Radhakrishnan P Iyer is the co-founder and Chief Scientific Officer of Spring Bank Pharmaceuticals. He has more than 25 years’ experience in the Biotechnology industry in drug discovery and development in diverse therapeutic areas including antivirals, inflammation, and immune-oncology. He is a leading innovator in the fields of nucleic acid chemistry, bioorganic chemistry and pharmaceutical sciences with over 100 publications and 200 issued, as well as, filed US and international patents. Prior to Spring Bank, he was the co-founder and VP of Discovery of Origenix Technologies and also served as Associate Director of Antisense Discovery at Hybridon, Inc. He currently serves on the Board of Directors of Spring Bank Pharmaceuticals and is a member of the Scientific Advisory Board of Oligomerix, Inc., NY.

Introduction: Immunotherapy has emerged as a transformative approach for the treatment of cancer. Recent work has highlighted a significant role for Stimulator of Interferon Genes (STING) agonists in immunotherapy. Conceptually, the activation of STING pathway in immune cells in the tumor microenvironment and/or tumor cells could result in the induction of innate and adaptive immunity through the activation of cytotoxic T cells and NK cells for profound and durable anti-tumor response. Herein, we describe the pharmacodynamic studies of a highly potent and selective first-in-class STING agonist SB 11285 and its structural analogs in different syngeneic tumor models.

Methods: For efficacy studies, SB 11285 was administered by intravenous (i.v.), intraperitoneal (i.p.) or intratumoral (i.t.) routes in the A20 lymphoma, CT26 colon carcinoma, B16 melanoma, and 4T1 breast cancer syngeneic mouse models (10 animals/group) and tumor growth inhibition (TGI) and tumor growth delay (TGD) assessed by measurement of mean tumor volumes (MTV). To check for the induction of immune memory, SB 11285 was administered i.t., (100μg, days 1,2,4,6,8) in the A20 model, monitored for 73 days and tumor-free survivors (TFS) were re-challenged with A20 cells and followed for an additional 45 days. Abscopal antitumor effect of i.t.-administered SB 11285 (100μg, days 1,2,4,6,8) was evaluated by implantation of tumors in the left and right flanks in the

CT26 model. Next, dose-ranging studies of SB 11285 were performed using i.t. (10 to 100μg), i.p. (1 to 9mg/kg) and i.v. (1 to 9mg/kg) routes in the CT26 model. Pharmacodynamic (PD) studies of SB 11285 was carried out in the 4T1 and CT26 models by

(i) measurement of cytokines in serum,

(ii) enumeration of cytotoxic T cells, as well as, MDSCs in blood, lymph , and spleen by flow cytometry; and

(iii) immuno-histochemistry of tumor tissues.

Cohen completed his medical studies at Washington University (St Louis). Postdoctoral studies were at the University of Chicago, the NIH and the University of Colorado. He has been a member of the faculty of Rutgers University, the University of Chicago and, most recently, the University of Illinois. Cohen has published more than 135 peer-reviewed papers, in the field of tumor immunology, numerous reviews and book chapters. Currently, Cohen is the CEO of Immune Cell Therapy, Inc., a tumor vaccine company.

Here, the author describes a unique strategy designed to identify dominant tumor antigens associated with lung cancer cells.Vaccines that induced immunity to dominant tumor antigens can induce therapeutic immune responses in tumor-bearing mice and patients. In a squamous carcinoma mouse model of non-small cell lung cancer, the antigen-discovery strategy described is based on the finding that genes encoding dominant tumor-associated antigens (TAA) (immunity to dominant tumor antigens can lead to tumor regression) are expressed in a highly immunogenic form by a nonmalignant, allogeneic fibroblast cell line transfected with a cDNA expression library from lung cancer cells. The transfected cells, which express the products of multiple genes specifying an array of antigenic determinants, including genes specifying dominant tumor antigens, were selected for antigen discovery. However, as only a small proportion of the transfected cell population was expected to have incorporated gene-segments that specified TAA (the vast majority specified normal cellular constituents), a unique strategy was developed that resulted in the identification of Cyp2e1, a derivative of cytochrome p450, as an immune dominant tumor antigen in murine squamous carcinoma cells and growth factor receptor-bound protein 10 GRB10 and Trop1 as immune dominant tumor antigens in murine breast cancer cells. The strategy consisted of dividing aliquots of the suspension of transfected cells into 10-15 small pools (initial inoculums 10E3, using a 96 well cell culture plate was used for this purpose, allowing the cells from each pool to increase in number (to approximately 10E7,) small starting inoculums increase the likelihood that some pools will contain greater numbers of cells that express dominant cancer antigens than others). Afterward, the transfected cell-population from each pool was divided into two portions. One portion was maintained frozen/viable for later recovery. The remaining portion was co-incubated with (mitomycin C-treated) squamous carcinoma cells. Two independent assays, (ELISPOT interferon gamma-release and 51-Cr release cytotoxicity) were used to identify pools that stimulated immunity to the squamous carcinoma cells to the greatest, (and for later use and as a control) to the least extent. Frozen cells from these pools were reestablished in culture; the cell-numbers were expanded and subdivided for additional rounds of immune selection. We reasoned that if the starting inoculums were sufficiently small, then randomly, some pools would contain greater numbers of cells that induced the antitumor immune response than others. After further rounds of immune selection, the microarray was used to identify the products of genes over-represented in the cell pool that stimulated the antitumor immune response to the greatest and (for use as a control) to the least extent.

Ahmed Shoker was trained in Internal Medicine at the University of British Columbia in Vancouver and moved to Toronto to complete his training in Nephrology and Transplantation Immunology. He moved to the University of Saskatchewan in 1991. Currently, he is a Professor of Medicine in Nephrology and Transplantation at the University of Saskatchewan. He is the Medical Director of the Saskatchewan Transplant Program. He has an interest in both basic and clinical investigation. He participated in over 35 national and international clinical studies in Transplantation and Nephrology. He has authored and co-authored over 130 peer-reviewed manuscripts. His current interest is in the area of cardiovascular disease in renal patients. Recent publications included measurement of inflammatory mediators in patients with decreased renal transplant function. Because of the significant impact of diabetes on the renal patient, he has focused his current interest in the management of diabetes mellitus in the kidney transplant patient and patients with chronic renal insufficiency.

As HLA-antibodies predict inferior graft and patient survival, potentially related to enhanced inflammation, this study aims to define patterns of increased circulating inflammatory cytokines (IL) and chemokine ligands (CCL) in sensitized patients awaiting kidney transplantation. Serum from 219 patients and 56 healthy controls were evaluated for HLA-Abs, 20 ILs, and 30 CLLs. Patients were distributed as: G1 (Non-sensitized) n=114, 52.1%; G2 (HLA-I-Abs) n=50, 22.8%; G3 (HLA-II-Abs) n=16, 7.3%; G4 (HLA-I/II-Abs) n=39, 17.8%. Within these groups, marker levels, marker clustering, and differences in levels within clusters were evaluated. Levels exceeding the 5th or 95th percentile values of controls in at least 60% of subjects within a profile were considered meaningfully altered. Correlation network analysis was used to recognize clusters; markers with intra-cluster correlations ≥ 0.80 were considered core. Among groups, 1-4, six, four, four and six clusters were recognized respectively, and five among controls. Profile differences in cluster configuration were noted, with G3 clustering appearing strongest. Of note, IL-4 was the only marker core to sensitized patient’s clusters. There were no quantitative differences among all patients’ groups, albeit many markers were significantly different from the control values. Thus, profile changes between sensitized and non-sensitized patients appear related to qualitative differences in marker relationships, rather than quantitative changes in which IL-4 may play a role.

Luiz Werber-Bandeira is the Head of Clinical and Experimental Immunology Unit - Santa Casa de Misericórdia do Rio de Janeiro, Brazil. He has a degree in Medicine; completed his Post-doctorate in Immuno-Genetics and; Ph.D. in Medicine-Immunology-Dermatology at Federal University of Rio de Janeiro. For 36 years in the profession, he has done Post-Doctorate in Immuno-Genetics from the Oswaldo Cruz Foundation (FioCruz-RJ), a master's degree and a Ph.D. from the Federal University of Rio de Janeiro (UFRJ). He is the coordinator of the Postgraduate Course in Immunology and Clinical and Laboratory Allergy, organizer responsible for the Research Line of the Clinical and Experimental Immunology Unit of the Santa Casa da Misericórdia in Rio de Janeiro, as well as a professor who participates in the line of research in photo-dermatology and Immunology of UFRJ. Dr. Luiz Werber-Bandeira was awarded by the City Council of Rio de Janeiro for services rendered to Continuing MedicalEducation in Medicine-Immunology with the Pedro Ernesto Medal.

Primary cutaneous T cell lymphomas (CTCLs) are characterized by hyperproliferation of malignant CD4+ T cells with primary localization on the skin. The common characteristics are the migration of the malignant mature T-lymphocytes into the epidermis, with hyperproliferation of malignant CD4+ T cells and epidermotropism. Sézary syndrome (SS) is the leukemic variant. It was established that CTCLs arise from a clonal expansion of CD4+ T cells with an identical rearrangement of the T cell receptor.

The purpose of this study was to evaluate the immunomodulation effect of photochemotherapy-A (psoralen plus ultraviolet A (PUVA). Pre- and post-PUVA punch skin biopsies of nine patients were stained immunohistochemically for CD34+, CD8+, CD7+, CD16+, CD56+, CD1a+, Bcl2+, p53+, CD45RA+, and CD45RO+ cells. The results showed a pre-PUVA cells/mm2 without significant difference among expansive or reactive cells. Post-PUVA analysis showed a significant decrease in the mean of expensive reactive cells. PUVA was immunomodulated decreasing cellular infiltrate. These findings could contribute to the comprehension of how PUVA acts. We achieved ectoscopic clearance of the lesions, although post-PUVA, there still was a mononuclear pathological infiltrate. This result demonstrates that the PUVA treatment should only be withheld when the histological analysis is normal.

Nagwa Elkhafif is a Professor of Clinical and Chemical Pathology and the current Head of the Electron Microscopic Research Department in the Theodor Bilharz Research Institute, a medical research institution affiliated to the Egyptian Ministry of Higher  Education and Scientific Research. She has completed her MD in the Faculty of Medicine at Cairo University. She focuses her research on the role of immune cells in combating hepatic diseases caused by helminthic (schistosomiasis), bacterial or viral infections (hepatitis virus) using electron microscopy and immunoelectron microscopy to visualize cellular changes accompanying such diseases. She was involved in scientific cooperative research with German and French institutions.

Schistosomiasis is the third most devastating tropical disease in the world, being a major source of morbidity and mortality for developing countries in Africa, South America, the Caribbean, the Middle East, and Asia. Schistosomiasis is due to immunologic reactions to Schistosoma eggs trapped in tissues. Antigens released from the egg stimulate a granulomatous reaction involving T cells, macrophages, and eosinophils that results in clinical disease. Symptoms and signs depend on the number and location of eggs trapped in the tissues. Initially, the inflammatory reaction is readily reversible. In the latter stages of the disease, the pathology is associated with collagen deposition and fibrosis, resulting in organ damage that may be only partially reversible. Complications of schistosomiasis include the following: gastrointestinal problems in case of S.mansonii and nephropathies in S. heamatobium which may end to hepatic or renal failure or even malignancies. Our study highlights the granuloma formation and modulation as an important sign of the immune response in murine hepatic schistosomiasis at the immunohistochemical and ultra-structural level aiming to understand and then find immunological approaches to prevent our stop complications of the disease at an early stage.

Maha Bakhuraysah has her expertise in evaluation and passion for improving the health and wellbeing. Her research focuses on the role of the Nogo receptor in multiple sclerosis, and the author is working with experimental autoimmune encephalomyelitis (EAE). Previous data has mentioned that there was no new role associated with the Nogo receptor, thus she has focused on the immunological arm in this model and author has discovered the existence of B-cells expressing NgR in EAE. It has been published recently that in MS patients’ B cells are localized in the brain, and we found it in mice. The studies haven't mentioned anything about the Nogo receptor but the author has found them too.

Despite clear evidence demonstrating that the deletion of Nogo-receptor 1 (NgR1) can protect against axonal degeneration and thus the progression of experimental autoimmune encephalomyelitis (EAE), an immunological role for this receptor is yet to yield mechanistic evidence. However, recently NgR has been suggested as an alternate receptor for the B-cell activating factor (BAFF) in the central nervous system (CNS). Therefore, our strategic aim was to define whether NgR contributes in the modulation of the adaptive immune response during EAE by promoting maturation and differentiation of BAFF reactive B-cells within the follicles during the induction of disease. The results showed that CNS-infiltrating blood cells revealed an augmented response in the B-cells, which expressed NgR1 and NgR3, observed in ngr1+/+ mice with the onset and progression of the disease that could not be demonstrated within the spinal cords of EAE-induced ngr1-/- mice. Remarkably, a cluster of B-cells-expressing NgR was present at the meninges of lumbosacral spinal cords of the ngr1+/+ EAE-induced mice at clinical score 1. Furthermore, there was a significant increase of secreted immunoglobulins from these NgR1-expressing B-cells. Importantly, these cells could be directed into the synthesis phase of the cell cycle, after stimulating sorted cells by extracellular BAFF in vitro; however, when BAFF signaling was blocked using either rBAFF-R, or NgR1-Fc, or NgR3 peptides, the cells were observed to be into G0/G1 phase. As a consequence, when we blocked NgR1- ligand signaling using a novel hematopoietic stem cell-based delivery of a therapeutic protein, immune lineage differentiated cells, including Zs green and the fusion protein, were trafficking into the CNS during acute EAE. Collectively, these data indicate that the existence of an inducible expression of NgR1 and NgR3 in specific immune lineage cells upon the induction of EAE and that the follicular-like NgR1 and NgR3-positive B-cells in the meninges may play an active role during the induction of EAE. Thus, our data reinforce the idea that is blocking the interaction of BAFF and NgR1 and NgR3 may be vital for neuroprotection during inflammatory insults.