An NCI-designated Comprehensive Cancer Center
By Letisia Marquez | September 27, 2018
Stephen J. Forman, M.D., the Francis and Kathleen McNamara Distinguished Chair in Hematology and Hematopoietic Cell Transplantation and leader of City of Hope’s Hematologic Malignancies and Stem Cell Transplantation Institute, is now an official member of the Parker Institute for Cancer Immunotherapy, which brings together the best scientists, clinicians and industry partners to work collaboratively on cancer immunotherapy. 
The research team at City of Hope includes Christine Brown, Ph.D., Heritage Provider Network Professor in Immunotherapy and associate director of City of Hope’s T Cell Therapeutics Research Laboratory; Xiuli Wang, M.D, Ph.D.Saul Priceman, Ph.D.Elizabeth Lihua Budde, M.D., Ph.D.; and Vanessa Jonsson, Ph.D.
As part of the membership, the Parker Institute will support Forman's research that focuses on chimeric antigen receptor (CAR) T cell therapy. In this approach, a patient’s own immune T cells are collected from the blood, genetically engineered to recognize and kill cancer cells, and reintroduced into the patient to fight the disease.
City of Hope is an international leader in CAR T cell therapy — the institution has one of the most comprehensive CAR T cell programs, targeting lymphoma, leukemia, myeloma, glioblastoma and other cancers, and currently has 15 ongoing clinical trials, with trials for prostate cancer and HER2-positive breast cancer with metastatic brain disease and multiple myeloma scheduled to open later this year.
The Parker Institute-funded projects will focus on creating best-in-class T cells by using specific CARs, their signaling properties, their functional regulation and other aspects like gene-editing technologies. 
In particular, the institute will support the following projects:

Vanessa D. Jonsson’s research on how to use data to improve the length of response in CAR T patients

Although CAR T therapy is effective against certain cancers, only a subset of patients exhibit durable responses. More research is needed to understand how a cancer escapes CAR T therapy and how to design successful immunotherapies for long-term cancer control.
Jonsson, Ph.D., an assistant professor at City of Hope whose research focuses on computational immuno-oncology within City of Hope’s T cell therapeutics research, will develop will develop data-driven mathematical methods to analyze the complex interactions between individual patients’ evolving cancer and immune system over the course of CAR T treatment.
The goal is to design intervention strategies that regulate immunological feedback systems to control the strength and timing of the anti-cancer response and to stop the cancer from returning.
They will do this by integrating tumor genomics and longitudinal immunological data collected from City of Hope’s CAR T blood and solid tumor trials. 
The key analysis that has shed light on this study is that of glioblastoma patient Richard Grady, M.D., who was treated with CAR T therapy on a protocol designed by Brown and Behnam Badie, M.D., Ph.D. The treatment resulted in Grady’s cancer regressing for 7.5 months. Jonsson and Brown have closely examined the underlying cancer-immune processes that led to the cancer regressing, and subsequently to progression and then escape from CAR T therapy.
“The complex interplay between tumor, host and environmental factors impacts the cancer-immunity cycle, and its understanding will underlie the success of durable immunotherapy,” Jonsson said.

Saul Priceman’s research on radiation, CAR T therapy and prostate cancer

Led by Priceman, assistant research professor in City of Hope’s Department of Hematology & Hematopoietic Cell Transplantation, this research project will test the effects and tumor-killing potential of radiation therapy, including a radioactive isotope Radium-223, when it’s combined with CAR T cells in prostate cancer that has metastasized in animal models.
Radiation therapy can effectively treat prostate cancer, but is typically short lived. To that end, City of Hope has developed a prostate-specific CAR T cell that targets the protein known as prostate cancer stem cell antigen (PSCA) that is abundantly expressed in prostate cancer and bone metastatic lesions, or cancer spots in the bone.
The clinical trial testing the prostate-specific CAR T is expected to start in late 2018 for patients with bone metastatic prostate cancer. But as Priceman explained, “while we think our therapy may have promise in this disease, prostate cancers have robust suppressive mechanisms that prevent immune responses, and is one of the major reasons that patients have, to date, responded poorly to immunotherapy.”
Priceman is thinking ahead and aims to combine CAR T cells with other therapies such as radiation to bolster the cells’ effectiveness against prostate cancer.
“We believe this combinatorial approach will synergize to generate a profound local and systemic anti-tumor immunity to control advanced disease,” he said.

Xiuli Wang’s research targeting tumor stem cells in hematological malignancies

With the aim of targeting tumor stem cells, a distinct and highly motile and aggressive subpopulation of cells that reside within a tumor, Xiuli Wang, Ph.D., research professor in City of Hope’s Department of Hematology & Hematopoietic Cell Transplantation, and her team constructed an improved CAR for CD44v6, a type of cell surface antigen that is overexpressed in acute lymphoblastic leukemia, acute myeloid leukemia and multiple myeloma. Preliminary test results in Wang’s lab demonstrate that targeting CD44v6 with a CAR T cell has the potential to treat various blood cancers.
With the Parker Institute’s support, Wang will now develop and evaluate the CD44v6 CAR as a therapy for other cancers.
She will test various combinations of a CAR molecular design to determine which one is the most effective in eradicating cancer cells. In addition, researchers will combine CD44v6 with other CARS to decrease tumor relapse and enhance the duration of remission.
“City of Hope is constantly looking for new CAR T therapies that can be used against more cancers, and that is our goal with this project,” Wang said.