Day 1 :
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
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.
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 TNF, 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.
MD Anderson Cancer Center, TX, USA
Time : 10:30-11:00
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.
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.
Global Product Manager- Bioassays, Promega Corporation, USA
Time : 11:20-11:50
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.
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
University of British Columbia, ViroGin Biotech Ltd, Canada
Time : 11:50-12:50
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.
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.
- Immunotherapy - Tumors Cancer Immunology & Immunotherapy Cancer Research Tumor Immunotherapy Research Tumor Markers and Drug Targetting
Location: Chicago, USA
Minia University, Egypt
Time : 14:45-15:10
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
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
Yonsei University College of Medicine, Seoul, Korea
Time : 15:10-15:35
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
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.
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 : 15:55-16:20
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.
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.
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
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.
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.
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
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
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.