Day 1 :
Keynote Forum
Weidong Han
Chinese PLA General Hospital China
Keynote: Chimeric antigen receptor modified T cell redirected to EGFR in patients with metastatic and advanced pancreatic adenocarcinoma and biliary tract cancers
Time : 10:00-10:30
Biography:
In 2001, Dr. Han obtained his Ph.D. degree in clinical hematology from Chinese PLA Postgraduate Medical School, and worked in Dept. of Molecule & Immunology of Chinese PLA General Hospital. In 2003, he did postdoctoral work at the University College London. In 2006, he was promoted to professor of molecular and cellular biology. Now, he is the director of department of molecular and cellular biology, Director of Clinical Translational Ward, the General Hospital of PLA. Since 2001, he focused on mechanism research involved in cancer-treatment resistance and clinical translation of cell therapy. He has published over 100 articles.
Abstract:
Statement of the Problem: Limited effective treatment opinions and dismal prognosis in metastatic pancreatic adenocarcinoma (mPA) and biliary tract cancers (BTCs) require developing novel therapeutic approaches. Methodology & Theoretical Orientation: Epidermal growth factor receptor (EGFR) is a well-known candidate therapeutic target due to its frequent overexpression in epithelium-derived tumors. The purpose of this study is to further expand our clinical trial (NCT01869166) of EGFR-specific chimeric antigen receptor-engineered autologous T cell (CAR T-EGFR)-based therapeutic modality to mPA and mBTCs to evaluate its feasibility and efficacy. Patients were enrolled when >50% EGFR+ ratio was observed in tumor specimens by immunohistochemical staining. CAR copy number in peripheral blood was serially measured to determine the therapeutic cycles. Findings: A total 34 of patients including 12 mPA and 22 mBTCs received 1 to 3-cycle cell infusions (Range from 0.6 to 4.1×106/kg, median dose is 2.3×106/kg) within 6 months. The acute toxicities included infusion-associated febrile syndrome (Grade 1/2 in 34 cases) and pulmonary edema/pleural effusion (Grade 3 in 4 cases). The common toxicities occurred 1 week after cell infusions included febrile syndrome (Grade 1/2 in 11 cases) accompanied with the elevation of serum cytokine such as IL6 and/or TNFï¡, and CRP, and mucosal/cutaneous damages (Grade 1/2 in 19 cases). Of 31 patients who were treated by nab-paclitaxel/cyclophosphamide conditioned cell infusions, 5 obtained 8-16 weeks PR and 5 had 4-12 week SD in mPA patients, and 1 obtained a 22-month ongoing CR and 10 had 6-56 week SD in BTCs patients. 3 BTC patients were treated by cell infusion alone given their tolerance and relatively small disease burden, 1 obtained a 20-month ongoing CR, 1 had 8.5-month PR, and 1 had 9-month SD. Conclusion & Significance: This trial further indicated the controllable safety and efficacy of EGFR-targeted CAR T therapy, providing basis for further optimal combination strategy.
Keynote Forum
Roza Nurieva
MD Anderson Cancer Center, TX, USA
Keynote: Absence of Grail promotes CD8+ T cell anti-tumor activity
Time : 09:30-10:00
Biography:
Dr. Roza Nurieva received her Ph.D. in 2000 from the Gabrichevsky Research Institute of Epidemiology and Microbiology, Moscow, Russia. Her postdoctoral fellowship, which was supported by the Arthritis Foundation, was with Dr. Chen Dong at the University of Washington, Seattle, USA, focusing on understanding the role of costimulatory molecules in regulating T helper cell activation, differentiation, and function. She is currently an Assistant Professor in the Immunology Departments at MD Anderson Cancer Center. Dr. Nurieva’s main research goal is to understand the molecular basis of T cell mediated immune responses with focus on the regulation of cytokine expression and how abnormal immune regulation leads to autoimmunity, inflammation and cancer.
Abstract:
T cell tolerance is a major obstacle to successful cancer immunotherapy; thus, it is of high priority to develop strategies to break immune tolerance. Here we report that expression of the E3 ubiquitin ligase Grail is significantly upregulated in CD8+ T cells infiltrated into transplanted lymphoma tumors and Grail-deficiency confers long-term tumor control. Importantly, therapeutic transfer of Grail-deficient CD8+ T cells was sufficient to repress established tumors. Mechanistically, loss of Grail enhanced anti-tumor reactivity and functionality of CD8+ T cells. In addition, Grail deficient CD8+ T cells exhibited increased IL-21R expression and hyper-responsiveness to IL-21 signaling as Grail promotes IL-21R ubiquitination and degradation. Moreover, CD8+ T cells isolated from lymphoma patients expressed high levels of Grail and lower levels of IL-21R compared with normal donors. Altogether, our data demonstrates that Grail is a crucial factor controlling CD8+ T cell function and is a potential target to improve CTL activity.
Keynote Forum
Jennifer Wu
Medical University of South Carolina, USA
Keynote: Novel antibody for cancer immunotherapy: beyond and synergistic with immune checkpoint blockade therapy
Time : 10:00-10:30
Biography:
Jennifer Wu has received her PhD from the University of British Columbia and Post doctorate training at the Fred Hutchinson Cancer Research Center. She has joined the Faculty of Medicine at the University of Washington and tenured as an Associate Professor. In 2011, she has accepted the faculty appointment at the Medical University of South Carolina and became a Member of Hollings Cancer Center Cancer Immunology Program. Her research focuses on understanding how cancer cells disable the immune system with the ultimate goal to develop effective immunotherapy of cancer. Her work was the first to shown that tumors shed NKG2D ligand sMIC to perturb the maintenance of tumor-killing NK cells and to facilitate tumor metastasis. Her research team is the first to demonstrate that antibody targeting sMIC refuels and revamps endogenous innate and adoptive anti-tumor responses. Her findings were extensively published in Nature, Journal of Clinical investigations, Clinical Cancer Research, Oncoimmunology. She has served as the elected Committee Chair of Cancer in the Federation of Clinical Immunology Society and Editorial Board of many cancer immunology related Journals.
Abstract:
During tumorigenesis, human cells were induced to express a family of MHC I-chain related molecules A and B (MICA and MICB, generally termed MIC) on the surface which serve as the ligands for the activating immune receptor NKG2D expressed by all human NK, CD8 T, NKT, and subsets of gd T cells. Theoretically, engagement of NKG2D by tumor cell surface MIC deemed to signal and provoke the immune system to eliminate transformed cells. Clinically, almost all advanced tumors in cancer patients produce soluble MIC through proteolytic shedding mediated by metalloproteases, or by release in exosomes derived from the cell membrane. Tumor-derived sMIC is known to be highly immune suppressive and profoundly insults the immune system by downregulating receptor NKG2D expression on effector NK and T cells, driving the expansion of tumor-favoring myeloid suppression cells, skewing macrophages into alternatively activated phenotypes, and perturbing NK cell peripheral maintenance. High levels of serum sMIC significantly correlate with advanced diseases of many types of cancer. These observations clearly endorse sMIC to be a cancer immune therapeutic target. However, due to mice lack homologues to human MIC, this concept was not proven until our recent studies. Using a “humanized” MIC-transgenic spontaneous mouse model which recapitulates the NKG2D-mediated onco-immune dynamics of human cancer patients, we show that neutralizing circulating sMIC with a first-in-field monoclonal antibody B10G5 alleviates the immune suppressive effect of sMIC and revamps endogenous anti-tumor immune responses. Therapy with B10G5 results in effective debulking of primary tumor and elimination of metastasis, with no observed toxicity. Furthermore, we show that clearing sMIC with B10G5 also enhanced the efficacy of other cancer immunotherapeutic modalities, such as immune checkpoint blockade or adoptive cell-based therapy pre-clinically. Our study has launched a new avenue of cancer immunotherapy which can be readily translated into clinical trials.
Keynote Forum
Gopal Krishnan
Global Product Manager- Bioassays, Promega Corporation, USA
Keynote: Quantitative and Reproducible Cell-Based Bioassays to Advance Immunotherapy Programs
Time : 10:50-11:20
Biography:
Gopal B Krishnan completed his PhD from the National Institute of Immunology, New Delhi and has worked on Early Embryonic Development and Role of Bone Morphogenetic Proteins in his Post-doctoral Fellowship at the University of Wisconsin, Madison. Before joining Promega Corp, he worked as the Team Lead for Development of DNA and siRNA transfection reagents at Mirus Bio. Currently, he is a Global Product Manager of genomics products at Promega Corp., Madison, WI. He has published over thirty peer reviewed articles, chapters and abstracts. In addition he has successfully launched fi ve new life science research products.
Abstract:
Chemotherapy and radiation therapy of cancer cells are associated with several side effects since a large population of rapidly dividing healthy cells also get destroyed. Such treatments reduce the patient’s quality of life. Therefore development of therapeutic antibodies against immune checkpoints for the treatment of cancers is gaining momentum and has already shown promising results in clinical trials. However, the functional screening and development of antibody drug candidates often relies on the use of human primary immune cells that are technically challenging to implement and highly variable. Primary peripheral blood mononuclear cells (PBMCs) are routinely used in traditional bioassays to measure potency, stability of antibody drugs. We have developed mechanism of action-based potency reporter bioassays using engineered cell lines that offer numerous advantages including optimized and rapid workflow, data reproducibility and robustness. For these reasons, and because they are easy to implement and transfer between global sites, reporter-based bioassays are now widely adopted in controlled drug development environments.
The presentation will discuss the development of reporter based Fc bioassays and immune checkpoint reporter assays for immune checkpoint receptors utilizing engineered cell lines to serve as the effectors cells and artificial antigen presenting cells. Promega bioassays are pre-qualified to assess repeatability, intermediate precision, specificity and linearity. These bioassays are principally developed to measure the function of ADCC and ADCP mediating antibodies and immune checkpoint blocking antibodies.
- Special Session
Location: Chicago, USA
Session Introduction
William Jia
University of British Columbia, ViroGin Biotech Ltd, Canada
Title: A novel oncolytic HSV-1 vector for cancer immunotherapy
Time : 11:20-12:20
Biography:
William Jia has completed his PhD in 1991 at University of British Columbia (UBC) in Molecular Neurosciences. He has been an Associate Professor since 1999 at UBC and an Associate Scientist of BC Cancer Research Centre. He has been a Conjunct Professor of Fudan University, Shanghai Institute of Pharmaceutical Industry and the VP (research) for Shanghai Innovative Research Centre of Traditional Chinese Medicine (SIRC-TCM). He was the first in Canada and the first few scientists in the world using human Herpes simplex virus to treat cancer, which pioneered the field of oncolytic virotherapy for cancer treatment. He has developed one gene therapy drug for malignant gliomas has completed a phase I clinical trial in China. His most recent contribution is to raise the concept of transcription and translation dual regulated (TTDR) oncolytic viruses for cancer treatment. In the past years, he has received many awards and research funds. Since 1997, he has been a Scholar of Canadian Institute of Health Research. He has also received Petro Canada Young Inventors Award in 2007.
Abstract:
Oncolytic virotherapy has attracted increasing attention as one modality of cancer immunotherapy, especially after FDA approval of T-VEC, the first oncolytic virus (OV) drug in North America. It is now widely accepted that OV induced tumor regression is multi-mechanistic and host immune reaction plays a pivotal role. In the present study, we reported a novel oncolytic HSV-1 virus VG161 that carries three immune stimulating factors: IL12, IL15 with its receptor alpha unit and a PDL-1 blocking peptide. We have shown that this virus expresses the three major factors in infected cancer cells and shown enhanced immune cell cytotoxicity in vitro when co-cultured with PBMC. We also showed that VG161 caused stable and complete tumor regression in both syngeneic mouse tumor and human tumor in nude mouse models. The same tumor failed to grow in previously treated animals. Transcriptional profiling of the tumors treated with VG161 demonstrated a dramatically changed immune microenvironment in the tumor compared to infection with a similar virus VG160 that does not carry the anti-tumor immune stimulating factors. The above results suggest that co-expressing multiple factors by an OV can have enhanced and durable anti-tumor efficacy.
- Cancer clinical trials Immune System- Tumors Combining Cancer Immunotherapies Cancer Micro and Immuno Environment Tumor Biology
Session Introduction
Manal Mohamed Saber
Minia University, Egypt
Title: Emap II-Induced Immune Suppression In Colorectal Cancer
Time : 11:20-11:45
Biography:
Manal Saber has completed her PhD from Nottingham University. She is an associate professor of Clinical Pathology, Minia University, Egypt. She has published papers in peer reviewed journals and has been serving as an editorial board member of others. She has interests in Cancer Studies, Immunotherapy and tumor Immunology
Abstract:
Statement of the Problem: Colorectal cancer (CRC) is being currently considered one of the most common, and deadly, malignancies in the world. Many CRC patients are likely to be immunosuppressive. Endothelial monocyte-activating polypeptide-II (EMAP-II) is a multifunctional cytokine with pro-inflammatory properties. It was demonstrated that EMAP-II induces lymphocytes apoptosis in CRC. The purpose of this study is to investigate the role of EMAP II in immune suppression in CRC.
Methodology & Theoretical Orientation: The immunosuppressive effect of EMAP II was verified by in vivo and in vitro experiments. The immunosuppressive mechanisms were analysed using flow cytometry, ELISA, immunohistochemistry, and T-lymphocytes assays.
Findings: EMAP II expression in CRC was associated with suppression of T cell activity and decreased infiltrating T cells. EMAP II blockade in mice bearing colorectal cancer reduced tumour burden and increased T cell responses. In this study, we found that colorectal cancer-infiltrating tregs expressed increased levels of EMAP II. Furthermore, EMAP-II levels correlated positively with serum IL-2 and TGF-β (p<0.001).
Conclusion & Significance: This study has demonstrated the role of EMAP II in immune suppression and the potential for immunotherapy via blocking EMAP II in CRC.
Leiming Xia
University of Michigan Comprehensive Cancer Center, USA
Title: Phase I clinical trials for the PD-1/MUC1 CAR-pNK92 immunotherapy
Time : 11:45-12:10
Biography:
Leiming Xia is an professor in University of Michigan Comprehensive Cancer Center, USA. he has published many artciles in reputed journals.
Abstract:
Mucin1 (MUC1), as an oncogene, overexpressed in many human carcinomas and plays a key role in the progression and tumorigenesis. MUC1 specific chimeric antigen receptors (CARs) modified T/NK cells has been shown to be an effective approach for inducing MUC1+ tumor cells death. However, treatment failure with CAR-T/NK therapy was usually caused by the high expression of negative immune-regulatory molecules in tumor microenvironment. PD-L1 has been identified as negative checkpoint molecules that promote immune evasion of tumor cells. The interaction of PD-1 and PD-L1 inhibits the function of tumor-infiltrating lymphocytes or infused T/NK cells while activating the negative immune-regulatory cells in tumor microenvironment. To conquer these barriers and transform the PD-1/PDL-1 suppression effect into a positive regulation, we engineered clinically applicable NK-92 cells by lentiviral gene transfer to express two kinds of chimeric antigen receptors (CARs) comprising an anti-MUC1 or anti-PDL1 scFv antibody fusion protein with CD28-CD137 as a signaling moiety and truncated PD1 peptide. Anti-MUC1-CAR expression by gene-modified NK92 cells speciï¬cally and efï¬ciently lysed MUC1 positive tumor cells in vitro and in vivo. In this study, 10 patients with different kinds of tumor (lung cancer, pancreatic cancer, colon cancer and ovarian cancer) were enrolled with PDL-1 and MUC-1 positive through pathological examination, then CAR-NK cells were infused several times into the patients (1×109 cells total). Of 10 patients, 2 patients were withdrawn, 7 patients (70%) showed stable disease and 1 patient (10%) showed progressive disease. We also monitored the cytokines level and hematological changes to evaluate the safety. Most patients didn`t shown cytokine storm or bone marrow suppression obviously. From these patients we found that CAR-NK therapy has a broad prospect of application as a novel immunotherapy related to its certain clinical effects, mild side effects and easy preparing. CAR-NK would play more obviously anti-tumor efficacy through Bi-target treatment.
Lu Wen
University of Michigan Comprehensive Cancer Center, USA
Title: Adoptively transferred B cells directly kill tumor cells via the CXCR4/CXCL12 and perforin pathways
Time : 11:45-12:10
Biography:
Lu Wen is an professor in University of Michigan Comprehensive Cancer Center, USA. he has published many artciles in reputed journals.
Abstract:
Over the years, the role of B cells in the host immune response to malignancy has been overshadowed by our focus on T cells. The role played by B cells in cancer immunology is complex and controversial. The observation made by our lab that activated B cells alone can mediate tumor regression in the adoptive immunotherapy of solid tumors is innovative. One novel mechanism by which activated B cells mediate tumor regression is via direct tumor cell cytotoxicity in the absence of antibodies. We reported that antitumor B cells directly kill tumor cells via the Fas/FasL pathway and are regulated by IL-10. In this study, we defined additional mechanisms involved in B cell antitumor immunity. Administration of IL-2 significantly augmented the therapeutic efficacy of adoptively transferred tumor-draining lymph node (TDLN) B cells which express IL-2R. Furthermore, we detected CXCR4 expression on 4T1 TDLN B cells, and 4T1 tumor cells produced its ligand CXCL12. Transwell experiments demonstrated the chemotraction of CXCR4-expressing 4T1 TDLN B cells towards CXCL12-producing 4T1 cells. Blockade of CXCR4 using a CXCR4-specific inhibitor, AMD3100, significantly reduced the killing of 4T1 tumor cells by 4T1 TDLN B cells. Blockade of FasL and CXCR4 concurrently inhibited B cell-mediated direct killing of tumor cells in an additive manner, indicating that both Fas/FasL and CXCL12/CXCR4 pathways are involved in the direct killing of 4T1 cells by 4T1 TDLN B cells. TDLN B cells produced perforin. Additional experiments showed that effector B cells could directly kill tumor cells via the Fas/FasL and CXCR4/CXCL12 pathways as well as perforin. These findings underscore the diversity of function by which B cells can play an important role in the host immune response to tumor, and clearly indicated that transferred effector B cells can act independently of T cells in causing tumor destruction in adoptive immunotherapy
Guohui Qin
Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Title: Comparative analysis of immune molecules in esophageal squamous cell carcinoma and adenocarcinoma
Time : 12:10-12:35
Biography:
As a PhD candidate, Ms Guohui Qin is majoring in tumor immunology, specially in tumor microenvironment. She has been studying on the role of immunosuppressive cells as myeloid-derived suppressive cells (MDSCs) and tumor initiating cells in the regulation of the proliferation and function of effective T cells in tumor microenvironment. And she has been committed to improve the efficiency of immunotherapy by blocking immunosuppressive factors. Moreover, her reports about “Blocking MDSCs accumulation in tumor site improves clinical prognosis” has been employed in Cold Spring Harbor Asia Conferences.
Abstract:
Backgrounds: Esophageal cancer has become the sixth common reason of cancer death and causes approximately 400,000 deaths worldwide annually. Esophageal cancer can be divided into esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EA) according to the histopathology. ESCC mainly distributes in Asia, correlated with smoking and drinking, while the incidence of EA which is related to gastric reflux, Barrett’s esophagus and obesity increased year by year in Western countries. Previous studies have demonstrated TP53 with a high mutation rate in both pathologies, whereas TP63/SOX2, which is associated with cell differentiation, has a high mutation rate in ESCC. However, there are few studies on the expression patterns of tumor-associated immune molecules in esophageal carcinoma. Here, we investigated the correlation between different molecules and the prognosis of different pathological esophageal cancer with the analysis of ESCC, EA and normal tissue from TCGA database. Materials and Methods: In this study, 94 different ESCC and 89 cases of EA were screened for the differentially expressed genes in tumor tissues. We investigate the distribution of increased genes in KEGG pathways. With Venn diagram Analysis we clarify the similarities and differences of gene distribution in the development of ESCC and EA. And the correlation between the screened genes and their prognosis significance was analyzed with Kaplan-Meier methods. Findings: Compared with normal tissues, the expression of 3109 genes in ESCC was increased, while 2571 genes elevated in EA. In further enrichment analysis of the elevated genes, we found that the cytokine-cytokine receptor interaction pathway may play a crucial role in the tumorigenesis and development of esophageal cancer. The Venn diagram Analysis showed that 57 genes were identical in ESCC and EA, but 18 genes were found specially increased in ESCC and other 37 related genes were only significantly elevated in EA. With survival analysis, we got that TNFRSF10B was positively and CXCL14 was negatively correlated with ESCC prognosis. And CXCL8 and IL17RB in EA were negatively correlated with survival. Our further experiments will analyze the role of TNFRSF10B, CXCL14, CXCL8 and IL17RB in ESCC and EA respectively.
Conclusion: Different molecular mechanisms play significant role in occurrence and development in ESCC and EA, which determines the different prognosis and target treatment in esophageal carcinoma.
Barbara Chirullo
Istituto Superiore di Sanità , Italy
Title: Bacteria: friends or foes? Anticancer immune strategy by attenuated mutant strain of Salmonella Typhimurium (STMZNUABC)
Time : 12:35-13:00
Biography:
Abstract:
Cancers are among the leading causes of death worldwide, entailing also what is now called financial toxicity. Conventional treatment modalities (surgery, chemo-†and radiotherapy) have considerable limitations, which often result in incomplete destruction of the tumors. Therefore, prevention and control of cancer diseases is an important task for today’s medicine, due to the possible implications of such diseases on public health and to their economic consequences. And to their economic consequences. Therefore, the development of new therapeutic strategies to fight cancer is a priority for research. In this regard, the use of bacteria as alternative cancer therapeutics, in particular their potential to selectively target cancer cells has been studied for more than a century.
We, therefore investigated the tumor targeting efficacy and the mechanism of action of a specific attenuated mutant strain of Salmonella Typhimurium (STMznuABC) devoid of the whole operon coding for the high-â€affinity zinc transporter ZnuABC, which is required for bacterial growth in environments poor in zinc and for conferring full virulence to different Gram-â€negative pathogens.
The results indicated that STMznuABC is able to penetrate and replicate into tumor cells in in- vitro and in vivo models. The subcutaneous administration of STMznuABC in mammary adenocarcinoma mouse model leads to both reduction of tumor growth and increase in life expectancy of STMznuABC treated mice. Moreover, investigating the potential mechanism behind the favorable clinical outcomes, we provide evidence that STMznuABC stimulates a potent inflammatory response and a specific immune pattern, recruiting a large number of innate and adaptive immune cells capable to contrast the immunosuppressive environment generated by tumors. Exploring the tumor microenvironment of STMznuABC-â€treated mice, we found that STMΔznuABC is able to increase the number of neutrophil cells, interferon gamma CD8+ cells and a Th1 immune profile phenotype. On the whole, our results support the potential STM as a promising anti-â€cancer therapy.
Zarina Arif
Aligarh Muslim University, U.P, India
Title: Projected role of modified-albumin in cancer
Time : 13:45-14:10
Biography:
Dr. Zarina Arif, has completed her Ph.D. in the year 1993 from Aligarh Muslim University, India. She has work as Research Assistant (23-9-1993 to 22-7-2008) at the College of Applied Medical Sciences, King Saud University, Riyadh, Kingdom of Saudi Arabia. It was research cum teaching job. She has worked as Research Associate for six month at Department of Biochemistry, Faculty of Medicine, AMU, Aligarh. She also worked as Postdoctoral Fellow of the University Grants Commission, New Delhi since 11 Feburary 2012 to 30 July 2015. She is presently working as Assistant Professor at the Department of Biochemistry, J.N. Medical College, Aligarh, India. She has attended several national and international conferences and has published 25 papers in international journals
Abstract:
Statement of purpose: Extensive research till date suggests that oxidative stress, chronic inflammation, and cancer are closely linked. Inflammation results in the production of numerous reactive oxygen, nitrogen and chlorine species, in addition to the products of lipid and sugar oxidation, some of these products are capable of chemically modifying amino acids in proteins. This in turn results in changes to the structure and function of proteins. Increasing evidence demonstrates that such post-translational modifications result in the generation of neo-epitopes capable of eliciting both innate and adaptive immune responses. Therefore, this study has analyzed the changes in human serum albumin upon modification with peroxynitrite, an endogenously produced powerful oxidizing and nitrating agent, and is implication in the etiopathogenesis of cancer.
Methodology & Theoretical Orientation: Various physico-chemical studies were carried out to establish the modification of albumin. Peroxynitrite-modified-albumin exhibited hyperchromicity at 278 nm, changed microenvironment of tyrosine, tryptophan along with the generation of 3-nitrotyrosine, nitrotryptophan and protein carbonyls. Moreover, we have observed immune cells may generate autoantibodies. Thus, peroxynitrite-modified-albumin was used as antigen for detecting autoantibodies in lung cancer patients by ELISA. IgG isolated from the sera of patients with lung cancer showed better recognition for neo-epitopes on the modified albumin, reflecting theresence of circulating autoantibodies in lung cancer patients.
Conclusion and Significance: Gross structural changes in albumin may favour autoantibodies induction in vivo under similar conditions. Peroxynitrite- modified –albumin may also be considered as potential antigenic candidates for eliciting autoimmune response in lung cancer patients.
- Immunotherapy - Tumors Cancer Immunology & Immunotherapy Cancer Research Tumor Immunotherapy Research Tumor Markers and Drug Targetting
Location: Chicago, USA
Session Introduction
Manal Mohamed Saber
Minia University, Egypt
Title: Diagnostic and prognostic markers in Non-Hodgkin 's Lymphoma
Time : 14:20-14:45
Biography:
Dr Manal Mohamed Saber, has earned her PhD from Nottingham, UK. she is focusing on cancer studies, EMAP II, immune suppression, molecular, cellular and laboratory techniques at a high level. She received excellent training in molecular and cellular techniques at the highest international level and has previously worked with cancer and immunology studies. Her dedication to cure cancer got her involved in cancer studies
Abstract:
Objectives:
Establishing diagnostic and prognostic factors are very important in the management of Non-Hodgkin Lymphoma (NHL). Our aim was to evaluate the clinical significance of serum cytokines and immunological markers, in NHL patients for assessing treatment response and prognosis of patients.
Methods: Serum EMAP-II, IL-19, IL-10, IL-24, TGF-β, CD3, CD5, CD10, CD19, CD20, CD22, CD23, CD68, CD79a, CD99, LCA, bcl-2, bcl-6 and anticardiolipin (aCA) IgM, aCA IgG, antinulclear antibodies (ANA) levels were measured in the serum of 64 NHL patients before and after treatment with CHOP-based chemotherapy by enzyme-linked immunosorbent assay. Correlations of marker levels to the laboratory, and clinicopathological markers were performed.
Results: Serum levels of EMAP-II, IL-10, CD3, CD5, CD10, CD19, CD20, CD99 and aCA IgG were higher before therapy and decreased significantly thereafter (P<0.001). Serum CD68, CD79a and bcl-6 did not change after therapy. Significantly higher levels of IL-19, IL-24, bcl-2, CD22, CD23, LCA, TGF- β, ANA, and aCA IgM were demonstrated in patients with relapse (P<0.001). Significant associations were found between serum markers, clinicopathological and laboratory findings.
Conclusion: Cytokines and immunological markers can serve as useful diagnostic markers in NHL patients. They assessed response to therapy. Serum IL-19, IL-24, bcl-2, CD22, CD23, LCA, TGF- β, ANA, and aCA IgM proved to be the most sensitive predictor of advanced disease and poor prognosis
Sung Hwan Lee
Yonsei University College of Medicine, Seoul, Korea
Title: Oncologic impact of postoperative delta-neutrophil index in pancreatic cancer
Time : 14:45-15:10
Biography:
Sung Hwan Lee is currently an Clinical & Research Fellow in the Department of Surgery at Yonsei University College of Medicine, Republic of Korea. His Academic Interests are Hepatobiliary and pancreatic surgery / Surgical oncology for pancreatic cancer / Molecular Imaging by two-photon microscopyPancreatic cancer microenvironment / Cancer metabolism
Abstract:
Background: Major cancer surgery can cause surgical stress and disturbs the immune system. The oncologic impact of perioperative immune disturbance is not yet known.
Methods: From December 2009 to December 2013, totally 154 patients who underwent pancreatic resection for pancreatic ductal adenocarcinoma were enrolled into this study. Perioperative leukocyte and lymphocyte counts assessed by an automated blood cell analyzer were obtained from institutional database. Clinicopathologic factors and survival data were identified from medical record.
Results: Immature granulocytes counted by delta neutrophil index (DNI) were significantly correlated with oncologic outcomes after curative resection of pancreatic ductal adenocarcinoma. The highest value, elevation period, and bimodality of DNI value were statistically significant predictive factors for cancer recurrence after pancreatic resection.
Conclusions: Postoperative DNI predicts the tumor recurrence after resection of pancreatic cancer. Well-designed clinical and translational researches for perioperative immune disturbance are mandatory for revealing crucial concepts for tumor immunology in veiled therapeutic viewpoint.
Qiaofei Liu
Peking Union Medical College & Chinese Academy of Medical Science, Beijing, China
Title: The tumor microenvironment is correlated with clinicopathological traits and indicates the adjuvant chemotherapeutic efficacy of gemcitabine in pancreatic cancer after curative Whipple procedure
Time : 15:10-15:35
Biography:
Dr. Liu is an attending surgeon of general surgery of Peking Union Medical College Hospital which successively ranks NO.1 during the last 7 years in China. He have been focusing on the integrated treatment of pancreatic cancer after curative resection, especially new treatment based on the tumor microenvironment, for more than 10 years. He has got three national grants to support his research and also got his papers published on prestigious academic journals, including cancer research, international journal of cancer, journal of immunology and cancer immunology immunotherapy, et al.
Abstract:
Pancreatic cancer is a devastating malignance with extremely complicated tumor microenvironment. Adjuvant gemcitabine treatment is the golden standard regimen for pancreatic cancer after curative resection, however its 5-year overall survival is only 20% for this kind of patients. The correlations between tumor microenvironment and the efficacy of gemcitabine has been seldom reported. By using tumor tissue microarray technology, we analyzed the landscape of the tumor microenvironment of 95 cases of pancreatic cancer patients who underwent pancreaticoduodenectomy (Whipple procedure) and adjuvant gemcitabine treatment. The different components in the microenvironment, including the immune cell populations（Pan-inflammatory cells, B cells, Th cell , CTL, Treg, DC, NK, macrophages and granulocyte）,Th1 related cytokines(IL-6, IFN-γ, TNF-α，) ，Th2 related cytokines(IL-10, TGF-β, IL-4,IL-17), M-CSF, MG-CSF, microvascular density(MVD) and micro lymphatic vessel density(MLVD), pancreatic cancer stem cells and the immune checkpoints(PD-L1 and CTLA-4) were immunohistologically stained. The correlations between the different patterns of tumor microenvironment and the efficacy of gemcitabine and the clinicopathological traits were analyzed. The results indicated that the tumor microenvironment was significantly correlated with the clinicopathological characteristics and the efficacy of gemcitabine. The tumor microenvironment could be a practical indicator for personal and percisional adjuvant gemcitabine chemotherapy in pancreatic cancer patients after curative resection.
Leiming Xia
University of Michigan Comprehensive Cancer Center, USA
Title: Phase I clinical trials for the PD-1/MUC1 CAR-pNK92 immunotherapy
Time : 15:55-16:20
Biography:
Leiming Xia is an professor in University of Michigan Comprehensive Cancer Center, USA. he has published many artciles in reputed journals.
Abstract:
Mucin1 (MUC1), as an oncogene, overexpressed in many human carcinomas and plays a key role in the progression and tumorigenesis. MUC1 specific chimeric antigen receptors (CARs) modified T/NK cells has been shown to be an effective approach for inducing MUC1+ tumor cells death. However, treatment failure with CAR-T/NK therapy was usually caused by the high expression of negative immune-regulatory molecules in tumor microenvironment. PD-L1 has been identified as negative checkpoint molecules that promote immune evasion of tumor cells. The interaction of PD-1 and PD-L1 inhibits the function of tumor-infiltrating lymphocytes or infused T/NK cells while activating the negative immune-regulatory cells in tumor microenvironment. To conquer these barriers and transform the PD-1/PDL-1 suppression effect into a positive regulation, we engineered clinically applicable NK-92 cells by lentiviral gene transfer to express two kinds of chimeric antigen receptors (CARs) comprising an anti-MUC1 or anti-PDL1 scFv antibody fusion protein with CD28-CD137 as a signaling moiety and truncated PD1 peptide. Anti-MUC1-CAR expression by gene-modified NK92 cells speciï¬cally and efï¬ciently lysed MUC1 positive tumor cells in vitro and in vivo. In this study, 10 patients with different kinds of tumor (lung cancer, pancreatic cancer, colon cancer and ovarian cancer) were enrolled with PDL-1 and MUC-1 positive through pathological examination, then CAR-NK cells were infused several times into the patients (1×109 cells total). Of 10 patients, 2 patients were withdrawn, 7 patients (70%) showed stable disease and 1 patient (10%) showed progressive disease. We also monitored the cytokines level and hematological changes to evaluate the safety. Most patients didn`t shown cytokine storm or bone marrow suppression obviously. From these patients we found that CAR-NK therapy has a broad prospect of application as a novel immunotherapy related to its certain clinical effects, mild side effects and easy preparing. CAR-NK would play more obviously anti-tumor efficacy through Bi-target treatment.
Guohui Qin
Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Title: Comparative analysis of immune molecules in esophageal squamous cell carcinoma and adenocarcinoma
Time : 16:20-16:45
Biography:
As a PhD candidate, Ms Guohui Qin is majoring in tumor immunology, specially in tumor microenvironment. She has been studying on the role of immunosuppressive cells as myeloid-derived suppressive cells (MDSCs) and tumor initiating cells in the regulation of the proliferation and function of effective T cells in tumor microenvironment. And she has been committed to improve the efficiency of immunotherapy by blocking immunosuppressive factors. Moreover, her reports about “Blocking MDSCs accumulation in tumor site improves clinical prognosis” has been employed in Cold Spring Harbor Asia Conferences.
Abstract:
Backgrounds: Esophageal cancer has become the sixth common reason of cancer death and causes approximately 400,000 deaths worldwide annually. Esophageal cancer can be divided into esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EA) according to the histopathology. ESCC mainly distributes in Asia, correlated with smoking and drinking, while the incidence of EA which is related to gastric reflux, Barrett’s esophagus and obesity increased year by year in Western countries. Previous studies have demonstrated TP53 with a high mutation rate in both pathologies, whereas TP63/SOX2, which is associated with cell differentiation, has a high mutation rate in ESCC. However, there are few studies on the expression patterns of tumor-associated immune molecules in esophageal carcinoma. Here, we investigated the correlation between different molecules and the prognosis of different pathological esophageal cancer with the analysis of ESCC, EA and normal tissue from TCGA database. Materials and Methods: In this study, 94 different ESCC and 89 cases of EA were screened for the differentially expressed genes in tumor tissues. We investigate the distribution of increased genes in KEGG pathways. With Venn diagram Analysis we clarify the similarities and differences of gene distribution in the development of ESCC and EA. And the correlation between the screened genes and their prognosis significance was analyzed with Kaplan-Meier methods. Findings: Compared with normal tissues, the expression of 3109 genes in ESCC was increased, while 2571 genes elevated in EA. In further enrichment analysis of the elevated genes, we found that the cytokine-cytokine receptor interaction pathway may play a crucial role in the tumorigenesis and development of esophageal cancer. The Venn diagram Analysis showed that 57 genes were identical in ESCC and EA, but 18 genes were found specially increased in ESCC and other 37 related genes were only significantly elevated in EA. With survival analysis, we got that TNFRSF10B was positively and CXCL14 was negatively correlated with ESCC prognosis. And CXCL8 and IL17RB in EA were negatively correlated with survival. Our further experiments will analyze the role of TNFRSF10B, CXCL14, CXCL8 and IL17RB in ESCC and EA respectively.
Conclusion: Different molecular mechanisms play significant role in occurrence and development in ESCC and EA, which determines the different prognosis and target treatment in esophageal carcinoma.
Qiao Li
University of Michigan Comprehensive Cancer Center, USA
Title: Cancer stem cell vaccine significantly reduced local tumor relapse and prolonged animal survival in the adjuvant setting
Time : 16:45-17:10
Biography:
Dr. Li is a member of the Tumor Immunology Program of the Comprehensive Cancer Center at the University of Michigan. His research to develop innovative cancer treatment approaches through adoptive immunotherapy is clinically relevant. Particularly, his recent studies focus on B cells and cancer stem cells (CSCs) represent two new directions in cancer immunotherapy. He and his team have published a series of papers for B cells as effector cells recently. These papers respectively provided direct experimental evidence for the involvement of antibody and B cells in antitumor reactivity, demonstrating for the first time that use of in vivo sensitized and in vitro activated B cells alone could mediate tumor regression in cancer adoptive immunotherapy, and observed that effector B cells could kill target tumor cells directly in the absence of complement and other effector cells
Abstract:
Therapeutic efficacy of cancer is limited by both local and distant recurrence. Effectively preventing local tumor recurrence remains a significant challenge. The existence of micro metastasis at the time of tumor resection represents an even greater therapeutic challenge, since 90% of tumor deaths are due to tumor metastasis. There is increasing evidence that many cancers are driven and maintained by cancer stem cells (CSCs) which contribute to tumor recurrence and metastasis. Targeting CSCs may thus increase the therapeutic efficacy of current cancer treatment. We described a strategy to target CSCs using CSC-dendritic cell (DC) vaccination. However, the efficacy of CSC targeted therapeutics may be greatest when they are deployed in the adjuvant setting. In this study, two mouse models were utilized: established s.c. SCC7 tumors were surgically removed from mice followed by treatment using ALDHhigh SCC7 CSC-DC vaccine, which significantly reduced local tumor relapse and prolonged animal survival. This effect was significantly augmented by simultaneous administration of anti-PD-L1 mAb. In the minimal disease setting of D5 melanoma, ALDHhigh CSC–DC vaccination significantly inhibited tumor growth, reduced spontaneous lung metastases resulting in increased survival. CCR10 and its ligands were down-regulated on ALDHhigh D5 CSCs and in lung tissues respectively in animals subjected to ALDHhigh D5 CSC–DC vaccination. Down-regulation of CCR10 by siRNA significantly blocked tumor cell migration in vitro and metastasis in vivo. T cells harvested from ALDHhigh D5 CSC–DC vaccinated animals selectively killed the ALDHhigh D5 CSCs. As a result, CSC-DC vaccination significantly decreased the percentage of ALDHhigh cells in residual tumors. These data indicate that, when used in an adjuvant setting, ALDHhigh CSC–DC vaccines effectively inhibit local tumor recurrence, reduce spontaneous lung metastasis, and prolong animal survival; compared with traditional DC vaccines and that simultaneous PD-L1 blockade can significantly enhance this effect.
- Poster Presentation
Session Introduction
Eman Tayae Elsayed
Alexandria University, Egypt
Title: Mitochondrial DNA Copy Number Variation as a Potential Predictor of Renal Cell Carcinoma.
Biography:
Abstract:
Biography:
Mai Moaaz is an assistant professor of Immunology. She has a passion in the field of tumor immunology and an expertise in tumor tissue culture system and experimenting new modalities for cancer immunotherapy. Her tissue culture system provides the ex vivo tissue architecture that is necessary to maintain or reconstitute an environment closely resembling that of the tumor tissue to reflect the complex tissue architecture of an individual tumor. The majority of preclinical cancer research is based on established cell lines that frequently have undergone multiple changes influencing their biological behavior and therefore no longer reflect that of the primary tumor of origin. She has built this model after years of experience in research, evaluation, teaching and administration both in hospital and education institutions. She is conducting current studies on tumors as an approach to cancer immunotherapy.
Abstract:
Statement of the Problem: Because of heterogeneity of gastric cancer (GC), searching for more accurate predictors of GC prognosis has become a growing interest. Infiltration of immune cells in tumors is associated with prognosis; among them are the immunosuppressive myeloid derived cells (MDSCs). Their accumulation constitutes an important mechanism of tumor immune evasion. Hence, their characterization is essential for diagnosis and therapeutics of cancer. Increased expression of microRNA-494 was noticed in MDSCs from tumor-bearing mice suggesting another new therapeutic objective for cancer treatment. It was also discovered that tumor-derived transforming growth factor beta (TGF-β) was responsible for the up-regulation of microRNA-494 in MDSCs. The purpose of this study is to address the suppressive effect of MDSCs on T cells in GC and its possible association with Micro-RNA-494 and TGF-β expression in tumor tissue. Methodology & Theoretical Orientation: A case control study on 40 GC patients and corresponding controls where done. Tissue samples and peripheral blood were used for isolation of CD33+11b+HLADR- MDSCs cells using flowcytometry. MDSCs were co-cultured with isolated T cells to assess proliferation and cytokine production. Real-time PCR and Enzyme linked immunosorbent assay were used to evaluate tumor expression of miRNA-494 and TGF-β respectively. Findings: MDSCs percentages were significantly elevated in GC patients than controls and significantly increased in tumor specimens than paraneoplastic tissue. This increased expression is accompanied with elevation of TGF-β production in tumor than surroundings. MiRNA-494 was also extensively expressed in tumor samples. Addition of MDSCs from cancer patients markedly suppressed the proliferation of autologous T cells and cytokine production; however, no inhibitory effect was observed for MDSCs from healthy donors. Conclusion & Significance: The result indicates that tumor-derived MDSCs but not MDSCs from healthy donors have the immunosuppressive effect on T cells. Infiltration of MDSCs in tumors is associated with the prognosis of GC.
Mai Moaaz 2
Alexandria University, Egypt
Title: The Interplay of Interleukin-17A (IL-17A) and Breast cancer tumor microenvironment as a novel approach to increase tumor immunogenicity
Biography:
Mai Moaaz is an assistant professor of Immunology. She has a passion in the field of tumor immunology and an expertise in tumor tissue culture system and experimenting new modalities for cancer immunotherapy. Her tissue culture system provides the ex vivo tissue architecture that is necessary to maintain or reconstitute an environment closely resembling that of the tumor tissue to reflect the complex tissue architecture of an individual tumor. The majority of preclinical cancer research is based on established cell lines that frequently have undergone multiple changes influencing their biological behavior and therefore no longer reflect that of the primary tumor of origin. She has built this model after years of experience in research, evaluation, teaching and administration both in hospital and education institutions. She is conducting current studies on tumors as an approach to cancer immunotherapy.
Abstract:
Statement of the Problem: Breast cancer is the most common cancer in females being the leading cause of cancer mortality in women. The continuous interactions of cancerous cells with their surrounding microenvironment infiltrating immune cells shape their immunogenicity as well as the ability to tumor progression and metastasis. Interleukin 17A (IL-17A) has a promoting role in carcinogenesis, tumor metastasis and resistance to chemotherapy. It enhances tumor cell survival and invasiveness and inhibits the antitumor immune response. Pro-tumor effects of IL-17A may occur via an increase in suppressive functions of myeloid-derived suppressor cells (MDSCs). The expression of IL-17A and programmed death ligand 1 (PDL1) is increased in breast cancer. The PDL1–PD1 (programmed death protein 1) signaling pathway promotes escape from immune surveillance in tumor cells. The purpose of this study is to address the potential suppressive effects of monoclonal anti-IL-17 antibodies on IL-17 tumorigenic activities in intact tumor microenvironment of BC as a novel immunotherapeutic reagent. Methodology & Theoretical Orientation: Fresh tumor tissue samples and peripheral blood were taken from 50 BC patients. IL-17A and PDL1 expression were primarily assessed. Cultures of tumor tissues either supplemented or not with anti-IL-17 monoclonal antibodies were subjected to evaluation of PDL1, MDSCs and T cell activities. Findings: Our results revealed that IL-17A stimulated PDL1 expression in tumor BC cultures and were correlated to clinicopathological features. Culturing with anti-IL-17 monoclonal antibodies suppressed PDL1 expression, and promoted T cell proliferation and functions. Tumors cultured with anti-IL-17 showed a significant decrease in the expression of MDSCs cells in the tumor microenvironment. Conclusion & Significance: The results indicate that recombinant anti-IL-17 monoclonal antibodies could represent a novel effective element of immunotherapeutic treatment strategy for BC. The selectivity and anti- potential of anti-IL-17 is highly hopeful in IL-17- abundant BC tumor microenvironment.
Naoki Ohtsu
Hokkaido University, Japan
Title: Inhibition of Eva1 degrade the formation and development of glioblastomas
Biography:
Naoki Otsu is interested in stem cell biology and tumorigenesis from stem cells. Based on Cancer stem cell theory, we are searching for cells with high tumorigenicity and membrane proteins intensely expressed in the cells. Currently, we focus on glioblastoma, a malignant brain tumor, and analyze membrane proteins that are molecular targets of antibody drugs. Using induced cancer stem cells derived from neural stem cells as model cells, strongly expressed membrane proteins were searched for multiple candidate proteins. This presentation introduces the molecules whose function and molecular mechanism are clarified among the obtained candidate.
Abstract:
Research focused on the property and targets of cancer stem cells, which have tumorigenicity and treatment-resistant, may contribute to the discovery of new therapeutic and diagnostic strategies. We have previously established mouse glioma-initiating cell (mGIC) lines from normal neural lineage cells, analyzed their gene expression profile, and reported functions of GIC-specific genes. We further focused on GIC-specific membrane proteins and found uncharacterized cell-membrane protein Eva1. Here we show the characterization of Eva1 in GIC: Eva1 is highly expressed in mouse GIC line, NSCL61, and human glioblastoma (GBM, WHO grade IV)-derived floating spheres, whereas it is not expressed in normal adult mouse and human brain. Eva1 expression is correlated with the malignancy of glioma. Indeed, we found that Eva1+ cells disseminate in human GBM tissue. Moreover, knockdown of Eva1 inhibited cell proliferation and tumorigenicity in mGIC and hGIC. Forced-expression of Eva1 enhanced malignancy of Low-grade human glioma (Diffuse Astrocytoma: DA, WHO grade II). The combination of polyclonal anti-Eva1 antibody and cytotoxic factor Saporin kills GIC, therefore it promised as a new target of antibody preparation. Using gene expression profiles between mGIC and Eva1-knockdown mGIC, we further found Eva1 signal pathway. Eva1 induced GIC proliferation through the activation of the RelB-dependent noncanonical NF-kB pathway by recruiting TRAF2 to the cytoplasmic tail. This signal pathway is important for human GBM formation. Taken together, these findings suggest that Eva1 is a potential target for immunotherapy.
Chunmna Lee
Osaka University, JAPAN
Title: Clinical study of Hemagglutinating virus of Japan envelope against chemotherapy resistant pleural mesothelioma
Biography:
Chunman Lee has his expertise in evaluation and passion in improving the antitumor efficacy of novel formulations against cancer dissemination. He started carrier as a surgeon at Osaka university hospital, and passed through the surgery program of Osaka university graduate school of medicine. Then he worked at University of Texas Southwestern Med. Ctr. at Dallas as a postdoctoral fellow. Now he researches the immunotherapy against pleural mesothelioma which is very refractory disease at Osaka university hospital as an associate professor.
Abstract:
Hemagglutinating virus of Japan envelope (HVJ-E) developed from HVJ virus. HVJ was first discovered in Japan in 1950’s. It is mouse parainfluenza virus, not human pathogen. The virus has become very famous, since the discovery of virus-mediated cell fusion. Using the fusion activity of HVJ, a versatile drug delivery system mainly gene transfection was developed. Recently we discovered that HVJ-E possesses the various antitumor activities. One is enhancing antitumor immunities such as activation of dendritic cells, induction of natural killer cells and cytotoxicic T lymphocytes, and suppression of regulatory T cells. Other activities are direct tumor-killing by the induction of cell death through the RIG-I/MAVS pathway. We already finished phase I trial against melanoma and castration resistant prostate cancer. Then, we did the phase I dose escalation safety/tolerability and preliminary efficacy study of intra-tumoral and subsequent subcutaneous administration of HVJ-E to the patients suffering from chemotherapy–resistant pleural mesothelioma who had not receive chemotherapy in the last 4 weeks, had a performance status of 0-1, had certain functions of bone marrow, liver, kidney, and lung, had evaluable lesion with Computed Tomography and FDG-PET scan, had lesion which can be administrated with HVJ-E. Exclusion criteria is presence of autoimmune disease, interstitial pneumonia needed to treat, and other malignant lesions, use of systemic steroids, a protocol is consisted of initial-tumor administration of HVJ-E and the subsequent three subcutaneous administrations within two weeks, and then washed out for two weeks. This one cycle is repeated twice. Six patients were registered, and they were finished receiving this clinical trial. The adverse events were evaluated by independent data monitoring committee. We will show the data of AEs and antitumor efficacy of HVJ-E in this clinical trials.
Nickolai Usachev
PSI Company, Ltd., Russia
Title: Is elevated troponin T reliable enough to be the only screen-out factor in pre-treated lymphoma patients?
Biography:
Nickolai Usachev has substantial practical expertise in cardiology and intensive care, combined with more than decade’s experience in the field of clinical studies. Since 2009 Dr.Usachev heads the Pharmacovigilance unit of PSI CRO.
Abstract:
Summarizing our experience of medical monitoring in clinical studies in patients with relapsed diffuse large B-cell lymphoma (DLBCL) pre-treated with standard Rituximab based scheme, we were surprised by a rather high incidence of increased Troponin T (TnT) in patients that had no detectable cardiac pathology. Such patients were screened out even if this lab finding was the only contraindication for inclusion. Purpose of the study: accumulate literature data confirming that in this particular group of patients mildly elevated TnT measured by immunoassay and not supported by any overt cardiovascular manifestations can be caused by reasons other than cardiovascular pathology. Therefore such patient can be included in the study and have potential benefit from treatment. Findings: about 10-11% of patient’s serum samples [1] may contain HAMA (human anti-mouse antibodies) [2], which lead to false positive results of troponin immunoassay [3; 4; 5]. Oncology patients, especially treated with monoclonal antibodies (Mab)–based immunotherapy are at significantly higher risk of HAMA development [2; 6; 7]. Available literature data suggest that quantitative measurement of HAMA in oncology patients has far more practical impact than simple confirmation of ambiguous immunoassay results. Survival benefit associated with HAMA in patients with B-cell malignancies [8] and with non-Hodgkin’s lymphoma treated with anti-lymphoma Mab [9; 10; 11] had been demonstrated. Conclusion: HAMA measurement in potentially eligible patients who had previously received Mab immunotherapy and whose only contraindication for inclusion into the clinical study is mildly elevated TnT, seems justified. First, the patients with the false-positive TnT results caused by HAMA, will be included and may have potential benefits from study treatment. Second, the result of the HAMA test may have predictive value for treatment benefit.
Guang-Yaw Liu
Chung Shan Medical University Hospital, Taichung, Taiwan
Title: T Helper Subset Cell Activation and Activated T Cell Autonomous Death (ACAD) Dedicated by Peptidylarginine Deiminase 2 through an ER Stress and Autophagy Mechanism
Biography:
Guang-Yaw LIU, PhD., Professor, Institute of Biochemistry, Microbiology & Immunology, Chung Shan Medical University.
Abstract:
Peptidylarginine deiminase type 2 (PADI2) is a post-translational modification enzyme that catalyzes arginine residues into the citrulline residues. Previous studies have shown that PADI2 promotes protein citrullinations in lymphocytes and it might play an important role in cell-mediated inflammation. We have found that overexpression of PADI2 promotes apoptosis in activated T cells previously. Whether does PADI2 participate in the pathway of activated T cell autonomous death (ACAD) is still curious. In this delicate PADI2-mediated ACAD study, we found that overexpression of PADI2 displayed higher levels of citrullinated protein which would induce the ER stresses significantly. The high levels of citrullinated protein results in unfolding protein response (UPR) of ER stresses and increases the huge protein degradation loading. Autophagy might embrace the engulfment and degradation capacity of the citrullinated and unfolding proteins. Herein, PADI2 could enhance autophagy in Jurkat T cells and lead to a degradation of p62 and the accumulation of LC3-II, BCEN1, ATG5 and ATG12. Autophagy and apoptosis are two critical mechanisms both which participate against cellular stresses and decide T cell activation, survival and immuno-homeostasis. PADI2-overexpressed Jurkat T cells caused the activation of Th17 cells due to the increase mRNA expression of cytokines, such as IL-17, IL-21, IL-22 and TNFα. Cytokines declined autophagy, provoked caspase cascade expression, and led to ACAD by IL-6 shRNA inspection. Simultaneously, autophagic BCEN1 could reduce Bcl-xL expression, increase caspase cascade and cause to cell insults. Knockdown of BCEN1 possibly will rescue Jurkat T cell activation, increase cytokine release and induce ACAD. We suggested that PADI2 participated in the activated T cell-induced autonomous death through triggering ER stress pathway coupling with regulating autophagic processing, and stimulating Th17 activation and the expression of cytokines by PADI2-citrullinating mechanism.
Hui-Chih Hung
National Chung Hsing University, Taiwan
Title: A Novel Mechanism Regulating Polyamine Homeostasis through an Antizyme Citrullination Pathway
Biography:
Hui-Chih Hung, Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan,
Abstract:
This study reveals a novel mechanism for the regulation of polyamine homeostasis through protein arginyl citrullination of antizyme (AZ), a natural inhibitor of ornithine decarboxylase (ODC). ODC is a tumor promoter and is critical for cellular polyamine production. AZ binds to ODC dimers and promotes the degradation of ODC via the 26S proteasome. This study demonstrates the protein citrullination of AZ catalyzed by peptidylarginine deiminase type 4 (PAD4) both in vitro and in cells. Higher levels of putrescine and citrullinated AZ proteins were observed in cells with PAD4 activation. The levels of ODC enzyme activity and protein increased with the level of citrullinated AZ proteins in PAD4-overexpressing cells. Our data also indicated that citrullinated AZ proteins have weaker binding affinities with ODC, greatly reducing the ability of citrullinated AZ protein to bind, inhibit, and promote the degradation of ODC. Based on LC-MS/MS analysis, eight citrullination sites of AZ were identified; Arg180 and Arg183 were identified as the critical citrullinated residues in AZ that impair the binding, inhibition, and degradation of ODC. This study is the first paper, to our knowledge, to demonstrate the post-translational modification of AZ by arginyl citrullination and reveals that AZ citrullination is involved in the up-regulation of cellular ODC and polyamines, strongly implying an association with cancer development.
Liyan Song
Jinan University, China
Title: Anti-tumor and immunomodulatory effects of Cordyceps militaris polysaccharide fraction
Biography:
Dr. Liyan Song is currently a Professor of Pharmacology in Biotechnological Institute of Chinese Materia Medica, Jinan University, China. She has worked with cancer and immunology studies in the past years. Specially, she is interested in mechanism research involved in cell signaling pathways. Her research team is also engaged in the development of novel antitumor drug, and financially supported by several foundations including Major National Science and Technology Projects/Significant New Drugs Creation as well as National Natural Science Foundation of China.
Abstract:
Statement of the problem: Although standard therapeutic protocols for cancer have been improved, it is still imperative to investigate novel anti-tumor strategies for eliminating cancer cells with little toxicity to normal cells. It is generally accepted that natural polysaccharides are capable of immunomodulatory activities. As a traditional Chinese medicine, Cordyceps militaris is widely used for health supplement. This study aims to investigate the anti-tumor and immunomodulatory effects of Cordyceps militaris polysaccharide fraction (CMPF). Methodology & Theoretical Orientation: The mouse model of S180 sarcoma was established and the effect of CMPF on tumor weight, organ index, and cytokines were examined in S180-bearing mice. The effect of CMPF on carbon clearance ability and DTH reaction of immunosuppressive mice were also investigated. Additionally, the immunomodulatory effect of CMPF and the possible mechanism were studied in macrophages and splenic lymphocytes. Findings: CMPF had no effect on proliferation of S180 cells in vitro. However, it inhibited tumor growth, increased levels of cytokines TNF-alpha and IL-2, and improved spleen and thymus indexes in S180-bearing mice. When combined with 5-fluorouracil, CMPF exerted synergistic effect and reduced toxicity of 5-fluorouracil. Other in vivo experiment results showed that CMPF enhanced carbon clearance ability and DTH reaction of immunosuppressive mice. On the other hand, in vitro assays revealed that CMPF promoted proliferation of splenic lymphocytes and cytotoxicity of NK cells to YAC-1 cells. CMPF also increased secretion of IL-2, development of cell cycle toward S phase, as well as T cell subpopulation. The phagocytosis function of macrophages and secretion of both NO and TNF-alpha by macrophages were also promoted by CMPF. Conclusion & Significance: These results indicate that CMPF possesses immunomodulatory effect on multiple immune cells in vitro. CMPF exhibited anti-tumor effect in vivo probably via immunomodulation. CMPF could potentially be used as a functional supplement candidate for tumor therapy.