bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A036: Anti-PD1 therapy and CD8 T cell invigoration in metastatic melanoma
Authors: Huang Alexander , Xu Wei , Harmon Shannon , Quagliarello Felix , Herati Ramin , Pauken Kristen , Bengsch Bertram , Schuchter Lynn , Amaravadi Ravi , McGettigan Suzanne , Gangadhar Tara , Wherry John 
Published: May 2016

Abstract
Antibodies targeting the PD-1 pathway can reverse T cell exhaustion resulting in re-invigoration of immune responses. Anti-PD1 therapies such as pembrolizumab have been shown to be efficacious across a broad range of human cancers including melanoma with clinical responses correlating with immune changes in the tumor microenvironment. However, our understanding of the immune mechanism of anti-PD1 therapy in humans remains incomplete. Specifically, there is relatively little information about changes in the differentiation, activation and reversal of exhaustion in peripheral blood CD8 T cells and correlation with clinical outcome. We collected peripheral blood at serial time points before and after pembrolizumab therapy on 39 consecutive patients with Stage IV melanoma and analyzed changes in T cell subsets and differentiation using 16 parameter flow cytometry. Here we show that pembrolizumab treatment results in increases in the peripheral blood CD8/Treg ratio, as well as invigoration of CD8 T cells. Focusing on key CD8 T cell subsets expressing combinations of T-bet, Eomes, PD-1 and other inhibitory receptors has allowed greater focus on populations responding to re-invigoration by pembrolizumab treatment. This invigoration can be demonstrated by upregulation of granzyme B (GzmB) and Ki67 in key CD8 T cell subsets. An early increase in GzmB+Ki67+ cells translates into a later increase in GzmB+ cells suggesting an early wave of proliferation giving rise to a pool of re-invigorated CD8 T cells. T cell subsets that express markers of exhaustion including T-bet, Eomes, and inhibitory receptors may represent populations that are invigorated by anti-PD1 therapy. These changes may also correlate with clinical outcomes and therefore may be useful as a biomarker of response. These results show that T cell responses to pembrolizumab treatment can be tracked in an easily accessible peripheral blood compartment during therapy. The kinetics of immune response in key CD8 T cell subsets may inform us of optimal treatment duration as well as the nature and timing of cancer response to therapy.
Citation Format: Alexander Huang, Wei Xu, Shannon Harmon, Felix Quagliarello, Ramin Herati, Kristen Pauken, Bertram Bengsch, Lynn Schuchter, Ravi Amaravadi, Suzanne McGettigan, Tara Gangadhar, John Wherry. Anti-PD1 therapy and CD8 T cell invigoration in metastatic melanoma. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A036.
Abstract A037: IMCgp100 ImmTAC: A new immunotherapeutic reagent for the treatment of malignant melanoma
Authors: Pentier Johanne , Connolly Mary , Canestraro Martina , Ryan Ruth , Weigand Luise , Hassan Namir , Vuidepot Annelise , Jakobsen Bent 
Published: May 2016

Abstract
For years cancer therapies were mainly concentrated around surgery, chemotherapy and radiotherapy. Recently, a new domain has emerged. Immunotherapies aim to exploit, enhance and optimise the patient's immune system to be more potent at eradicating tumours. T-cell immunotherapies, however, often encounter challenges with low cell surface expression of tumour-associated-antigens (TAAs), down-regulation of class I MHC molecules and low T-cell avidity for TAAs, all contributing to tumour escape.
To address these challenges, Immunocore Ltd. has developed ImmTAC (Immune Mobilising mTCR Against Cancer) technology that aims to recruit and redirect circulating T-cells to target and kill cancer cells with high specificity. ImmTACs are composed of an affinity enhanced monoclonal T-cell receptor (mTCR) combined with an anti-CD3 specific antibody fragment (CD3-scFv). The mTCR targets cancer cells that express TAAs displayed on class I MHC molecules, with high affinity. The CD3-scFv effector domain then drives the recruitment and activation of T-cells. ImmTACs enable an immune synapse to form, leading to the destruction of cancer cells by T-cells.
TAA candidates are selected according to their level of gene expression by measuring their mRNA levels by RT-PCR in healthy and cancer cells, in order to reduce off-target toxicity, as well as by measuring their cell surface expression on class I MHCs by mass spectrometry, to verify target presentation.
We present here our current clinical ImmTAC candidate, IMCgp100, which targets the melanoma-associated gp100 antigen presented on HLA-A2. IMCgp100 has been extensively studied in vitro and is undergoing a phase IIa clinical trial in advanced melanoma patients in the UK and US. The maximum tolerated dose has been established and a dose expansion phase is currently underway. T-cell mobilisation, relevant cytokine release as well as tumour shrinkage have been monitored. The very encouraging results observed so far in our clinical trials show ImmTAC technology to be a promising efficient immunotherapy for cancer.
Citation Format: Johanne Pentier, Mary Connolly, Martina Canestraro, Ruth Ryan, Luise Weigand, Namir Hassan, Annelise Vuidepot, Bent Jakobsen. IMCgp100 ImmTAC: A new immunotherapeutic reagent for the treatment of malignant melanoma. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A037.
Abstract A039: Caspase-2 and oxidative-ER stress crosstalk regulates the exposure of “eat me” signal calreticulin by high hydrostatic pressure treated cancer cells
Authors: Moserova Irena Kusova , Truxova Iva , Garg Abhishek G, , Agostinis Patrizia , Cartron Piere Francois , Vosahlikova Sarka , Spisek Radek , Fucikova Jitka 
Published: May 2016

Abstract
Immunogenic cell death (ICD) is a type of cell death induced by various chemotherapeutics, physical modalities such as photodynamic therapy, radiotherapy and high hydrostatic pressure (HHP). HHP induces immunogenic cell death of cancer cell is currently tested in running II. and III. phase of clinical trial for preparation of active cellular cancer immunotherapy (DCVAC). Previous studies have shown that the immunogenicity of ICD mainly relies on surface exposed calreticulin (ecto-CRT); CRT is normally located in the lumen of the endoplasmic reticulum (ER) and may translocate to the cell surface within hours after treatment. Although ICD can be triggers by HHP, underlying danger signaling pathways remain unclear. Therefore ovarian (OV90) cancer cell line was treated by HHP, UV-B and anthracycline (Idarubicin). The kinetics of ICD markers and key components of ER stress-mediated apoptotic pathway were analyzed by flow cytometry, western blotting and confocal microscopy.
In this work we described the ability of HHP triggers oxidative ER-stress (the production of reactive oxygen species (ROS) together with ER stress response) which results in phosphorylation of PERK and eIF2α. We also observed a rapid caspase-8 activation subsequently followed by BAP31 cleavage, Bid activation and caspase-3 activation. While caspase-8 activation was necessary for cell surface exposure of calreticulin (ecto-CRT) after HHP treatment, proapoptotic proteins Bax and Bak were dispensable for this process. Moreover, we identified that HHP treatment leads to caspase-2 activation. Whereas Idarubicin treatment has no effect on ecto-CRT exposure in Caspase-2 knockdown tumor cells, ecto-CRT was significantly decreased in these cells after HHP treatment. In addition, phagocytosis of HHP-treated Caspase-2 knockdown tumor cells was compromised in contrast to Idarubicin-treated knockout tumor cells.
In conclusion, we characterized the molecular mechanism of ecto-CRT exposure pathway induced by HHP which is analogous to that induced by anthracycline treatment. For the first time we provide evidence that caspase-2 might play an important role in the HHP-mediated ecto-CRT exposure.
Citation Format: Irena Kusova Moserova, Iva Truxova, Abhishek G, Garg, Patrizia Agostinis, Piere Francois Cartron, Sarka Vosahlikova, Radek Spisek, Jitka Fucikova. Caspase-2 and oxidative-ER stress crosstalk regulates the exposure of “eat me” signal calreticulin by high hydrostatic pressure treated cancer cells. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A039.
Abstract A045: Dendritic cell vaccination with partial Treg depletion in relapsed glioblastoma – results from the pilot phase of the HIT-HGG Rez Immunvac study
Authors: Eyrich Matthias , Krauss Jürgen , Löhr Mario , Technau Antje , Rachor Johannes , Monoranu Camelia , Warmuth-Metz Monika , Wölfl Matthias , Kramm Christof , Schlegel Paul Gerhardt 
Published: May 2016

Abstract
Efficacy of therapeutic dendritic cell vaccines (DCV) can be limited by immunosuppressive mechanisms such as regulatory T cells (Treg) overrepesented in the micromilieu of the tumor. Here, we investigated whether a reduction of Treg with metronomic cyclophosphamide (metrCyc) might be a feasible option to improve vaccine efficacy. 7 patients with replased glioblastoma were treated in the pilot phase of the HIT-HGG Rez Immunovac study (5 pediatric, 2 adult patients). After reoperation and monocyte-apheresis, patients received 4 weekly doses of autologous, TNFa/IL-1ß matured DCs pulsed with tumor lysate. Thereafter 4 monthy, and subsequently threemonthly boosts with tumor lysate were given. The intradermal injection site was prepared with topical imiquimod. Additionally, patients were pretreated with oral metrCyc 2-4 weeks before the first vaccination. MetrCyc was well tolerated with one mild and transient leukopenia in a patient, who received a parallel re-irradiation boost. All patients received at least 7 vaccines (4xDCs, 3xlysate boosts). Treg frequency decreased by 32%, but returned to normal levels after cessation of metrCyc. Importantly, 6/6 analyzed patients showed a positive (&gt;1.5fold increase) IFNg-response of varying magnitude and duration towards the autologous tumor lysate in a IFNg-PCR assay. Furthermore, we observed an increase in VLA4+ T-cells induced by the vaccine, both in the CD4 as well as the CD8 compartment. So far, all patients relapsed after a mean of 4.8 months, however, overall survival is currently 15.2 months with 4/7 patients being still alive after a median follow-up of 21 months (range 12-27 months). One patient is disease-free after reoperation and continuation of vaccination for 26 months now. 6-month overall survival was 86%. We conclude that DC vaccination in combination with partial Treg depletion with metrCyc is feasible, safe, and possibly related with a higher than expected frequency of positive IFNg-responses towards tumor tissue. These pilot data warrant verification in the full HIT-HGG Rez Immunovac trial (Eudra-CT 2013-000419-26), which will start to recruit patients soon.
Citation Format: Matthias Eyrich, Jürgen Krauss, Mario Löhr, Antje Technau, Johannes Rachor, Camelia Monoranu, Monika Warmuth-Metz, Matthias Wölfl, Christof Kramm, Paul Gerhardt Schlegel. Dendritic cell vaccination with partial Treg depletion in relapsed glioblastoma – results from the pilot phase of the HIT-HGG Rez Immunvac study. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A045.
Abstract A048: Phase 1 clinical trial of a therapeutic prostate cancer vaccine containing PSA/IL-2/GM-CSF in PSA defined biochemical recurrent prostate cancer patients
Authors: Head Jonathan F. , Daniels Gregory A. , McKinney Michelle , Ongkeko Weg , Wang-Rodriguez Jessica , Sakamoto Kyoko , Elliott Robert L. 
Published: May 2016

Abstract
Immunotherapy for cancer has had two main approaches that have lead 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 (whole cells or proteins) 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 Phase 1b examines the rate of DLAEs with a continued course of an additional 6 vaccinations (“maintenance vaccine”). All patients will receive intradermal injections of the PSA/IL-2/GM-CSF vaccine at weeks 1, 2, 3, 7, 11, and 15. In an additional 28 patients the six maintenance vaccines will alternate IL-2 and the complete vaccine (PSA/IL-2/GM-CSF) at weeks 23, 27, 31, 35, 39 and 43. To date, twelve of twenty patients in the Phase 1a portion of the trial have received at least one vaccine injection and ten patients have received all 6 vaccines. Seven of the ten patients that have received 3 vaccines had increased responses to PSA in a lymphocyte blastogenesis assay and five of the nine patients had an increase in their response after 6 vaccines. None of the patients vaccinated in the Phase 1a portion have had a DLAE and enrollment continues in the Phase 1a.
Citation Format: Jonathan F. Head, Gregory A. Daniels, Michelle McKinney, Weg Ongkeko, Jessica Wang-Rodriguez, Kyoko Sakamoto, Robert L. Elliott. Phase 1 clinical trial of a therapeutic prostate cancer vaccine containing PSA/IL-2/GM-CSF in PSA defined biochemical recurrent prostate cancer patients. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A048.
Abstract A053: Therapy with a non-blocking monoclonal antibody targeting soluble NKG2D ligand MIC revamps endogenous innate and adaptive anti-tumor responses and eliminates primary and metastatic tumors
Authors: Wu Jennifer 
Published: May 2016

Abstract
The human tumor-derived soluble NKG2D ligand, the MHC I-chain related molecule (sMIC), is highly immune suppressive in cancer patients and correlates with poor prognosis. However, the therapeutic effect of targeting sMIC has not been determined, due to the limitation that mice do not express homologs of human MIC. With a clinically relevant transgenic mouse models, we aimed to determine the therapeutic efficacy of a non-blocking sMIC-neutralizing anti-MIC mAb antibody. Treatment of the engineered MIC-expressing “humanized” TRAMP/MIC bi-transgenic mice at advanced disease stages with a sMIC-neutralizing non-blocking mAb effectively induced regression of primary tumors and eliminated metastasis without inducing systemic toxicity. The therapeutic effect is conferred by revamping endogenous anti-tumor immune responses, exemplified by restoring NK cell homeostasis and function, enhancing susceptibility of MIC+-tumor cells to NK cell killing, reviving and sustaining antigen-specific CD8 T cell responses, augmenting CD4 T cells to Th1 responses, priming dendritic cells for antigen presentation, and remodeling tumor microenvironment to be more immune reactive. With a transplantable syngeneic sMIC-expressing B16 melanoma model, we also demonstrated that therapy with the sMIC-neutralizing mAb significantly enhanced the anti-tumor responses of adoptively transferred antigen-specific CD8 and CD4 T cells. We conclude that therapy with a sMIC-neutralizing non-blocking anti-MIC mAb can effectuate anti-tumor immune responses against advanced MIC+ tumors. Our study provided strong rationale for translating sMIC-neutralizing therapeutic mAb into clinics, either alone or in combination with current ongoing standard immunotherapies.
Citation Format: Jennifer Wu. Therapy with a non-blocking monoclonal antibody targeting soluble NKG2D ligand MIC revamps endogenous innate and adaptive anti-tumor responses and eliminates primary and metastatic tumors. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A053.
Abstract A055: Potent therapeutic and immunological effects of the first T-BiTE derived from a TCR-mimic antibody targeting intracellular oncoprotein WT1
Authors: Dao Tao , Pankov Dmitry , Scott Andrew , Korontsvit Tatyana , Zakhaleva Victoriya , Guerrerio Manuel Direito de Morais , Xu Yiyang , Xiang Jingyi , Yan Su , Veomett Nicholas , Veomett Nicholas , Dubrovsky Leonid , Curcio Michael , Doubrovina Ekaterina , Liu Cheng , O'Reilly Richard J. , Scheinberg David A. 
Published: May 2016

Abstract
Bi-specific T cell engager antibody (BiTE) therapy has recently emerged as an effective immunotherapy by redirecting polyclonal T cell cytotoxicity against cell surface protein on tumor cells. We generated the first BiTE construct derived from a TCR-mimic monoclonal antibody (mAb), ESK1, specific for a peptide from an intracellular oncoprotein, WT1, in the context of HLA-A*02:01 molecules. Despite the low density peptide/HLA-A2 complex on the cell surface, ESK-BiTE was able to selectively activate and induce proliferation of cytolytic human T cells to kill multiple leukemias and cancers in vitro and in mice. Surprisingly, we also discovered that in an autologous setting, ESK-BiTE induced a robust secondary CD8 T cell response specific for antigens other than WT1, including HLA-A2-restricted her2-neu-derived peptide 369-377, in patients with her2- positive ovarian cancer. Therefore, the study demonstrated a new vaccinal mechanism for BiTE mAb action that could contribute to more effective long-term therapeutic activity of BiTE's and further broaden their reach to other tumor antigens not previously known or originally targeted.
Citation Format: Tao Dao, Dmitry Pankov, Andrew Scott, Tatyana Korontsvit, Victoriya Zakhaleva, Manuel Direito de Morais Guerrerio, Yiyang Xu, Jingyi Xiang, Su Yan, Nicholas Veomett, Nicholas Veomett, Leonid Dubrovsky, Michael Curcio, Ekaterina Doubrovina, Cheng Liu, Richard J. O'Reilly, David A. Scheinberg. Potent therapeutic and immunological effects of the first T-BiTE derived from a TCR-mimic antibody targeting intracellular oncoprotein WT1. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A055.
Abstract A073: Carrier-free delivery of cytokine to specifically expand adoptively transferred T cells for enhanced cancer immunotherapy
Authors: Tang Li , Zheng Yiran , Mabardi Llian , Irvine Darrell J. 
Published: May 2016

Abstract
Adoptive cell transfer (ACT) with autologous tumor-reactive T cells is a promising strategy in cancer immunotherapy, but treatment of solid tumors is limited by the rapid decline in function of the transplanted T cells. In order to maintain high numbers of viable antigen-specific cytotoxic T cells in tumors, co-administration of supporting immunostimulant agents together with transferred cells is often necessary in clinical practice. However, the high systemic doses of such agents needed to enhance T cell functionality can also result in serious side effects. Here, we developed a carrier-free strategy to deliver cytokines specifically to adoptively transferred T cells for cancer immunotherapy. IL2-Fc or an IL-15 superagonist were chemically crosslinked with a disulfide linker to form protein nanogels (NGs), which were conjugated to the plasma membrane of ACT T-cells. These NGs had exceptionally high loading of cytokines (~70 wt%) and released native protein in physiological conditions in a sustained manner through breakdown of the degradable disulfide linker in response to the activated T cell surface reduction activity. Cytokine-NGs were chemically conjugated onto the plasma membrane of donor T cells, enabling continuous pseudo-autocrine release of cytokine for stimulation of transferred CD8+ T cells. Transferred pmel-1 CD8+ T cells with optimized number of NGs conjugated per cell showed enhanced expansion and long persistence in B16F10 tumor bearing mice. Quantification of transferred Thy1.1+CD8+ T cells in tumors at Day 13 showed that T cells with conjugated cytokine-NGs expanded ~80 fold more than the T cells with systemically administered free cytokine. We demonstrated that the cytokine-NG-T cell conjugation strategy could augment transferred T-cell expansion efficiently and specifically in vivo, and thus improve the therapeutic efficacy. This T cell-NG “back pack” approach provides a readily generalizable strategy to provide autocrine protein drug support to donor cells to enhance the safety and efficacy of ACT.
Citation Format: Li Tang, Yiran Zheng, Llian Mabardi, Darrell J. Irvine. Carrier-free delivery of cytokine to specifically expand adoptively transferred T cells for enhanced cancer immunotherapy. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A073.