The latest in stem cell research and regenerative medicine

DUARTE, Calif. — City of Hope, a world-renowned independent research and treatment center for cancer, diabetes and other life-threatening diseases, will host a focus session on June 26 to share the latest in stem cell research and regenerative medicine.

“Although best known as a comprehensive cancer center, City of Hope is the largest stem cell therapeutics center in California based on its bone marrow transplantation program. In addition, it has a burgeoning team of stem cell scientists who are using the latest stem cell engineering technologies to address incurable diseases such as HIV, a devastating neurological condition called Canavan disease and blood diseases,” said John Zaia, M.D., principal investigator of the California Institute for Regenerative Medicine-funded Alpha Stem Cell Clinic at City of Hope.

The focus session, entitled “City of Hope: Stem Cell Engineering for Therapeutic Applications,” is part of the 2019 International Society for Stem Cell Research (ISSCR) Annual Meeting. Six presentations will be hosted on June 26 from 9 a.m. to noon at the Los Angeles Convention Center. It will be in room 403A on the second floor and will address two areas of research: stem cell-derived therapeutics and disease-specific stem cell therapies.

Scientists from Beckman Research Institute of City of Hope will share their expertise and research on novel nuclease-based genome editing of human stem cells, epigenomic editing of embryonic stem cells to change the activity of specific DNA segments and the engineering of defense systems into pluripotent stem cell-based therapies. Pluripotent stem cells are “master cells” that can produce any regenerative cell or tissue the body needs.

Novel approaches for targeted stem cell genome editing – 9 to 9:20 a.m.

Kevin Morris, Ph.D., associate director of the Center for Gene Therapy at Beckman Research Institute of City of Hope

The CCR5 gene has been linked to two stem cell transplants that appear to have cured two patients of HIV. CCR5 is also the gene that the infamous Chinese scientist He Jiankui disabled in the world’s first genetically-edited babies.

Beckman Research Institute of City of Hope has been conducting research on the CCR5 gene for over a decade. Scientists there have developed and are experimentally investigating two distinct technologies to target either CCR5 or CD34 protein-expressing cells that disrupt the CCR5 gene, which may be a safe harbor site for the targeted insertion of therapeutically relevant genes. The goal is to develop the next generation of targeted gene therapeutics.

Targeted methylation of epigenomic editing of embryonic stem cells – 9:25 to 10:45 a.m.

Joshua Tompkins, Ph.D., assistant research professor in the Department of Diabetes Complications & Metabolism at Beckman Research Institute of City of Hope

Pluripotent (“master”) stem cells hold great promise in regenerative medicine and represent essential models for profiling epigenetic features of human development and disease. Using these master cells, Tompkins’ research group models and remodels the epigenome in derived lineages relevant to cardiac development, cancer and diabetes complications. In this session, techniques for CG site-specific or CG “island”-wide DNA methylation editing will be detailed. Observations of long-term epigenetic engineering maintenance will be connected to translatable epigenetic therapies.

Gene editing to establish a safeguard system for pluripotent stem cell-based therapies – 9:50 to 10:10 a.m.

Jiing-Kuan Yee, Ph.D., professor in the Department of Translational Research & Cellular Therapeutics at Beckman Research Institute of City of Hope

Human pluripotent (“master”) stem cells (hPSC) hold great promise as a therapeutic; however, “teratoma formation” – tumor-like formations that contain stem cells at different levels of maturity in the therapeutic cell product – remains an obstacle. City of Hope scientists and their colleagues used gene editing to insert a “suicide gene,” iC9, into a specific spot in human embryonic stem cell line H1. They showed that undifferentiated H1-iC9 cells were induced to cell death after treatment with the iC9 inducer AP1903. The same treatment, however, had little effect on the viability of differentiated cell lineages, including hematopoietic cells, neurons and islet beta-like cells. The scientists showed that AP1903 selectively removed undifferentiated H1-iC9 cells without affecting their differentiated progeny from a mixed cell population. Their results demonstrate an effective strategy to remove undifferentiated hPSCs before transplantation of a stem cell-derived product, thus preventing teratoma formation. This strategy provides a layer of safety control to reduce the risk of using hPSC-derived cell products in therapy.

iPSC approach to neurological diseases – 10:35 to 11:50 a.m.

Yanhong Shi, Ph.D., director of the Division of Stem Cell Biology Research at Beckman Research Institute of City of Hope

Shi will discuss a study that aims to establish a treatment for Canavan disease, a devastating rare neurological disease that does not yet have a cure. Shi established a way to mass produce human induced pluripotent stem cells (iPSC) that differentiate later or can be used for genetic modification. Her team tested the therapeutic efficacy of the human iPSC-based cellular product in a Canavan disease mouse model. This study could provide an effective therapeutic approach and eventually lead to a cure for Canavan disease and other related neurological diseases.

Engineering of the graft for improved blood stem cell transplantation – 11 to 11:20 a.m.

Angelo A. Cardoso, M.D., Ph.D., director of the Laboratory for Cellular Medicine, Center for Gene Therapy at Beckman Research Institute of City of Hope

Newer technologies are driving the ability to produce cellular products for regenerative medicine. Investigators at City of Hope’s Laboratory of Cellular Medicine focus on applying these methods to patient treatments. New methods range from ways to isolate and genetically modify blood stem cells to removing immune cells that can cause adverse reactions against the recipient after a stem cell transplantation. Some of these emerging technologies and their potential applications will be described.

Neural Stem Cells for Cancer Therapy – 11:25 to 11:45 a.m.

Karen Aboody, M.D., professor in the Department of Developmental and Stem Cell Biology and Division of Neurosurgery at Beckman Research Institute of City of Hope

Aboody and her colleagues have developed a modified human neural stem cell (NSC) line that homes selectively to metastatic tumor sites – whether injected into the brain (for malignant brain tumors), or delivered intravenously (for metastatic cancers) or into the peritoneum (for ovarian and other type of abdominal metastases). These stem cells have already demonstrated safety in several first-in-human gene therapy brain tumor trials.

City of Hope is currently using these NSCs as a platform to deliver the oncolytic virus selectively to tumor sites to overcome the current limitations of oncolytic virotherapy. Oncolytic virotherapy uses viruses to infect cancer cells and replicate continuously until the tumor cell bursts, releasing more virus and amplifying its anti-cancer effect until normal tissue is reached. Importantly, this strategy is effective in destroying tumors even if they are chemo-resistant or radio-resistant. This oncolytic virotherapy can also stimulate the host immune system to recognize cancer cells, supporting a secondary mechanism for tumor killing. However, the efficacy of this therapy has been limited due to fast clearance of the virus en route to the tumor sites, poor penetration and distribution through tumor sites, and undesirable side effects. NSCs can 1) protect the virus from clearance en route to tumor sites, 2) significantly improve penetration and distribution through tumor sites – allowing for increased tumor-killing, and 3) minimize any off-target side effects – potentially improving quality of life during treatment.

City of Hope scientists are currently performing clinical trials using their NSC line to deliver a tumor-restricted oncolytic adenovirus in newly diagnosed glioma patients. They are now using these same NSCs to deliver several novel oncolytic viruses to metastatic cancers in preclinical tumor models to improve both efficacy and safety. While their initial focus is on ovarian cancer, they will also test these NSC-delivered virotherapy treatments for other metastatic solid tumors.

###

About City of Hope

City of Hope is an independent biomedical research and treatment center for cancer, diabetes and other life-threatening diseases. Founded in 1913, City of Hope is a leader in bone marrow transplantation and immunotherapy such as CAR T cell therapy. City of Hope’s translational research and personalized treatment protocols advance care throughout the world. Human synthetic insulin and numerous breakthrough cancer drugs are based on technology developed at the institution. A National Cancer Institute-designated comprehensive cancer center and a founding member of the National Comprehensive Cancer Network, City of Hope is ranked one of America’s “Best Hospitals” in cancer by U.S. News & World Report. Its main campus is located near Los Angeles, with additional locations throughout Southern California. For more information about City of Hope, follow us on Facebook, Twitter, YouTube or Instagram.