The Pediatric Ohio-New York Cancer (Peds-ONC) Immunotherapy Center’s overarching hypothesis is that, in addition to adaptive immunotherapies, innate immune mechanisms of resistance in pediatric cancers can be leveraged as cancer immunotherapeutics.
The center is comprised of five distinct but cross-informative projects and a novel genomics and immune monitoring shared resource, bringing together five Project Leaders and a Shared Resource Director, all of whom are highly accomplished scientists or physician-scientists, to address and overcome barriers to effective immunotherapies for pediatric cancers.
Our goal is to generate a sufficient body of knowledge with compelling data to inform the rational design of future combinatorial innate mediated immunotherapy clinical trials.
The center’s current aims include:
- Identifying and overcoming barriers to utilizing NK cells as cancer therapeutics
- Breaking tolerance to “self” cancer-associated proteins by targeting innate immunity
- Enhancing immunotherapies by targeting suppressive myeloid cells
- Modulating tumor metabolic microenvironment to support T cell anti-tumor activities
Current Center Projects
Lead: Dean A. Lee, MD, PhD
Although T cells are best known as the “executioner” cell of the immune system, natural killer (NK) cells are similarly potent cell killers and activate the same death mechanisms. However, NK cells differ in that they are not dependent on recognition of unique antigens or neoantigens.
NK cells are activated via broad recognition of danger- and stress-related proteins and simultaneously activate adaptive immunity through multiple mechanisms that increase antigen recognition. Until recently, however, NK cell therapy lagged behind other immunotherapeutic approaches due to the inability to generate large numbers of active NK cells for adoptive transfer.
Dr. Lee’s team solved this problem and can generate large numbers of clinical-grade NK cells which have been successfully delivered in several clinical trials to adults and children with cancer.
Dr. Lee seeks to enhance the anti-tumor efficacy of adoptively transferred NK cells by improving our understanding of mechanisms mediating NK recruitment to tumors as well as their sensitivity to TGFβ and IDO/TDO metabolites. He proposes several manipulations he will test including enhanced activation states, AHR-deleted, and TGFβ resistant cells. He will test these modifications for their ability to enhance intratumoral NK cell recruitment and activity, including crosstalk with T cells. He will use xenograft engineered cell line and patient-derived sarcoma models to investigate the mechanisms underlying these interactions and test therapeutic strategies for translation to the clinic.
About Dr. Lee
Dr. Lee is the Director of Cellular Therapy and Cancer Immunotherapy both at Nationwide Children’s Hospital and the Ohio State University Comprehensive Cancer Center. He is also a principal investigator in the Nationwide Children’s Hospital Center for Childhood Cancer and a professor of Pediatrics at the Ohio State University College of Medicine. He brings to the Peds-ONC Immunotherapy Center expertise in CAR-T and NK cell biology, GMP processes and clinical-translational aspects of adoptive cellular therapy.
From 2006-2016 Dr. Lee was on faculty at MD Anderson Cancer Center as a member of the Cell Therapy Section in the Division of Pediatrics, where he led the NK cellular therapy program. He moved his laboratory to Columbus in 2016 where he has rebuilt his investigative team. He is also director of the Cell Based Therapy GMP facility at Nationwide Children’s Hospital and has overseen the development of relevant processes and standard operating procedures. The first clinical-grade product produced in that facility under his leadership is currently being used in a New Approaches to Neuroblastoma Therapy (NANT) Consortium trial. Clinically, he attends on the pediatric Blood and Marrow Transplant service at Nationwide Children’s Hospital.
Lead: Mitch Cairo, MD
The Cairo laboratory has identified and developed a number of strategies to circumvent several resistance mechanisms to NK cell mediated therapy against pediatric solid tumors. In Project 2 he will pursue three overarching aims to circumvent chemoradiotherapy resistance in the sarcoma tumor microenvironment.
- In collaboration with Dr. Dean Lee, he will investigate the safety and efficacy of ex-vivo expanded NK cells that have been electroporated to either ROR1 or MCAM CAR NK cells in-vitro and in-vivo in human sarcoma NSG xenografts.
- He will further explore the combinatorial effects of IL-15 agonists, OV-IL-15 (in collaboration with Dr. Kevin Cassady), anti-GD2 monoclonal antibodies, anti-GD2/anti-CD16 bi-specific NK cell engager (BiKE) on the functional activation and persistance of these CAR-NK cells against sarcoma. He will further collaborate with Dr. Lee to determine the additive and synergistic effects of a knock-in to the SOCS3 locus of STAT3 activating domains to further enhance CAR-NK proliferation and persistance.
- He will collaborate with Dr. Lee, Dr. Cripe, and Dr. Cassady on mechanisms and combinatorial strategies to overcome tumor microenvironment resistance by utilizing TGF-imprinted CAR NK cells, combining CAR NK cells with M7824 (anti-PD-1-anti-TGF-Trap), combinational virotherapy and enhancing expression of NK cell activating receptor ligands on sarcoma cells and/or determining expression of NK cell inhibitory ligands.
With each of the three aims, Dr. Cairo will work with Dr. Elaine Mardis to investigate immunoprofiling of the CAR-NK cells and genomic characteristics of resistant sarcoma cells.
About Dr. Cairo
Dr. Cairo is an internationally renowned translational scientist and a pioneer in developmental therapeutics and immunotherapy approaches in both pediatric hematological cancers and solid tumors. Dr. Cairo is the division chief of Pediatric Hematology, Oncology and Stem Cell Transplantation and professor of Pediatrics (with tenure), Medicine, Pathology, Microbiology & Immunology and Cell Biology & Anatomy at New York Medical College and Maria Ferari Children’s Hospital. Dr. Cairo is also the scientific and medical director of the GMP laboratory Cellular and Tissue Engineering laboratory.
Dr. Cairo has developed a number of chimeric antigen receptor (CAR) NK cell targets to several different receptors on many pediatric cancers and has been investigating mechanisms of NK cell resistance and combinatorial immunological approaches to circumvent mechanisms of resistance. Dr. Cairo has over 410 peer reviewed publications and has been and is currently the PI on several multicenter, multidisciplinary early investigations and is the IND holder on several early phase, first in child studies.
Lead: Kevin A. Cassady, MD
Oncolytic viruses work by a variety of pathways and mechanisms, including both direct lysis of cancer cells and the induction of innate and adaptive antitumor immunity. We have included them in the Peds-ONC Immunotherapy Center because of the robust antitumor responses and even apparent cures in numerous mouse models of pediatric cancer and the absence of significant toxicities in preclinical and clinical studies. In addition, the FDA recently approved the first oncolytic herpes simplex virus (oHSV), T-VEC (talimogene laherparepvec, a.k.a. Imlygic) for intralesional therapy of melanoma, validating the use of these agents as bone fide cancer therapeutics; unfortunately, T-VEC is not safe for systemic or intracranial administration.
Dr. Cassady has already utilized his expertise in virology and vectorology to create a novel oHSV recombinant, C134, that IS SAFE for intracranial injection and that activates immunostimulatory antiviral pathways while replicating better in tumor cells. The virus has been produced by the NIH’s NExT (formerly RAID) program, has received regulatory approval (FDA and RAC), and is now entering clinical trials for adult patients with aggressive gliomas.
Oncolytic HSV infection induces a brisk immune mediated response against infected cells that can break immune tolerance leading to both bystander and durable immune mediated damage against host antigens.
In Project 3, Dr. Cassady postulates that by further modifying his next generation oHSV to express known tumor-selective cell surface proteins he will be able to harness the virus’s inherent ability to break immune tolerance to improve immune recognition of tumor associated “self-antigens” (e.g. aberrantly expressed fetal proteins) and induce durable anti-tumor immune responses against pediatric cancers.
Oncolytic HSV infection stimulates immune effector recruitment but also suppresses host gene expression in the infected cell. This allows the virus to selectively express its genes in infected cells. Dr. Cassady proposes that by engineering tumor antigens into the viral genome, he can increase tumor antigen expression, antigen priming and overall viro-immunotherapeutic activity. He also proposes that he can further engineer the multimodal antigen expressing virus such that it will be effective and modulate the immunosuppressive myeloid-rich tumor microenvironment.
For the final aim he proposes combining virotherapy with NK directed cytotoxicity in the immunoedited environment. Through his flexible viral based platform, Dr. Cassady’s studies integrate with innate approaches (Project 1, 2 and 4) and can also utilize adaptive cellular therapies to target MHC-immunoedited tumors.
About Dr. Cassady
Dr. Cassady is a clinical virologist and a principal investigator in the Nationwide Children’s Hospital Center for Childhood Cancer and an associate professor of Pediatrics and Infectious Disease at the Ohio State University College of Medicine. He brings to the Center expertise in virology, vectorology, oncolytic virotherapy, innate immunity, and clinical translation for neurogenic tumors, including high grade gliomas and malignant peripheral nerve sheath tumors.
Dr. Cassady has focused most of his research career on the development of novel vectors based on herpes simplex biology for use in brain tumors, with a special emphasis on understanding and overcoming cell intrinsic innate responses to infection. His work has been supported by K08, P01, P20, P30, and P50 as well as a recent X01 RAID award for vector production and R01 award for clinical translation of this cGMP product. He has published extensively on the cancer cell intrinsic innate responses to virus infection and has identified pre-existing activation of pattern recognition and JAK-STAT signaling to be a barrier to virotherapy. A novel oncolytic vector he created is now in clinical trials for adults with glioblastoma.
Dr. Cripe’s lab is focused on improving our understanding of cancer-mediated immunosuppressive factors and developing rational strategies to augment immunotherapies through pharmacologic modulation of the tumor microenvironment. The central premise of this project is that a better understanding of how an oncolytic virus interacts with the tumor immune microenvironment will enable us to devise rational, effective combination therapies for use with virotherapy.
Dr. Cripe recently described effective targeting of M2-like macrophages and MDSC in the microenvironment using the combination of a “myelolytic” (Clodrosome or Trabectedin) with proinflammatory stimulus (oncolytic herpes virus). His project aims to deepen our understanding of the microenvironmental changes following this combination therapy and combine myelolytic targeting with different types of T and NK based therapies. His project directly interacts with Projects 1 (NK), 2 (CAR-NK), and 3 (oHSV) and utilizes the expertise of the Genomics & Immune Monitoring Shared Resource.
About Dr. Cripe
Dr. Cripe is the chief of the Division of Pediatric Hematology/Oncology at Nationwide Children’s Hospital, a principal investigator in the Center for Childhood Cancer, a professor of Pediatrics at the Ohio State University College of Medicine, and a member of the Ohio State University Comprehensive Cancer Center. He brings to the Peds-ONC Immunotherapy Center leadership experience, laboratory and preclinical expertise in combining oncolytic virotherapy with small molecules and antibody modifiers of the immune microenvironment, and clinical trial and clinical care expertise in pediatric oncology. His success in growing the clinical division at Nationwide Children’s Hospital from 14 hematology/oncology faculty to 31 over the past seven years gives him the required protected research time for both administrative leadership and scientific aspects of the Peds-ONC Immunotherapy Center. In 2016-2017 he served as Chair of the FDA’s Cellular, Tissue, and Gene Therapy Advisory Committee, and he was an ad hoc member of the Oncologic Drug Advisory Committee that voted to approve Tisagenlecleucel (CART019) for relapsed/refractory acute lymphoblastic leukemia in children.
Dr. Cripe is a leading figure in oncolytic viroimmunotherapy for pediatric oncology, having published over 120 papers in the field over the past 20 years on preclinical studies and co-authoring publications of pediatric phase I trials spanning four different viruses. He recently completed an R01 from the FDA Orphan Drug Grant Program for his most recent study, for which he served as the Sponsor-Investigator (BB-IND-13196). His work on combining TGF inhibitors with oncolytic virotherapy is currently supported by a 3-year grant (2018-2021) from the Department of Defense through the Congressionally Directed Medical Research Program.
Lead: Ruoning Wang, PhD
Interactions between the immune system and tumors are complex and dynamic processes that dictate tumor initiation, progression, and responses to therapy. Dr. Wang’s lab is focused on understanding the impact of the interplay between cell metabolic programs and cell signaling programs on tumorigenesis and immunity.
In this project, Dr. Wang’s lab explores how to develop novel metabolic modulations on anti-tumor T effector cells to improve the efficacy and broaden the therapeutic uses of immunotherapy within pediatric solid tumors. Specifically, Dr. Wang seeks to improve the metabolic fitness of anti-tumor T effector cells at the level of precise biochemical reaction and determine which molecular interactions may be amenable to pharmacologic manipulation.
Dr. Wang’s lab has identified the metabolite inosine as a powerful supporter of T cell immune response. Inosine largely promotes T cell proliferation in the tumor microenvironment. But, inosine’s immediate precursor, adenosine, is functionally the opposite — suppressing T-cells in two ways. Through a cell surface receptor, adenosine acts as a signaling molecule to suppress. When taken up by T cells, adenosine suppresses important metabolic processes the cells need in order to function.
Dr. Wang and colleagues will study how adenosine and inosine are broken down into specific metabolites, with the goal of determining which affect T cell immune responses and understanding how the process works. This may enable the lab to develop modulations to reduce or avoid T cell suppression and support anti-tumor activities.
Dr. Wang’s lab will collaborate with the labs of Dr. Kevin Cassady, Dr. Timothy Cripe and Dr. Lee Dean to design a variety of approaches that can be used to modulate adenosine and inosine metabolism and tested in the preclinical models of pediatric cancer.
About Dr. Wang
Dr. Wang is a principal investigator in the Center for Childhood Cancer and Blood Diseases at the Abigail Wexner Research Institute at Nationwide Children’s Hospital and an associate professor of pediatrics at The Ohio State University College of Medicine. Dr. Wang earned his bachelor’s degree in Medicinal Chemistry at China Pharmaceutical University, followed by a master’s degree in biochemistry at Nanjing Medical University and a PhD in the Genes & Development program at the University of Texas MD Anderson Cancer Center. He was further trained in immunology and cancer biology at St. Jude Children’s Research Hospital as a postdoctoral fellow.
The overarching theme of his research is to understand the interplay between metabolic pathways and signaling cascades, and how such interplay impacts cell division, death and differentiation in the context of tumorigenesis and immune response. Specifically, his lab focuses on: 1) understanding the cellular mechanism of metabolic checkpoint, 2) delineating metabolic signatures of immune cells and tumor cells, and understanding how the altered metabolic landscape impacts the immunosuppressive nature of the tumor’s microenvironment, and, 3) translating the above knowledge to novel therapeutic strategies to treat cancers and autoimmunity.
Genomics & Immune Monitoring Shared Resource Core
This Core includes a comprehensive set of analytical technologies including sequencing, conventional flow cytometry, and mass cytometry (CyTOF) analyses. The Core is directed by Elaine Mardis, PhD, with several assistant directors:
- Genomics (Peter White, PhD)
- Single cell transcriptomics (Ryan Roberts, MD, PhD)
- Pathology and immunhistochemistry (Michael Arnold, MD)
- Conventional flow cytometry (Chun-yu Chen, PhD)
- Mass cytometry (Gregory Behbehani, PhD)
The Peds-ONC Immunotherapy Center will utilize whole exome sequencing and transcriptomic profiling via RNAseq to characterize each of our cancer models. Using established bioinformatic algorithms to evaluate the RNAseq data, we will determine the predicted immune cell composition and inflammatory state of each tumor model.
The Genomics & Immune Monitoring Shared Resource Core will also directly support each of the center’s projects by helping determine the effects of various therapies on the immunologic microenvironmental profiles over time. In studies complementary to and validating of the genomic analyses, the Core will also directly measure intratumoral mouse immune cells by flow cytometry and CyTOF. It will support all four projects by profiling tumors at baseline and post-treatment using well established antibodies and conditions.
About Dr. Mardis
Dr. Mardis is the executive co-director of the Institute for Genomic Medicine at Nationwide Children’s Hospital. She is a professor of Pediatrics at the Ohio State University College of Medicine and a member of the Ohio State University Comprehensive Cancer Center. She brings to the Peds-ONC Immunotherapy Center world-renowned expertise in genomics with over 350 publications. She was involved in the original NIH-led human genome project, The Cancer Genome Atlas, and more recently the St. Jude – Washington University pediatric cancer initiative. Her work has been funded by numerous NIH grants including R01s, U01s, U54s, P01s, P50s, and numerous private foundations. She is supported in the Core activities by several assistant directors, some of whom are young investigators and each are experts in their respective areas spanning from genomics, genetics, and single cell transcriptomics to immunhistochemistry, flow cytometry, and mass cytometry.