bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A14: Surgical removal of metastatic lesions increases T-cell reactivity to tumor-associated antigens in stage III melanoma patients
Authors: Coaña Yago Pico de , Gunnarsdóttir Fríða Björk , Wolodarski Maria , Brage Suzanne Egyhazi , Masucci Giuseppe , Hansson Johan , Kiessling Rolf 
Published: February 2019

Abstract
Currently, there are hardly any peripheral blood biomarkers that allow for identification of patients’ prognosis or survival in advanced melanoma patients. Our main objective was to compare the reactivity of peripheral blood T cells of patients with stage III or IV metastatic melanoma to Tumor-Associated Antigens, before and after surgery where metastatic lesions were removed. Peripheral blood mononuclear cells were isolated from blood samples taken before and after surgery and were stimulated over the course of two weeks with overlapping peptide pools of three known melanoma antigens: MelanA, NY-ESO-1, and Cripto-1. After 12 days, cells were re-stimulated and analyzed using multicolor flow cytometry. CD4 and CD8 positive cells were analyzed for cytokine production. McNemar’s test was used to analyze changes before and after surgery, and correlation between cell reactivity and cytokine production with progression free survival was determined by Kaplan Meier analysis. Surgical removal of metastatic lesions changed reactivity of T cells to MelanA, NY-ESO-1 and Cripto-1. The presence of CD4 T cells that produced IL-17 and/or TNF-a after stimulation was correlated with a worse progression-free survival (PFS). We show here that surgical removal of metastases increases T-cell reactivity in melanoma patients and that certain cytokine profiles may be associated to PFS. This could provide insight into the complexity of the correlation between a specific T-cell response and a favorable immune response to metastatic melanoma.
Citation Format: Yago Pico de Coaña, Fríða Björk Gunnarsdóttir, Maria Wolodarski, Suzanne Egyhazi Brage, Giuseppe Masucci, Johan Hansson, Rolf Kiessling. Surgical removal of metastatic lesions increases T-cell reactivity to tumor-associated antigens in stage III melanoma patients [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A14.
Abstract A28: Tumor cell intrinsic BPTF inhibits NK cell activity and the abundance of natural cytotoxicity receptor co-ligands
Authors: Mayes Kimberly , Elsayed Zeinab , Alhazmi Aiman , Waters Michael , Alkhatib Suehyb , Roberts Mark , Song Carolyn , Peterson Kristen , Chan Vivian , Ailaney Nikhil , Malapati Pumoli , Blevins Tana , Lisnic Berislav , Dumur Catherine , Landry Joseph 
Published: February 2019

Abstract
Using syngeneic BALB/c mouse breast cancer models, we show that the chromatin remodeling subunit bromodomain PHD finger transcription factor (BPTF) suppresses natural killer (NK) cell antitumor activity in the tumor microenvironment (TME). In culture, BPTF suppresses direct natural cytotoxicity receptor (NCR) mediated NK cell cytolytic activity to mouse and human cancer cell lines, demonstrating conserved functions. Blocking mouse NCR1 in vivo rescues BPTF KD tumor weights, demonstrating its importance for the control of tumor growth. We discovered that BPTF occupies heparanase (Hpse) regulatory elements, activating its expression. Increased heparanase activity results in reduced cell surface abundance of the NCR co-ligands: heparan sulfate proteoglycans (HSPGs). Using gain and loss of function approaches we show that elevated heparanase levels suppress NK cell cytolytic activity to tumor cells in culture. These results suggest that BPTF activates heparanase expression, which in turn reduces cell surface HSPGs and NCR co-ligands, inhibiting NK cell activity. Furthermore, gene expression data from human breast cancer tumors shows that elevated BPTF expression correlates with reduced antitumor immune cell signatures, supporting conserved roles for BPTF in suppressing antitumor immunity. Conditional BPTF depletion in established mouse breast tumors enhances antitumor immunity, suggesting that inhibiting BPTF could provide a novel immunotherapy.
Citation Format: Kimberly Mayes, Zeinab Elsayed, Aiman Alhazmi, Michael Waters, Suehyb Alkhatib, Mark Roberts, Carolyn Song, Kristen Peterson, Vivian Chan, Nikhil Ailaney, Pumoli Malapati, Tana Blevins, Berislav Lisnic, Catherine Dumur, Joseph Landry. Tumor cell intrinsic BPTF inhibits NK cell activity and the abundance of natural cytotoxicity receptor co-ligands [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A28.
Abstract A29: Multimeric anti-human OX40 induces robust immune responses
Authors: Madireddi Shravan , Yang Yanli , Yeh Sherry , Gu Chen , Sanchez Patricia L. , Brezski Randall , Chiu Henry , Erickson Hans , Cubas Rafael A. , Lazar Gregory , Kim Jeong 
Published: February 2019

Abstract
Agonistic antibodies to co-stimulatory members of the TNF Receptor Superfamily (TNFRSF) have demonstrated impressive antitumor immune responses in murine tumor models and are currently under investigation in the clinic. In order to induce efficient co-stimulatory signaling, the majority of TNFRSF members require supermolecular cluster formation on the immune cell surface. Recent studies have revealed that agonistic antibodies achieve this in part by Fcγ receptor (FcγR) mediated cross-linking, enabling antibodies to cluster the TNFRSF member expressed on the opposing immune cell. Agonistic antibodies to OX40 (CD134; TNFRSF4), which primarily target T cells are currently in clinical trials for cancer immunotherapy. However, as OX40 needs clustering for efficient signaling, these antibodies can only function in microenvironments where FcγR bearing cells are abundant. To overcome this limitation, we generated multimeric anti-human-OX40 antibodies, which cluster OX40 independent of FcγR mediated cross-linking. In vitro, we found that multimeric anti-OX40 induces robust signaling independent of FcγR. Compared to the bivalent antibodies, multimeric anti-OX40 generated superior immune responses in vaccination and tumor settings, in vivo. Together, multimeric antibody platforms have important implications for effective targeting of OX40 and possibly other TNFRSF members.
Citation Format: Shravan Madireddi, Yanli Yang, Sherry Yeh, Chen Gu, Patricia L. Sanchez, Randall Brezski, Henry Chiu, Hans Erickson, Rafael A. Cubas, Gregory Lazar, Jeong Kim. Multimeric anti-human OX40 induces robust immune responses [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A29.
Abstract A30: Ron kinase inhibition to improve immunotherapy for breast cancer metastasis
Authors: Lai Shu Chin Alicia , Ekiz Atakan , Welm Alana 
Published: February 2019

Abstract
Metastasis is the cause of death for nearly all types of cancer, including breast cancer. An exciting new area of research in metastatic breast cancer centers on immune therapy. Although new immune checkpoint blockade therapies have provided benefit for a fraction of patients tested so far, the majority of patients still do not respond to these drugs. A better understanding of how the immune system can be harnessed against metastatic breast cancer is required in order to improve patient outcomes in this area.
We previously discovered that macrophage Ron receptor tyrosine kinase promotes breast cancer metastasis by inhibiting CD8+ cytotoxic T lymphocyte activity. We hypothesized that dual blockade of Ron activity and existing immune checkpoint molecules would unleash a more effective CD8+ T cell response to control or eliminate metastatic breast cancer. Our strategy would simultaneously disable tumor-mediated immune evasion mechanisms on both the innate and adaptive immune systems. To test the potential of combination therapy, the Ron inhibitor BMS-777607 and/or the immune checkpoint blocking agents anti-PD1 or anti-CTLA4, were administered in our mouse mammary tumor model to examine the effects on breast tumor progression. To examine Ron-specific effects of BMS-777607, we also examined the effect of genetic deletion of host Ron signaling activity in combination with immunotherapy. The anti-tumor immune response was comprehensively examined by multi-color flow cytometry and immunohistochemical staining for tumor-infiltrating lymphocytes (TILs). Our data suggest that the combination of Ron inhibition with immune checkpoint blockade may be an effective therapy in breast cancer.
Citation Format: Shu Chin Alicia Lai, Atakan Ekiz, Alana Welm. Ron kinase inhibition to improve immunotherapy for breast cancer metastasis [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A30.
Abstract A33: Tumor derived T cell clones for evaluation of check point inhibitor therapeutics
Authors: Shields Robert L. , Saux Sabine Le , Li Sophie , Sathe Manjiri , McClanahan Terri , Malefyt Rene De Waal 
Published: February 2019

Abstract
Improving clinical outcomes using immunotherapeutics in cancer treatments will depend on a variety of factors including the composition and phenotype of effector T cell in tumors, the inhibitory factors from myeloid, tumor and stromal compartments of the tumor and selection of efficacious combination of therapeutic immunomodulatory agents that either neutralize immune checkpoint inhibitors or activate T cell costimulatory pathways.
To address the issue of selecting optimal combinations of immune modulating agents we developed an in-vitro culture system for allo-stimulating and expanding tumor infiltrating lymphocytes (TILS) from tumor digests with an MHC Class II alloantigen expressing cell line. We selected allo-specific CD4 and CD8 clones from expanded TILS with an exhausted phenotype confirmed by cell surface expression of PD-1, LAG3 and TIGIT. T cell clones were incubated with the alloantigen expressing cell lines transduced with different combinations of immodulatory ligands and compared the effect of single agent versus combinations of checkpoint inhibitory monoclonal antibodies on T cell proliferation and cytokine production. Taqman and flow cytometry analysis was performed on several clones following allo-stimulation. A decrease in TIL clonality with repeated allo-stimulation was confirmed by TcR beta chain sequencing. In-vitro IFN gamma and Granzyme B production was enhanced with anti-PD-1 antibodies in combination with either anti-LAG3 or anti-TIGIT antibodies. This in-vitro system has the potential of screening combinations of immodulatory antibodies in a variety of TILS from different tumor types and can improve our understanding of new checkpoint inhibitor combinations.
Citation Format: Robert L. Shields, Sabine Le Saux, Sophie Li, Manjiri Sathe, Terri McClanahan, Rene De Waal Malefyt. Tumor derived T cell clones for evaluation of check point inhibitor therapeutics [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A33.
Abstract A45: Preliminary results of a phase 1 clinical trial of a PSA, IL-2, GM-CSF containing prostate cancer vaccine in PSA defined biochemical recurrent prostate cancer patients
Authors: Head Jonathan F. , Daniels Gregory A. , McKinney Michelle , Ongkeko Weg , Sakamoto Kyoko , Wang-Rodriguez Jessica 
Published: February 2019

Abstract
Immunotherapy for cancer has had two main approaches that have led to clinical applications. The first is stimulating immune responses to tumor cells with cytokines or cellular immunotherapy and the second is blocking tumor immune evasion and the associated inhibition of T-cell activation with antibodies to the CTLA-4 receptor, PD-1 receptor or PD-L1. We have taken a different approach and have developed therapeutic cancer vaccines that are a combination of tumor antigens (proteins overexpressed by tumors) with biological adjuvants (the cytokines IL-2 and GM-CSF). This study is a Phase 1a/1b clinical trial of a PSA/IL-2/GM-CSF vaccine in recurrent prostate cancer in hormone-naïve and hormone-independent patients. Major inclusion criteria include adenocarcinoma of the prostate, rising serum PSA and no measurable disease. Phase 1a examines the rate of dose limiting adverse events (DLAEs) in an initial course of 6 vaccinations (“induction vaccination”). The patients will receive intradermal injections of the PSA/IL-2/GM-CSF vaccine at weeks 1, 2, 3, 7, 11 and 15. Enrollment of the twenty patients in the Phase 1a has been completed. To date, 14 patients in the Phase 1a portion of the trial have received all 6 vaccines. Twelve of the 15 patients who have received vaccines have increased immune responses to PSA in a lymphocyte blastogenesis assay by week 19. After 6 vaccines, 9 of 14 patients had an increase in the doubling time of their serum PSA, suggesting a slowing of the progression of the cancer. Median follow up after the first vaccine is 33 months. None of the patients vaccinated in the Phase 1a portion have had a DLAE.
Citation Format: Jonathan F. Head, Gregory A. Daniels, Michelle McKinney, Weg Ongkeko, Kyoko Sakamoto, Jessica Wang-Rodriguez. Preliminary results of a phase 1 clinical trial of a PSA, IL-2, GM-CSF containing prostate cancer vaccine in PSA defined biochemical recurrent prostate cancer patients [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A45.
Abstract A68: Targeting metabolic vulnerabilities of MDSCs to enhance the antitumor activity of PD-1 blockade
Authors: Kim Sun Hye , Li Man , Trousil Sebastian , zheng bin 
Published: February 2019

Abstract
Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that differentiate from bone marrow precursors and expand in cancer-bearing hosts. MDSCs significantly contribute to tumor-induced immune suppression and represent a promising target for cancer immune therapies. Biguanides, such as the diabetes therapeutics metformin and phenformin, have demonstrated antitumor activity both in vitro and in vivo. However, their potential effects on the tumor microenvironment are largely unknown. Here we report that phenformin, a mitochondrial complex I inhibitor, selectively inhibits granulocytic myeloid-derived suppressor cells (G-MDSCs) in spleens of tumor bearing mice and ex vivo. Metabolomics analysis reveal that, compared to CD11b+Ly6G- cells, CD11b+Ly6G+ MDSCs have lower levels of glutathione and NADPH/NADP+ ratio, suggesting these cells have higher level of endogenous ROS. Interestingly, phenformin further induces production of ROS in G-MDSC, whereas co-treatment of the antioxidant N-acetylcysteine dampens ROS levels in these cells and rescues the effect of phenformin on reducing the numbers of G-MDSCs. Importantly, co-treatment of phenformin enhances the effect of anti-PD-1 antibody therapy on inhibiting tumor growth in the BRAF V600E/PTEN null melanoma mouse model. Combination of phenformin and anti PD-1 cooperatively induces CD8+ T cell infiltration and decreases levels of proteins that are critical for immune suppressive activities of MDSCs. Our findings demonstrate a selective, inhibitory effect of phenformin on G-MDSCs-driven immune suppression and support that phenformin improves the anti-tumor activity of PD-1 blockade immunotherapy in melanoma.
Citation Format: Sun Hye Kim, Man Li, Sebastian Trousil, bin zheng. Targeting metabolic vulnerabilities of MDSCs to enhance the antitumor activity of PD-1 blockade [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A68.
Abstract A75: A radiosensitivity gene signature and PD-L1 expression are predictive of the clinical outcomes of patients with lower-grade glioma in The Cancer Genome Atlas dataset
Authors: Jang Bum Sup , Kim In Ah 
Published: February 2019

Abstract
Background: Identifying predictive factors for the clinical outcome of patients with low grade gliomas following radiotherapy could help optimize patient treatments. Here, we investigate the predictive efficacy of both a previously identified “31 gene signature” and programmed death ligand-1 (PD-L1) expression.
Methods: We identified 516 patients with low grade glioma in The Cancer Genome Atlas dataset and divided them into two clusters: radiosensitive (RS) and radioresistant (RR). Patients were also classified as PD-L1-high or PD-L1-low based on CD274 mRNA expression. Five-year survival rates were compared across patient groups, and differentially expressed genes were identified via a gene enrichment analysis.
Results: Patients in the RS group had a higher survival rate than in the RR group, but only when treated with radiotherapy (63% vs. 52%, p = 0.019; univariate analysis). Patients in the RR group who were also PD-L1-high had a lower survival rate than other patients (50% vs. 60%, p = 0.010). Furthermore, a Cox multivariate analysis demonstrated that both belonging to this patient population and expressing wild-type isocitrate dehydrogenase were predictive of lower survival rates (p = 0.048). Differentially expressed genes associated with this group were found to play a role in the immune response, including the T-cell receptor signaling pathway.
Conclusions: We validated the predictive value of a 31 gene signature and PD-L1 expression in a dataset of patients with low-grade glioma. Our results suggest that the patient population classified as both RR and PD-L1 high may benefit most from radiotherapy combined with anti-PD1/PD-L1 treatment.
This work was supported by a grant from the Ministry of Science, ICT & Future Planning (NRF#2017R1A2B4002710 & & 2017M2A2A7A01018438) to In Ah Kim.
Citation Format: Bum Sup Jang, In Ah Kim. A radiosensitivity gene signature and PD-L1 expression are predictive of the clinical outcomes of patients with lower-grade glioma in The Cancer Genome Atlas dataset [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A75.
Abstract A77: Cripto-1 vaccination elicits protective immune response to metastatic breast cancer and breast cancer stem cells
Authors: Witt Kristina , Ligtenberg Maarten Alexander , Conti Laura , Lanzardo Stefania , Ruiu Roberto , Tufvesson-Stiller Helena , Ostling Jeanette , Rolny Charlotte , Lladser Alvaro , Lundqvist Andreas , Cavallo Federica , Kiessling Rolf 
Published: February 2019

Abstract
Metastatic breast cancer is a fatal disease responding poorly to classical treatments. Cancer vaccines targeting antigens expressed by metastatic breast cancer and cancer stem cells (CSC) have the potential to become potent anti-cancer therapies. Cripto-1 is an onco-fetal protein frequently overexpressed in invasive breast cancer and cancer-initiating cells. It is involved in cellular processes such as cell migration, epithelial-mesenchymal transition, and invasion, hallmarks of aggressive cancers. In this study we explored the potential of a Cripto-1 encoding DNA vaccination to target metastatic breast cancer and breast cancer stem cells in preclinical models.
Mice were vaccinated with a DNA vaccine encoding for mouse Cripto-1 (mCR) prior tumor challenge. In the 4T1 metastatic breast cancer model vaccination against mCR resulted in reduced primary tumor growth and significantly reduced metastatic burden in the lung. We further identified Cripto-1 specific antibodies in this model generated by the vaccination. TUBO is a Cripto-1 negative breast cancer cell line and vaccination against mCR in the transplantable BALB/c TUBO model did not result in protection. We show that spheroid culture of TUBO results in up-regulation of Cripto-1 on the cell surface. In addition, TUBO spheres display cancer stem cell phenotype. Consequently, tumor progression was inhibited in anti-mCR vaccinated mice challenged with TUBO spheres but not in control vaccinated mice.
Our data indicates that DNA vaccination against Cripto-1 results in a protective immune response against mCR expressing tumors. Targeting Cripto-1 by vaccination is a promising potential immunotherapy for treatment of metastatic breast cancer.
Citation Format: Kristina Witt, Maarten Alexander Ligtenberg, Laura Conti, Stefania Lanzardo, Roberto Ruiu, Helena Tufvesson-Stiller, Jeanette Ostling, Charlotte Rolny, Alvaro Lladser, Andreas Lundqvist, Federica Cavallo, Rolf Kiessling. Cripto-1 vaccination elicits protective immune response to metastatic breast cancer and breast cancer stem cells [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A77.
Abstract A78: Analysis of ROR1 protein expression in mice with reconstituted human immune system components
Authors: Leung Carol SK 
Published: February 2019

Abstract
Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal antigen expressed on multiple solid tumors and leukemias, but not on normal human tissues except at very low levels in adipose tissue. ROR1 is highly upregulated in chronic lymphocytic leukemia (CLL) B cells. NOD-scid IL2rγnull (NSG) mice engrafted with human fetal liver CD34+ hematopoietic progenitor cells (huNSG) achieved multi-lineage human immune cell reconstitution including B cells, T cells, NK cells and Dendritic cells. Like the CLL patients, most of huNSG mice have abnormal high frequency of B cells in the periphery, and a percentage of CD19+ B cells express CD5. In light of this, we aim to determine whether ROR1 is expressed in B cells of huNSG mice, we analyzed the protein level of ROR1 in B cells of huNSG mice by flow cytometry. ROR1 protein was highly expressed in a proportion of B cells in the blood, spleen and bone marrow. As huNSG mice have autologous T and NK cells, plus the B cells with ROR1 expression, this could act as a B cell malignant disease model for studying immunotherapeutic targeting ROR1, including bispecific T cell engagers and chimeric antigen receptor T cells.
Citation Format: Carol SK Leung. Analysis of ROR1 protein expression in mice with reconstituted human immune system components [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A78.