bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A158: MAGED4B specific peptides: Short or long or combination?
Authors: Lim Kue Peng , Chun Ai Leng , Ponniah Sathibalan , Cheong Sok Ching 
Published: May 2016

Abstract
Immunotherapy has emerged as one of the most efficacious form of cancer therapy. We have previously demonstrated MAGED4B short peptides are efficacious in inducing patients' immune responses in vitro. However, effective vaccination against tumours requires generation of both CD8+ and CD4+ T-cell responses. A critical role of CD4+ helper T cells in the development of CD8+ tumour-specific effector function has been shown by numerous studies. In this pilot study, we aim to compare the efficacy of MAGED4B specific-short peptides (SP), long peptide (LP) and the combination of both short and long peptides in inducing patients' immune responses in vitro. Briefly, peripheral blood mononuclear cells (PBMC) from HLA-A2 positive healthy volunteers were incubated with 10 μg/ml of peptide in the presence of IL-2 and IL-7 for 7 days; peptide exposed PBMC were then incubated with cancer cells expressing MAGED4B overnight. Capability of T cells to secrete IFN-γ was accessed using ELISPOT assay and CEF peptides pool was used as positive control. Our data demonstrated that all MAGED4B peptides (short and long) are capable to induce similar and/or higher cytokine secretion compared to CEF peptides pool suggesting that these peptides are highly immunogenic. MAGED4B specific SP are better in inducing cytolytic activity compared to MAGED4B specific LP; however when both LP and SP were mixed as a cocktail, we observed a reduction in cytokine secreting T cells when the immune cells were co-incubated with MAGED4B expressing cell line, advocating an inhibition instead of synergizing reaction. In summary, our data has corroborated our previous finding that HLA-A2 restricted MAGED4B specific SP are immunogenic. However, we did not observed a synergistic event when SP and LP were used in a cocktail, questioning the combinatorial effect of CD4+ and CD8+ T cells. These preliminary findings would need to be validated in a bigger cohort of patients.
Citation Format: Kue Peng Lim, Ai Leng Chun, Sathibalan Ponniah, Sok Ching Cheong. MAGED4B specific peptides: Short or long or combination? [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 A158.
Abstract A169: NY-ESO-1 protein cancer vaccine with TLR 3 and 4 agonists
Authors: Takeoka Tomohira , Nagase Hirotsugu , Miyazaki Yasuhiro , Takahashi Tsuyoshi , Kurokawa Yukinori , Makino Tomoki , Yamasaki Makoto , Takiguchi Shuji , Mori Masaki , Doki Yuichiro , Wada Hisashi 
Published: May 2016

Abstract
NY-ESO-1 is expressed in wide range of human malignancies expect testis in normal tissues and induces spontaneous antibody in patients with cancers expressing NY-ESO-1. Because of its unique expression and high immunogenicity, NY-ESO-1 is promising as a target of cancer vaccine. We have conducted serial clinical trials with the NY-ESO-1 protein since 2004 and antigen-specific immune responses were observed in most of patients immunized. Some patients showed feasible clinical responses however they were limited and novel immune modulators which could make NY-ESO-1 protein vaccination effective are needed. Recently, stimulation through the Toll-like receptors (TLRs) enhance the induction of antigen-specific immune responses upon cancer vaccine has become apparent. In this study, we conducted a phase I cancer vaccine clinical trial using NY-ESO-1 protein combined with Poly ICLC and Picibanil OK-432 as TLR 3 and 4 agonist, respectively.
This trial was designed to evaluate the safety, induction of immune response and clinical response. Patients with advanced cancers expressing NY-ESO-1 were eligible. 200μg NY-ESO-1 protein mixed with Montanide in combination of Poly ICLC and/or Picibanil OK-432 was administered subcutaneously once every 2 weeks in six times. Seven patients with esophageal cancer, three with gastric cancer, two with lung cancer, two with ovarian cancer and one with malignant melanoma were enrolled in four groups, i) NY-ESO-1 protein alone (n=3), ii) NY-ESO-1 protein with OK-432 (n=3), iii) NY-ESO-1 protein with Poly ICLC (n=3), iv) NY-ESO-1 protein with OK-432 and Poly ICLC (n=6). All patients developed an injection-site reaction and fever (grade1 or 2) but no severe adverse events related to the drug were observed. An increase in the NY-ESO-1 antibody response was observed in all patients after vaccination. Earlier induction and higher frequency of NY-ESO-1 responsible T cells were observed in patients immunized with Poly ICLC than those without Poly ICLC. NY-ESO-1 protein vaccine with Poly ICLC and OK432 was safe and antigen-specific immune responses were induced in all patients. TLR agonists would be useful and effective immune modulators for cancer vaccines.
Citation Format: Tomohira Takeoka, Hirotsugu Nagase, Yasuhiro Miyazaki, Tsuyoshi Takahashi, Yukinori Kurokawa, Tomoki Makino, Makoto Yamasaki, Shuji Takiguchi, Masaki Mori, Yuichiro Doki, Hisashi Wada. NY-ESO-1 protein cancer vaccine with TLR 3 and 4 agonists. [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 A169.
Abstract A179: Ex vivo generation of clinical grade T cells by using activating and propagating feeder cells to cross-link T cell receptor
Authors: Jena Bipulendu , Taguchi Hiroaki , Nowicka Aleksandra , Korngold Ana B. , Huls Helen , Cooper Laurence JN 
Published: May 2016

Abstract
Success of T-cell based immunotherapy depends largely on exogenous modification and propagation of patient or donor derived T cells. The conventional paradigm is to stimulate primary T cells cross-linking endogenous CD3-complex with a monoclonal antibody (mAb) such as CD3ε targeting OKT3 alone or in combination with super-agonist mAb anti-CD28. The crosslinking via agonist mAb(s) lead to downstream activation signaling, phosphorylation of immunotyrosine activation motif and associated Ca2+ influx resulting in T-cell division and proliferation in vitro. We report an alternate approach to targeting T-cell signaling complex by cross-linking αβ-TCR of T cells through a novel TCR-specific single chain antibody. Towards this objective, first we generated several TCR targeted monoclonal antibodies. Next, we designed a panel of high affinity scFvs derived from a mAb clone A79 from which a specific mutant named SAYON-15 (Single chain AffinitY Optimized Novel mutant 15) possessing highest affinity towards TCR α-chain was selected. Affinity enhancement was achieved in silico via homology modeling and scanning mutations in the original scFv (A79). SAYON-15 in combination with either truncated human CD8 transmembrane or truncated human IgG1-Fc chain scaffold was expressed on K562 (HLA C-neg) cells. As activating and propagating feeder cells K562 HLA C-neg expressing SAYON-15 could drive expansion of αβ TCR+ T cells from donor derived peripheral or umbilical cord blood mononuclear cells in comparable fashion to gene modified K562 cells loaded with CD3ε specific mAb (OKT3). Ex vivo propagated T cells growth kinetics, phenotypic composition, TCR repertoire were studied and compared between two separate T-cell activation strategies described here. We analyzed ex vivo cultured T-cells immune repertoire with respect to TCRV gene rearrangement, clonal diversity, CDR3 composition by next generation sequencing. SAYON-15 expressing AaPc when compared with OKT3 expressing AaPC showed greater clonality, equivalent level of functional V-gene rearrangement, CDR3 chain length and V-J combinations. In summary, we report a novel TCR-specific scFv and harnessed its ability to numerically expand T cells ex vivo. This could potentially be used for clinical applications in the context of adoptive cell therapy.
Citation Format: Bipulendu Jena, Hiroaki Taguchi, Aleksandra Nowicka, Ana B. Korngold, Helen Huls, Laurence JN Cooper. Ex vivo generation of clinical grade T cells by using activating and propagating feeder cells to cross-link T cell receptor. [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 A179.
Abstract A181: Dissecting the spatiotemporal functions of WAVE complex during chemotaxis using CRISPR and optogenetics
Authors: Graziano Brian R. , Weiner Orion D. 
Published: May 2016

Abstract
Neutrophils comprise a crucial component of the innate immune system and rely on chemotaxis to track down, engulf, and destroy pathogens. However, neutrophils also migrate to sites of developing tumors where they may promote angiogenesis and set the stage for metastasis to occur. The WAVE regulatory complex (WRC) serves a central role in mediating chemotaxis, as it links the actin dynamics powering cell movement to the signaling cascade which responds to environmental stimuli. Actively migrating neutrophils must respond quickly (within seconds) to changes in their environment; unfortunately, traditional methods one may use to alter WRC activity (e.g, RNAi and gene deletion) require hours/days to take effect. Consequently, while we know that WRC is generally required for efficient chemotaxis, its specific functions during each temporal phase, such as establishment and maintenance of a chemotactic response, remain unknown. Furthermore, the roles of WRC in this process are convoluted by additional actin assembly and assembly-promoting factors that act alongside WRC to drive neutrophil movement: Cells may compensate for prolonged loss of WRC through altering the activities of one or more of these factors.
Here, I employed CRISPR to knockout the HEM1 subunit of WRC in neutrophil-like HL60 cells. Lacking functional WRC, these cells exhibit impaired chemotaxis, similar to cells where HEM1 expression is knocked-down. Unexpectedly however, the knockout neutrophils display additional defects in morphology and actin organization that are never observed in knockdown cells, despite knockdown cells containing less than 10% of normal Hem1 levels. I have also, in parallel, generated and validated optogenetic tools that can be used to rapidly and reversibly recruit WRC to different subcellular locations. When expressed in neutrophils lacking HEM1, these tools will open up the possibility of acutely ‘activating’ or ‘inactivating’ WRC during different temporal stages of chemotaxis (e.g., polarity establishment or maintenance). Ultimately, a more nuanced understanding of neutrophil chemotaxis should lead to the identification of new drug targets that may be used to block the accumulation of neutrophils at sites of tumor growth.
Citation Format: Brian R. Graziano, Orion D. Weiner. Dissecting the spatiotemporal functions of WAVE complex during chemotaxis using CRISPR and optogenetics. [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 A181.
Abstract A193: Bioengineered Dectin-1 CAR+ T cells to control invasive fungal infection
Authors: Kumaresan Pappanaicken R. , Albert Nathaniel , Singh Harjeet , Olivares Simon , Maiti Sourindra N. , Mi Tiejuan , Huls Helen , Champlin Richard E. , Kontoyiannis Dimitrios P. , Cooper Laurence J.N. 
Published: May 2016

Abstract
Myelosuppressive and ablative regimens are used to deplete lymphocytes in some patients before adoptive cell therapy. CD19-specific engineered T-cells have been used successfully to eliminate B-cells in patients with B-cell leukemias and lymphomas. Prolonged immunosuppression, including B-cell aplasia is associated with increased risk of invasive fungal infection (IFI). Thus, patients will benefit if bio-engineered T cells can control IFI as well as kill tumor cells. The Sleeping Beauty gene transfer system was used to render T cells to express a chimeric antigen receptor (CAR) on the cell surface to redirect specificity via Dectin-1. Upon binding with the β-1,3-glucan sugar moiety found in IFI, Dectin-1 CAR+ T cells signal via chimeric CD28 and CD3-ζ signaling domain. The activated T cells secrete perforin, granzyme and granulysin to damage hyphae and thus inhibit the hyphal growth of Aspergillus and Candida. The T cells also secrete IFN-γ to activate other immune cells to target IFI. To ready the Dectin-1 CAR-modified T cells for the human application, we have modified the Fc domain of the extracellular stalk to alleviate deleterious uptake by Fcγ receptors and thus in vivo loss of infused T cells. We have shown that the Dectin-1 CAR+ T cells do not kill the yeast form of Candida so normal commensals in the gut microbiota should not be affected. We have also demonstrated that Dectin-1 CAR+ T cells can control Aspergillus infection in the presence of immunosuppressive drugs at physiological concentrations. Finally, we have generated dual CAR+ T cells by co-expressing a CD19-specific CAR with Dectin-1 CAR rendering the resultant genetically modified T cells able to target both B-cell malignant cells as well as fungal hyphae. These dual CAR-T cells can thus control both leukemia and invasive fungal infections. These data provide a path forward for clinical trials testing Dectin-1 CAR+ T cells.
Citation Format: Pappanaicken R. Kumaresan, Nathaniel Albert, Harjeet Singh, Simon Olivares, Sourindra N. Maiti, Tiejuan Mi, Helen Huls, Richard E. Champlin, Dimitrios P. Kontoyiannis, Laurence J.N. Cooper. Bioengineered Dectin-1 CAR+ T cells to control invasive fungal infection . [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 A193.
Abstract B009: Design and development of HDAC6-selective inhibitors for hematological cancer treatment and solid tumor immunotherapy
Authors: Shuttleworth Stephen J. 
Published: May 2016

Abstract
Despite its name, HDAC6 is primarily a tubulin deacetylase, not a histone deacetylase, and it has emerged as a particularly interesting – and unique – cancer target as it plays an essential role in stress response and in aggresomal protein degradation: specifically, HDAC6 binds polyubiquitinated misfolded proteins and recruits misfolded protein cargo to dynein motors for transport to aggresomes. Cells deficient in HDAC6 fail to clear these misfolded protein aggregates from the cytoplasm, cannot form aggresomes properly, and are hypersensitive to the accumulation of misfolded proteins, which leads to activation of apoptosis. Further, recent evidence has emerged of HDAC6 modulating immune-related pathways in solid tumors, notably regulating PD-L1 expression through STAT3 modulation. In order to explore the clinical potential of HDAC6 in both hematological and solid tumor immunotherapy, we have de novo-designed a class of highly-potent, ultra-selective and orally-active HDAC6 inhibitors with potential in the treatment of multiple tumor types, including through immunotherapeutic mechanisms. Additionally, owing to the selectivity we have achieved for HDAC6 with our lead compounds, much greater opportunities for broader combination modalities can be realized, and we have established potentiation of our leads with other tumor immunotherapeutics in in vivo syngeneic models. The profile of our preclinical development candidate will be presented.
Citation Format: Stephen J. Shuttleworth. Design and development of HDAC6-selective inhibitors for hematological cancer treatment and solid tumor 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 B009.
Abstract B022: Functional bifurcation in T cells expressing chimeric antigen receptors
Authors: Chang ZeNan L. , Silver Pamela A. , Chen Yvonne Y. 
Published: May 2016

Abstract
Adoptive transfer of T cells engineered to express chimeric antigen receptors (CARs) can induce durable regressions in cancer patients, particularly in the treatment of B-cell malignancies. The production and expansion of CAR-T cells relies on in vitro T-cell stimulation and more work is needed to explore the phenotypic changes that occur in this process to elucidate features that are predictive of anti-tumor functionality. Here, we present a systematic study of T cells expressing a second-generation, anti-CD19 CAR and use flow cytometry to interrogate the dynamic phenotypic and functional changes exhibited by CAR-T cells undergoing varied antigen stimulation courses. By tracking CAR–T-cell viability, proliferation, cytokine production, lytic abilities, and expression of various T-cell activation markers and inhibitory receptors across time, we find that CAR-T cells consistently bifurcate into two distinct subpopulations with dramatically different functional capacities and surface marker expression profiles. Furthermore, the proportion of CAR-T cells that demonstrate the superior functions is dependent on the particular degree of antigen stimulation and the composition of the T cell population (CD4 vs CD8, T-cell memory compartment breakdown, % transduced). Altogether, the systematic characterization methods and results reported here can guide future efforts to improve CAR–T-cell therapies.
Citation Format: ZeNan L. Chang, Pamela A. Silver, Yvonne Y. Chen. Functional bifurcation in T cells expressing chimeric antigen receptors. [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 B022.
Abstract B035: Self-tumor-antigen-specific CD8 T cells were suppressed by regulatory T cells
Authors: Maeda Yuka , Nishikawa Hiroyoshi , Sakaguchi Shimon 
Published: May 2016

Abstract
Background: Naturally occurring regulatory T (Treg) cells play an essential role for immunological unresponsiveness to self-tumor-antigens. Yet, how they stably suppress self-tumor-antigen-specific T cells remains unclear. In particular, it is unknown whether Treg cell-mediated suppression for a limited period has a critical long-lasting effect on cell fate and antigen reactivity of self-tumor-antigen-specific T cells.
Experimental procedures: To demonstrate Treg-cell effect on proliferation, cytokine production, and cell fate of self-tumor-antigen-specific CD8+ T cells, CD8+ T cells from peripheral blood mononuclear cells (PBMCs) of healthy individuals were stimulated with a melanocyte differentiation antigen Melan-A/ MART-1, expressed by normal melanocytes and some melanoma cells, with/without FoxP3+CD25+CD4+ Treg cells. Melan-A/ MART-1-specific CD8+ T-cell induction and their phenotypes were investigated.
Results: Melan-A/ MART-1-specific CD8+ T-cell induction was reduced by the presence of Treg cells. Self-tumor-antigen-specific CD8+ T cells co-cultured with Treg cells underwent one cell division and stopped further proliferation due to the lack of co-stimulation from antigen-presenting cells through Treg-cell suppression. They harbored low-affinity T-cell receptors and an anergic phenotype (i.e., hypo-proliferative and cytokine hypo-producing upon antigen re-stimulation) defined by expression of CCR7 and co-inhibitory molecules such as CTLA-4. Melan-A/ MART-1-specific CD8+ T cells with this anergic phenotype were detected ex vivo in the periphery and contributed to the tolerance of self-tumor-antigens.
Conclusions: Treg-cell-mediated induction of anergy in self- antigen tumor-specific CD8+ T cells inhibits their activation in cancer patients after immunotherapy, and neo-antigens associated with tumor-specific gene mutations may become a main target of CD8+ T cells inducing actual tumor regression.
Citation Format: Yuka Maeda, Hiroyoshi Nishikawa, Shimon Sakaguchi. Self-tumor-antigen-specific CD8 T cells were suppressed by regulatory 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 B035.
Abstract B037: Improved CD8+ T-cell recognition of neuroblastoma after innate immune attack by natural killer cells
Authors: Spel Lotte , Boelens Jaap J. , Til Niek van , Steen Dirk M. van der , Blokland Nina J.G. , Noesel Max M. van , Molenaar Jan J. , Heemskerk Mirjam H.M. , Boes Marianne , Nierkens Stefan 
Published: May 2016

Abstract
Neuroblastoma is the most common solid tumor in children, with mortality rates after conventional treatments still being 80% for high-risk (stage 4) disease. There is a clear medical need for development of new treatment strategies. Recently, immunotherapy has gained traction. However, restrained MHC I expression evades recognition of neuroblastoma by immune cells, for a suppressed immunogenic status of neuroblastoma tumors. We here describe a preclinical study aimed to improve neuroblastoma immunogenicity. We found that neuroblastoma cells significantly increase surface expression of MHC I upon exposure to active NK cells and thereby readily sensitize neuroblastoma cells for recognition by cytotoxic T lymphocytes (CTLs). We show that oncoprotein PRAME serves as a T-cell antigen in neuroblastoma as NK-modulated neuroblastoma cells are recognized by PRAMESLLQHLIGL/A2-specific CTL clones. Furthermore, NK cell induced MHC I upregulation in neuroblastoma cells requires IFNγ production by NK cells that is triggered by neuroblastoma contact. Our results demonstrate remarkable plasticity in the immunogenic properties of neuroblastoma cells, which are exposed when neuroblastoma cells attempt to escape innate immune attack. These findings support the exploration of NK cells in combined immunotherapy to enforce tumor-specific CTL responses, and thereby strengthen immune-mediated tumor reactivity.
Citation Format: Lotte Spel, Jaap J. Boelens, Niek van Til, Dirk M. van der Steen, Nina J.G. Blokland, Max M. van Noesel, Jan J. Molenaar, Mirjam H.M. Heemskerk, Marianne Boes, Stefan Nierkens. Improved CD8+ T-cell recognition of neuroblastoma after innate immune attack by natural killer 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 B037.