City of Hope's CEACAM Research Comes Full Circle with New CAR T Approach

February 9, 2018 | by Jyoti Madhusoodanan

In the 1960s, scientists comparing samples of colon cancer to adjacent healthy tissue identified a single protein that was unique to the diseased specimens. This particular protein, later dubbed carcinoembryonic antigen (CEA), is now known to be produced in over 70% of all human cancers. And it’s not just cancer. CEA derives its name because it was isolated from embryonic tissue samples, where it’s seen early in development and disappears later—only to re-emerge when a tumor starts to form. 
 
Clinical tests for serum CEA levels were developed shortly after its discovery. More than 50 years later, CEA remains one of the most widely used clinical markers of cancer. As the diverse roles of CEA and its family members, known as CEA-related cell adhesion molecules (CEACAMs), have grown clearer, researchers at City of Hope are working on a new wave of clinical tools and therapies.
 
CEACAM5, in particular, has been identified as a protein frequently expressed on the surface of prostate cancer cells. Researchers think that CEACAM5 may be an ideal therapeutic target for a specific type of prostate cancer known as lethal neuroendocrine prostate cancer (NEPC). There are currently no effective therapies for NEPC and the average survival is less than one year from the time of diagnosis. 
 
Now, the Prostate Cancer Foundation (PCF) has awarded a $1 million grant to support collaborative research on the use of CEACAM5-directed CAR T therapy for the treatment of NEPC. The shared grant will be split between UCLA and City of Hope over two years.
 
Saul Priceman, M.D. - Profile Photo Saul Priceman, Ph.D.
The research team includes City of Hope’s Stephen J. Forman, M.D., the Francis & Kathleen McNamara Distinguished Chair in Hematology and Hematopoietic Cell Transplantation, and Saul Priceman, Ph.D., assistant research professor in the Department of Hematology & Hematopoietic Cell Transplantation. Other members include Owen Witte, M.D., who is leading the study, and John Lee, M.D., both from the University of California Los Angeles (UCLA).
 
The team will test optimized CEACAM5-targeted CAR T cells in preclinical models for efficacy against NEPC and to identify potential toxicities. Tumors that are resistant to CEACAM5-targeted CAR T cells will be evaluated to determine mechanisms of resistance.
 
To minimize toxicities caused by targeting non-tumor cells that express low levels of CEACAM5, a “dual-gate” CAR T strategy will be developed in which T cells will be uploaded with TROP2-inhibitory CARs in addition to the CEACAM5-activating CARs. The TROP2-inhibiotory CAR will block the T cells from killing any cells that also express TROP2, a protein overexpressed on many normal and cancer cell types, but downregulated in NEPC.
 
If successful, the result will be CAR T cells that selectively target NEPC but not normal cells.
 
“We are thrilled to be working with the UCLA team on this PCF-funded project,” Priceman said. “We are close to initiating a CAR T cell clinical trial for patients with advanced prostate adenocarcinoma that was developed here and also funded by PCF. The successful completion of this new project will identify another unique CAR T cell for the lethal neuroendocrine subtype of prostate cancer, and we envision these two clinical programs will increase the number of patients with advanced disease that may benefit from CAR T cell therapy in the near future."
 
The grant brings full circle City of Hope’s early work with CEA.
 
Much of the ongoing research on CEA, CEACAM5 and other related proteins was facilitated by early studies conducted at City of Hope. In the early 1980s, John Shively, Ph.D.; Arthur D. Riggs, Ph.D., the Samuel Rahbar Chair in Diabetes & Drug Discovery; and other City of Hope researchers were the first to generate a fully functional mouse antibody against CEA by expressing the protein in the common laboratory bacteria E.coli, purifying and reconstituting the constituent peptide chains. Prior to this, mammalian proteins could only be made using immortalized cell cultures known as hybridomas. The ability to make these mouse antibodies in bacteria laid the grounds for modern immunobiology, enabling the large-scale production of antibodies for research and therapeutics.
 
“We owe a huge debt of gratitude to pioneering City of Hope researchers like Dr. Riggs and Dr. Shively,” said Priceman. “Their foundational work with carcinoembryonic antigen informs the work of not only our team, but cancer researchers all over the world.”
 
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