bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B045: Immunosuppressive plasmocytes impede T-cell-dependent immunogenic chemotherapy
Authors: Shalapour Shabnam , Karin Michael 
Published: May 2016

Abstract
Cancer-associated genetic alterations induce expression of tumor antigens that can activate CD8+ cytotoxic T cells (CTLs), but the microenvironment of established tumors promotes immune tolerance through poorly understood mechanisms. Recently developed therapeutics that overcome tolerogenic mechanisms activate tumor-directed CTLs and are effective in some human cancers. Immune mechanisms also affect treatment outcome and certain chemotherapeutic drugs stimulate cancer-specific immune responses by inducing immunogenic cell death and other effector mechanisms. Because castrate-resistant prostate cancer is refractory to most therapies, we examined B cell involvement in the acquisition of chemotherapy resistance. Here we focus on oxaliplatin, an immunogenic chemotherapeutic that is effective in aggressive prostate cancer. Mouse B cells modulate the response to low-dose oxaliplatin, which promotes tumor-directed CTL activation by inducing immunogenic cell death. Three different mouse prostate cancer models were refractory to oxaliplatin unless genetically or pharmacologically depleted of B cells. The crucial immunosuppressive B cells are plasmocytes that express IgA, interleukin (IL)-10 and programmed death ligand 1 (PD-L1), the appearance of which depends on TGFβ receptor signaling. Elimination of these cells, which also infiltrate human-therapy-resistant prostate cancer, allows CTL-dependent eradication of oxaliplatin-treated tumors.
Citation Format: Shabnam Shalapour, Michael Karin. Immunosuppressive plasmocytes impede T-cell-dependent immunogenic chemotherapy. [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 B045.
Abstract B049: Evaluation of attenuated HSV1716 in combination with chimeric antigen receptor T cells for solid tumors
Authors: Haile Samuel , Conner Joe , Mackall Crystal 
Published: May 2016

Abstract
Neuroblastoma, osteosarcoma, and rhabdomyosarcoma are among the most prevalent childhood solid tumors. Each of these tumor types as well as melanomas exhibit increased levels of the tumor associated carbohydrate, GD2 on their cell surface making them ideal targets for chimeric antigen receptor (CAR) T cell-directed therapies. Despite the ability of GD2 CAR T cells to target GD2-expressing tumor cells in vitro, there is great interest in improving tumor clearance in vivo, especially for solid tumors where current outcomes remain poor. We hypothesize that the immunosuppressive milieu present within the solid tumor microenvironment serves as a major factor limiting the effectiveness of GD2 CAR T cells and propose that administration of oncolytic viruses could induce inflammation within the tumor microenvironment that may enhance, rather than inhibit, the effectiveness of immune based therapies. GD2 CAR T cells composed of the 14G2a single chain variable fragment linked to the cytoplasmic signaling domains of CD28 and CD3 zeta (GD2-28z) were expressed in murine lymphocytes and evaluated for the ability to target and lyse GD2-expressing tumor cells. Additionally GD2-28z T cells were co-cultured with tumor cells to access their ability to secrete proinflammatory cytokines IFNγ and IL-2. In order to determine the oncolytic ability of attenuated HSV1716, tumor cells were cultured in the presence or absence of HSV1716 and relative cell survival was measured. We observed specific lysis of GD2-expressing tumor cells when co-cultured with GD2-28z, but not mock T cells. Furthermore, GD2-28z T cells secrete IFNγ and IL-2 following co-culture with GD2-expressing tumor cells. Interestingly, melanoma cell lines were not susceptible to oncolytic lysis while rhabdomycosarcoma (RMS) cell lines were susceptible. Using a melanoma model, GD2-28z T cells displayed anti-tumor activity. The combination of GD2-28z and HSV1716 enhanced CAR persistence in a melanoma model. Given that the melanoma cells in our model are not susceptible to oncolytic lysis yet we observe an increased T cell persistence when used in combination with HSV1716, this supports our hypothesis that HSV1716 in inducing inflammation, which is then triggering T cell expansion.
Citation Format: Samuel Haile, Joe Conner, Crystal Mackall. Evaluation of attenuated HSV1716 in combination with chimeric antigen receptor T cells for solid 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 B049.
Abstract B057: Optimizing the high throughput in vitro priming of tumor specific T cells
Authors: Prokop Lea , Souczek Stefanie , Peper Janet , Rammensee Hans-Georg , Stevanović Stefan 
Published: May 2016

Abstract
Peptide-based vaccines are a promising strategy for immunotherapy against cancer. Our group has characterized large numbers of HLA ligands from tumor cells; among them many that might be used for in vivo induction of tumor-specific immune responses. For the development of peptide-based immunotherapies such peptides should be able to induce in vivo tumor-directed immune responses, especially by CD8+ T cells that have a key role in inducing death of tumor cells. The aim of our work is to establish a fast and efficient workflow for immunogenicity testing of tumor-extracted HLA ligands. T cells usually depend on professional antigen presenting cells such as autologous dendritic cells (DCs) for specific induction and expansion. Since the generation of dendritic cells is expensive and time consuming with varying quality and amount of differentiated DCs, we established an artificial system to replace cell-based in vitro priming of T cells, streptavidin-coated artificial antigen presenting cells loaded with defined amounts of recombinant HLA molecules and costimulatory antibodies such as anti-CD28. Using the standard protocol, CD8+ T cells are stimulated three times with artificial antigen presenting cells in weekly intervals in the presence of IL-2 and IL-12. Peptide-specific CD8+ T cells are identified by tetramer staining. Our group started to vary different parameters of this protocol to increase the frequency and number of antigen specific T cells. Alternate costimulatory antibodies and cytokines proved successful to reach that goal. Employing artificial APCs for in vitro priming of tumor-reactive T cells will foster immunogenicity analysis of novel peptides for immunotherapy.
Citation Format: Lea Prokop, Stefanie Souczek, Janet Peper, Hans-Georg Rammensee, Stefan Stevanović. Optimizing the high throughput in vitro priming of tumor specific T 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 B057.
Abstract B060: The canonical NF-κB pathway is crucial for Treg homeostasis during the antitumor response
Authors: Grinberg-Bleyer Yenkel , Ho Hyunju , Schmid Roland , Klein Ulf , Ghosh Sankar 
Published: May 2016

Abstract
Cancers use a wide variety of mechanisms to dampen tumor immune response. Among them, CD4+Foxp3+ regulatory T cells (Tregs) are largely described to inhibit the function of effector cells. In several murine models of cancer, Treg depletion suppresses tumor growth. Interestingly, it has been proposed that anti-CTLA-4 therapies exert their anti-tumor effects by targeting Tregs. Therefore, precisely understanding the mechanisms governing Treg homeostasis may be a valuable strategy to enhance immune responses against cancer. We and other have previously shown that transcription factor NF-κB plays a major role in Treg development; we are now analyzing the role of different NF-κB subunits in Tregs by using conditional knock-out mice.
We found that both p65 (RelA) and c-Rel subunits of NF-κB in Tregs, were required for both development of thymic Treg progenitors and subsequent differentiation into Foxp3-expressing mature Tregs. Ablation of NF-κB also prevented in vitro differentiation of inducible Tregs. Furthermore, specific deletion of either p65 or c-Rel subunits in natural Tregs using FoxP3-cre led to the development of a lethal autoimmune syndrome by 8 to 15 weeks of age. Ablation of both subunits further shortened the lifespan of animals to around 3 weeks of age. This was associated with profound changes in the molecular signature of NF-κB deficient Tregs, which down-regulated Treg-associated genes while acquiring an effector-like phenotype. Also, tamoxifen-induced acute deletion of NF-κB in mature Tregs reduced their survival and expression of Treg-associated markers. These data highlight a crucial role for NF-κB in maintaining Treg identity in vivo.
We next explored the role of NF-κB in Treg homeostasis during tumor growth. Strikingly, melanoma growth was drastically reduced in mice lacking c-Rel, but not p65, in Tregs. This was associated with an increased polyclonal and antigen-specific effector T cell activation. Besides, CD8 T cell depletion abolished the protection against tumor growth. We are now proceeding to test the effect of specific c-Rel inhibitors on tumor growth. We believe our work reveals a central molecular mechanism in the maintenance of Treg identity and thus highlights novel therapeutic target for the treatment of cancer.
Citation Format: Yenkel Grinberg-Bleyer, Hyunju Ho, Roland Schmid, Ulf Klein, Sankar Ghosh. The canonical NF-κB pathway is crucial for Treg homeostasis during the antitumor response. [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 B060.
Abstract B064: The effects of tumor-associated calreticulin mutants on antigen presentation
Authors: Arshad Najla , Cresswell Peter 
Published: May 2016

Abstract
The phenomenon of antigen processing and presentation aids the immune system in distinguishing between normal and malignant cells. In cancer cells, Major Histocompatibility Complex (MHC) proteins present tumor-associated antigens (TAAs) that may serve as targets of immunotherapy. Antigen presentation by MHC class I-β2m heterodimers (MHC-I) requires peptide association to occur in in the endoplasmic reticulum (ER). Binding is facilitated by the Peptide Loading Complex (PLC), which consists of the TAP transporter, tapasin, the thiol-oxidoreductase ERp57, and a lectin chaperone, calreticulin (CRT). CRT associates with MHC-I via the single, conserved, glycan present on MHC-I, drawing it into the PLC to facilitate peptide loading.
CRT is comprised of an N-terminal lectin domain, a proline-rich central P domain, and a negatively charged C-terminal domain (CTD) that contains an ER retention motif. Two recent studies report a mutant CRT associated with myeloproliferative neoplasms (MPNs). These MPNs carry a somatic frame-shift CRT mutation (CRTFS) that generates a novel CTD that lacks the ER-retention signal and renders it positively charged. Previous studies have shown that ablation of CRT expression in mouse embryonic fibroblast cells result in decreased surface expression of MHC-I, which is reversed on reconstitution of full-length CRT. Interestingly, reconstitution of CRT lacking the CTD did not restore MHC-I expression, indicating a role for the CTD in MHC-I expression. We therefore suspect that antigen presentation in MPNs carrying the CRTFS is altered.
To address the role of CRTFS in antigen presentation in a human cell line, we have generated a CRT knockout of HeLaM cells using CRISPR/Cas9 technology. The expression of MHC-I in HeLaM cells dramatically increases on exposure to interferon-γ and we are currently assessing the alterations in MHC-I expression in these CRT knockout cells using various biochemical techniques. Future experiments include analysis of the peptide repertoire displayed on the surface of these cells as well as changes in the molecular interactions of the mutant CRT with other members of the PLC. After a preliminary study in HeLaM cells, we will study the effect of CRTFS in antigen presentation in MPN cell lines to identify unique TAAs to facilitate the specific targeting of these cells by immunotherapy.
Citation Format: Najla Arshad, Peter Cresswell. The effects of tumor-associated calreticulin mutants on antigen presentation. [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 B064.
Abstract B075: CD103 integrin promotes T-cell recruitment and activation within epithelial tumors
Authors: Boutet Marie , Mami-Chouaib Fathia 
Published: May 2016

Abstract
Cancer immunotherapies specifically target tumors by optimizing the capacity of host cytotoxic T lymphocytes (CTL) to recognize and kill malignant cells. To destroy their target, CTL must migrate to the tumor, infiltrate the stroma and then interact with cancer cells. Recruitment of T lymphocytes within the tumor involves several sequential steps regulated by molecular interactions with a variety of stromal cell types and coordinated by chemotactic agents, extracellular matrix proteins and cell surface adhesion molecules. Integrins are one of the major families of adhesion molecules that contribute to lymphocyte development, migration, extravasation and activation. CD103 integrin and its ligand, the epithelial cell marker E-cadherin, play a crucial role in promoting both tumor cell cytotoxicity and cytokine secretion. Accumulating evidence also indicates that CD103 on CD8+ tumor-infiltrating lymphocytes (TIL) is associated with increased intraepithelial T-cell infiltration and that an enhanced CD103+ TIL subset correlates with improved patient survival in several cancers. However, the contribution of CD103 to promoting T-cell recruitment within epithelial tumor regions, and the influence of TGF-beta, abundant within the tumor microenvironment, on integrin functions and signaling remain poorly understood. In the present study we provide evidence that CD103 is directly involved in T-cell recruitment within epithelial tumor islets and in local early T-cell signaling. Moreover, TGF-beta triggers integrin-mediated functional activities by promoting phosphorylation of integrin-linked kinase (ILK) and its subsequent binding to CD103, thus initiating an “inside-out” signaling leading to activation and clustering of the integrin and thereby initiating an “outside-in” signal that contributes to T-cell stimulation, spreading and cytotoxicity. We conclude that TGF-beta, while known for its protumoral effects, promotes an antitumor CTL response by activating CD103 integrin.
Citation Format: Marie Boutet, Jr., Fathia Mami-Chouaib, Sr. CD103 integrin promotes T-cell recruitment and activation within epithelial 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 B075.
Abstract B077: Evaluating oncolytic vaccines targeting mutated epitopes in a murine fibrosarcoma model CMS-5
Authors: Stephenson Kyle , Atherton Matthew , Bell John , Lichty Brian 
Published: May 2016

Abstract
Oncolytic viruses have traditionally been used as stand alone therapy delivered to animals and patients to lytically destroy tumor tissue. However, it has recently become clear that involvement of the immune system is an extremely important aspect of these therapies. To further enhance anti-tumor immune responses we have utilized an oncolytic vaccine approach. This approach involves priming the immune system to a specific tumor associated antigen (TAA) with an Adenovirus and then subsequently delivering an oncolytic Rhabdovirus expressing the same tumor antigen leading to robust anti-tumor immune responses and improved efficacy.
For the studies presented herein we have developed oncolytic vaccines targeting mutated epitopes expressed in CMS-5. Immune responses generated towards these epitopes through oncolytic vaccination will be characterized and their ability to control tumor growth will be evaluated. We hypothesize that the foreign nature of these mutated epitopes will allow for the generation of substantial immune responses following oncolytic vaccination in tumor bearing mice.
In preliminary studies, oncolytic vaccination has been able to generate robust immune responses leading to as many as 60% of circulating CD8+ T cells responding to a single mutated epitope in tumor free animals. Therapeutic oncolytic vaccination of CMS-5 tumor bearing animals was still able to generate large anti-tumor immune responses, however these responses were cut in half compared to tumor free animals. The resultant anti-tumor immune response was able to significantly control tumor growth, and the magnitude of these responses correlated with survival. Even though there was a delay in tumor growth following therapy, the responses were not durable and all mice ultimately failed the therapy.
We are currently engaged in studies to further characterize the immune responses generated and determine what, if any, immunosuppression led to failure of our therapy; even in the presence of anti-tumor immune responses exceeding 20% of peripheral CD8+ T cells. Nanostring analysis of the tumor microenvironment are being conducted focusing on gene signatures for immune cells and inflammation and these data will be confirmed by histology and flow cytometry. These studies will help shed light on potential mechanisms of immune evasion/suppression following oncolytic vaccination and point to potential targets for modulation of the oncolytic vaccine induced immune response.
Citation Format: Kyle Stephenson, Matthew Atherton, John Bell, Brian Lichty. Evaluating oncolytic vaccines targeting mutated epitopes in a murine fibrosarcoma model CMS-5. [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 B077.
Abstract B090: A Toll-like receptor 5 agonist entolimod as a potential anticancer immunotherapeutic agent
Authors: Brackett Craig , Kojouharov Bojidar , Gollnick Sandra , Gudkov Andrei , Burdelya Lyudmila 
Published: May 2016

Abstract
Liver metastases are a major common cause of mortality of patients with different types of cancer due to lack of effective treatment options. Anticancer immunotherapy provides an attractive approach for developing a more effective systemic therapy for patients with metastatic liver cancer. We generated a Toll-like receptor 5 (TLR5) agonistic agent entolimod™ (CBLB502), a pharmacologically optimized derivative of bacterial Salmonella flagellin that is now at advanced stage of clinical development as a medical countermeasure to reduce adverse side effects of radiation therapy. We also found that entolimod, in addition to its radioprotective properties, has anticancer effects against a variety of TLR5-positive tumors and TLR5-negative tumors residing in a TLR5-expressing environment such as the liver in mice. We hypothesized that entolimod can suppress tumor growth in a TLR5-responsive microenvironment such as the liver independently of the TLR5 status of tumor cells. We tested the therapeutic potential of entolimod against TLR5 responsive and non-responsive tumors using mouse triple negative 4T1 breast and CT26 colorectal adenocarcinoma models mimicking clinically occurring development of post-surgery liver metastases in cancer patients. Our results demonstrate that entolimod treatment was efficient in suppressing metastatic growth when injected systemically in both models. Investigating the mechanism of entolimod's antitumor activity we found that several major transcriptional factors, such as NF-κB, STAT-3 and AP-1, are rapidly activated in hepatocytes leading to a short-term neutrophilic infiltration and long-term NK cell accumulation and activation that coordinate CD8+ and CD4+ T cell immunity against liver metastases. This resulted in significant improvement of long-term tumor-free survival and durable, tumor-specific T cell memory. Importantly, unlike other TLR agonists entolimod is safe and does not show signs of septic shock even with systemic administration. Moreover, the results of two phase 1 clinical trials with 150 healthy volunteers and 26 patients with advanced cancers demonstrated good tolerability and safe profile of the response, which supports entolimod's potential as an immunotherapeutic agent. This also suggests that entolimod can be potentially combined with radiation, chemotherapeutic, targeted, and other immunotherapeutic agents to improve the efficacy of anticancer therapy.
Citation Format: Craig Brackett, Bojidar Kojouharov, Sandra Gollnick, Andrei Gudkov, Lyudmila Burdelya. A Toll-like receptor 5 agonist entolimod as a potential anticancer immunotherapeutic agent. [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 B090.