Published: February 2019

Abstract
Improved therapeutic outcomes for children with embryonal brain tumors (EBTs) hinge on the development and optimization of novel, targeted therapies able to eradicate tumors without serious treatment-related damage to the central nervous system (CNS). To this end, we describe the design and validation of optimized chimeric antigen receptors (CARs) T-cells that target the EBT-associated antigen Her2. Our studies demonstrate that Her2CAR extracellular spacer domains actively influence T-cell in vitro functional outputs and in vivo responses, with the medium (M-) spacer able to confer the greatest antitumor activity against the most common EBT, medulloblastoma. Furthermore, we show that the juxtamembrane epitope targeted on Her2 precluded short spacer Her2CAR activity; yet, this activity could be rescued when the targeted epitope was expressed in a membrane distal position. Similarly, while modifications that abrogate Fc region interactions in the long spacer Her2CAR rescued in vivo activity, the resultant functional outputs failed to reach the antitumor potency elicited by the M-spacer CAR. Here we also demonstrate the in vitro and in vivo activity of M-spacer CAR T-cells produced by our clinical manufacturing process. Results from this preclinical dataset have directed the implementation of a clinical trial that delivers Her2CAR T-cells locoregionally to patients with EBT tumors, coined BrainChild-01. Collectively, these results reiterate the necessity to tailor CARs to their respective targeted antigen epitope and describe the optimization of Her2-targeted CARs for the treatment of EBT tumors.
Citation Format: Adam J. Johnson, Cindy A. Chang, Michael L. Baldwin, Jason K. Yokoyama, Michael C.M. Jensen. Chimeric antigen receptor (CAR) targeted epitope determines optimal CAR spacer length for therapy against medulloblastoma [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A032.
Abstract A034: High-throughput identification of naturally occurring T-cell receptors with therapeutic potential against tumor-associated, viral and neoantigens
Authors: Klinger Mark , Ebert Peter , Osborne Edward , Taniguchi Ruth , Hu Joyce , Hayes Tim , Benzeno Sharon , Carbo Adria , Laur Melanie , Eggers Erica , Robins Harlan 
Published: February 2019

Abstract
The growing use of immunotherapy to treat advanced cancers has brought about a revolution in techniques to mobilize the immune system to antitumor effect. Chimeric antigen receptor (CAR) T-cells targeting CD19 constitute the first modified T-cell products to garner FDA approval for clinical use. However, CAR technologies can only targeT-cell surface antigens, representing approximately one quarter of potential targets. In contrast, T-cell receptor (TCR) therapies can target peptides presented by the major histocompatibility complex (MHC), including those derived from intracellular antigens. Hitherto, such receptors have generally been identified through low-throughput techniques using cancer patients’ blood, followed by affinity-maturation of TCRs, a step that can decrease safety. Here, we demonstrate a novel pipeline for the identification of potential therapeutic TCRs from the naïve repertoire of healthy individuals. Using a technique called Multiplexed Identification of T-cell Receptor Antigen specificity (MIRA), we input hundreds of antigens of interest, including tumor-associated antigens, viral antigens and neoantigens, and identify thousands of TCRs to these antigens. These TCRs then undergo evaluation for affinity, avidity, cytokine release, cytotoxicity and safety. Cytotoxicity is demonstrated using both peptide-loaded and endogenously presented peptides. Safety is evaluated using alanine-glycine scans; evaluation of reactivity of TCRs againsT-cell lines and primary cells is planned. We have fully characterized several TCRs targeting clinically relevant targets, which demonstrated improved avidity and cytolysis relative to a benchmark TCR, and a promising preliminary safety profile. In the recent year, cancer neoantigens as targets for natural and therapeutic antitumor responses have also gained momentum given their attractive product profile. Hereto, we also show data for TCRs against shared neoantigens.
Citation Format: Mark Klinger, Peter Ebert, Edward Osborne, Ruth Taniguchi, Joyce Hu, Tim Hayes, Sharon Benzeno, Adria Carbo, Melanie Laur, Erica Eggers, Harlan Robins. High-throughput identification of naturally occurring T-cell receptors with therapeutic potential against tumor-associated, viral and neoantigens [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A034.
Abstract A041: Hypoxia-responsive CAR T-cells
Authors: Sarén Tina Anna , Senz Anne Marie , Ramachandran Mohanraj , Yu Di , Essand Magnus 
Published: February 2019

Abstract
In recent years, CD19 CAR T-cell therapy has been successfully implemented against therapy-resistant B-cell malignancies. The results are especially striking for acute lymphoblastic leukemia (ALL), while results are somewhat less stunning when it comes to lymphoma. This is in part due to the semi-solid structure of lymphoma with an immune suppressive tumor microenvironment and less oxygenated areas within the tumors. These obstacles become even more pronounced in solid tumors. Furthermore, in the case of solid tumors the lack of tumor-specific antigens represents a major challenge. Instead, overexpressed tumor-associated antigens (TAAs) are often used as targets in CAR T-cell therapy of solid tumors. However, as TAAs are also expressed to some extent in normal tissue, targeting these antigens may result in severe OFF-tumor ON-target toxicity. In the case of CD19 CAR T-cell therapy of B-cell malignancies, OFF-tumor ON-target toxicity causes B-cell aplasia.The aim of this study was to reduce OFF-tumor ON-target toxicity by engineering CAR T-cells that mainly express the CAR molecule in the hypoxic tumor microenvironment. Hypoxia-inducible factor 1 (HIF1) is a transcription factor that is a major mediator of hypoxia-induced gene expression as it binds to hypoxia response elements (HREs) in promoter regions of hypoxia-responsive genes and initiates their expression. In this study, a cassette of HREs was inserted together with a minimal CMV (mCMV) promoter in front of the CD19 CAR cassette to promote expression during hypoxic conditions. Chemically induced hypoxia augmented CD19 CAR expression over time in hypoxia-responsive CD19 CAR T-cells (HRE-mCMV-CD19CAR-GFP), whereas CAR expression was unaffected in CD19 CAR T-cells with constitutively expressed CAR (EF1α-CD19CAR-GFP). Furthermore, hypoxia-responsive CAR T-cells had an increased activation status and killing capacity upon antigen encounter in hypoxic compared to normoxic conditions. This design could be evaluated in the clinic to reduce B-cell aplasia in CD19 CAR T-cell therapy of lymphomas and especially to reduce OFF-target toxicities from CAR T-cells targeting TAAs in solid tumors.
Citation Format: Tina Anna Sarén, Anne Marie Senz, Mohanraj Ramachandran, Di Yu, Magnus Essand. Hypoxia-responsive CAR T-cells [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A041.
Abstract A069: NIM15 blockade – A new stroma-targeting approach for the treatment of epithelial ovarian cancer
Authors: Ferber Dyke , Suarez-Carmona Meggy , Momburg Frank , Meyer Marten , Rothenheber Rebecca , Lenoir Bénédicte M.A. , Schott Sarah , Zoernig Inka , Jäger Dirk , Halama Niels 
Published: February 2019

Abstract
Despite the immense research over the past decade in the cancer immunology field, which has led to several clinical trials and FDA and EMA approvals of biologicals for the reinvigoration of T-cell-mediated cancer cell killing in diverse tumor entities, the long-term survival of patients with advanced epithelial ovarian cancer is still devastating. These results therefore imply the need for a more intensive investigation of the tumor microenvironment in this cancer type in order to enhance disease outcome and improve the effectiveness of current immunotherapeutics. We herein show for the first time efficacy data of a novel treatment approach for the specific targeting of the stromal tumor compartment in a human tissue explant culture model of high-grade serous ovarian cancer. Antibody-mediated blockade of NIM15, a protein suspected to be predominantly expressed by tumor-associated macrophages and cancer-associated-fibroblasts in ovarian cancer, has the potential to polarize the immune landscape in a subset of patients from a stromal-dense and immunosuppressive one into a Th1-M1-supportive microenvironment, as measured by cytokine pattern analyses and semiautomated immune cell quantification. Abrogating the effects of secreted NIM15 unleashes in vitro proliferation of T-cell subsets and increases the production of cytokines and chemokines involved in innate and adaptive antitumor immune responses in our tissue culture explant model. In order to unravel the mechanistic relations behind the observed effects, we plan further experiments to prove whether these might be due to a disruption of the collagen-dense tumor stroma and a repolarization of the secretory profile of tumor-associated macrophages and fibroblasts. In summary, we hope to develop a pharmacologic tool that converts immune-depleted, “cold” cancer types into T-cell infiltrated ones and therewith provide a rationale for combination treatment approaches, like anti-PD1 blockade or adoptive cell transfer, to further ameliorate the so far poor response of metastasized, refractory ovarian cancer.
Citation Format: Dyke Ferber, Meggy Suarez-Carmona, Frank Momburg, Marten Meyer, Rebecca Rothenheber, Bénédicte M.A. Lenoir, Sarah Schott, Inka Zoernig, Dirk Jäger, Niels Halama. NIM15 blockade – A new stroma-targeting approach for the treatment of epithelial ovarian cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A069.
Abstract A072: Calreticulin exposures by malignant blasts correlate with robust anticancer immunity and improved clinical outcome in AML patients
Authors: Fucikova Jitka 
Published: February 2019

Abstract
Cancer cell death can be perceived as immunogenic by the host only when malignant cells emit immunostimulatory signals (so-called “damage-associated molecular patterns,” DAMPs), as they die in the context of failing adaptive responses to stress. Accumulating preclinical and clinical evidence indicates that the capacity of immunogenic cell death to (re-)activate an anticancer immune response is key to the success of various chemo- and radiotherapeutic regimens. Malignant blasts from patients with acute myeloid leukemia (AML) exposed multiple DAMPs, including calreticulin (CRT), heat-shock protein 70 (HSP70), and HSP90 on their plasma membrane irrespective of treatment. In these patients, high levels of surface-exposed (ecto)-CRT correlated with an increased proportion of natural killer cells and effector memory CD4+ and CD8+ T-cells in the periphery. Moreover, CRT exposure on the plasma membrane of malignant blasts positively correlated with the frequency of circulating T-cells specific for leukemia-associated antigens, indicating that ecto-CRT favors the initiation of anticancer immunity in patients with AML. Finally, although the levels of ecto-HSP70, ecto-HSP90, and ecto-CRT were all associated with improved relapse-free survival, only CRT exposure significantly correlated with superior overall survival. Thus, CRT exposure represents a novel powerful prognostic biomarker for patients with AML, reflecting the activation of a clinically relevant AML-specific immune response.
Citation Format: Jitka Fucikova. Calreticulin exposures by malignant blasts correlate with robust anticancer immunity and improved clinical outcome in AML patients [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A072.
Abstract A075: A protective role for group 3 innate lymphoid cells in colitis-associated colorectal cancer
Authors: Goc Jeremy , Bessman Nick , Sahota Sheena , Laure Flamar Anne , Putzel Gregory , Withers David , Arthur Janelle , Shah Manish , Sonnenberg Gregory 
Published: February 2019

Abstract
Chronic inflammation is recognized as a causative factor in the development of cancer and recent paradigms suggest that microbe-driven chronic inflammation is causally associated with the development and progression of cancer in the colon. Further, recent studies in mice have implicated innate lymphoid cells (ILC) as a key cell population that regulates intestinal inflammation. Group 3 innate lymphoid cells (ILC3) are essential regulators of immunity, inflammation and tissue homeostasis in the intestine, yet their role in cancer remains poorly defined. Here, we identify that ILC3 are associated with both human and mouse colon tumors. Tumor-associated ILC3 are selectively localized within lymphoid aggregates and exhibit a unique phenotypic profile as compared with nonmalignant tissue. Critically, mice with a selective deletion of ILC3-specific MHCII exhibit a striking increased susceptibility to intestinal tissue damage and develop highly invasive and flat colorectal tumors. These data demonstrate a protective role for antigen-presenting ILC3 in the context of cancer development and progression in the intestine, and suggest that further interrogation may lead to the development of novel immunotherapeutic strategies in colon cancer.
Citation Format: Jeremy Goc, Nick Bessman, Sheena Sahota, Flamar Anne Laure, Gregory Putzel, David Withers, Janelle Arthur, Manish Shah, Gregory Sonnenberg. A protective role for group 3 innate lymphoid cells in colitis-associated colorectal cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A075.