Genetically engineering disease-fighting cells

November 08, 2016

The human body produces T cells to recognize and fight disease. Each T cell has a unique T cell receptor (or TCR) on its surface that surveils small fragments of proteins presented by other cells. Upon detecting evidence of cancer or infection, a subset of T cells binds the diseased cells and orchestrates their elimination. When tumors and infections cannot be eradicated naturally, researchers employ immunotherapies to boost the immune system's effectiveness.

By inserting genes encoding a tumor-specific TCR into a patient's T cells, researchers can engineer a large population of T cells to target tumor cells. This approach, called TCR gene therapy, has yielded clinical successes where conventional cancer treatments have failed. However, TCR gene therapy is not without risk. The introduced receptor can become tangled with the resident receptor in each engineered T cell, causing some of these cells to attack healthy cells. A new technique developed by Caltech researchers prevents this from happening, increasing the safety of TCR gene therapy.

The technique, called domain swapping, was developed in the laboratory of David Baltimore, president emeritus and the Robert Andrews Millikan Professor of Biology. A paper describing the findings appears in the November 8 issue of the journal eLife.

The specificity of the TCR in each T cell results from the pairing of two protein chains--called an alpha chain and a beta chain--each of which has constant domains (shared between all TCRs) and variable domains (unique to each T cell). Normally, each T cell encodes only one alpha chain and one beta chain, which pair to form a single TCR. In TCR gene therapy, the introduction of genes encoding a tumor-reactive TCR results in T cells that express two alpha chains and two beta chains, with four possible pairings. This non-physiological situation poses a risk of autoimmunity.

"As T cells are produced, the immune system 'auditions' them, eliminating those that react to healthy cells and selecting those with potential to recognize diseased cells," says Michael Bethune, senior postdoctoral scholar in biology and biological engineering, and lead author on the study. "However, in T cells engineered to express a second TCR, the introduced chains can mispair with the resident chains, resulting in TCRs with unintended and unpredictable specificity. These mispaired TCRs are not auditioned by the immune system, and some will target healthy cells causing autoimmunity." Indeed, up to 90 percent of mice administered TCR-engineered T cells develop autoimmune disease, and cultured human T cells that are engineered to express two TCRs also react with healthy cells.

The group's solution was to generate hybrid genes encoding TCR chains with their alpha and beta constant domains swapped in a compensatory fashion. When correctly paired, these domain-swapped TCRs retain all of the domains necessary to function. Indeed, the group found that domain-swapped TCRs and unmodified TCRs both function in human T cells, and they prevented tumor growth in mice to a similar extent. However, whereas unmodified TCRs mispaired with resident TCR chains in both mouse and human T cells, and caused autoimmunity in mice, domain-swapped TCRs did not.

"Mispairing between domain-swapped chains and resident chains results in TCRs that lack domains needed for functional assembly of the TCR complex," Bethune says. "This ensures that only correctly paired domain-swapped TCRs function at the surface of the cell."

In addition to preventing mispairing, domain-swapped TCRs highlight a surprising robustness to the function of the TCR complex. The Caltech group teamed with Mike Kuhns at the University of Arizona to determine that domain-swapped TCRs assemble in a similar manner to unmodified TCRs despite significant structural rearrangement of the constituent protein chains. Domain-swapped TCRs may be useful tools for further study of the structure and function of the TCR complex.

Finally, in collaboration with Wolfgang Uckert at the Max Delbrück Center for Molecular Medicine in Berlin, the researchers showed that domain-swapped TCRs were expressed at higher levels on the T cell surface when the resident TCR genes were silenced.

"Our paper focuses on the increased safety afforded by domain-swapping, but combining these two solutions may result in a therapy with improved safety and efficacy compared to current practice," Bethune says.
-end-
The work, titled "Domain-swapped T cell receptors improve the safety of TCR gene therapy," was funded by the National Institutes of Health and the Prostate Cancer Foundation Challenge Award. In addition to Bethune and Baltimore, other Caltech-affiliated coauthors on the paper are alumnus Marvin Gee (BS '13), alumna Meghana Pagadala (BS '16), former postdoctoral scholar Jing Zhou, and James Heath, the Elizabeth W. Gilloon Professor and Professor of Chemistry.

California Institute of Technology

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.