NOV 11, 2016 10:29 AM PST

Genetically Engineered T Cell Armies to Fight Cancer

WRITTEN BY: Kara Marker
Scientists are hard at work improving immune cells called T cells, which are naturally designed to recognize and target foreign invaders. They are vulnerable to error, though, and tinkering with their cell components can often reduce the amount of mistakes they make. A new technique developed from scientists at the California Institute of Technology now produces the best-ever engineered T cells that can be used to treat cancer.
Artist's concept of a domain-swapped T cell receptor (TCR) engaging a peptide presented by a tumor cell on a major histocompatibility complex (MHC) molecule. Credit: Caltech
T cells are unique. Each immune cell as a T cell receptor (TCR) that recognizes specific antigens, so two T cells with different TCRs recognize different antigens and are used to fight different diseases. The specificity of an individual T cell is written by the pairing of two protein chains: alpha and beta. The two chains both have domains that are “constant” and “variable,” meaning domains that are reserved throughout all T cells and domains that are unique to one specific T cell, respectively.

Cells specifically designed to present antigens to T cells gather parts of a foreign cell to present to T cells for analysis. If a T cell deems the antigen worthy of attack, whether it’s pathogenic or cancerous, an immune response ensues. Therefore, without the effectiveness of the TCR, T cells cannot accurately recognize antigens that need to be attacked. Demonstrated in the new technique from CalTech, scientists have developed immunotherapies to boost the immune response as a way to treat cancer.

The new technique, called domain swapping, was developed in the laboratory of David Baltimore, president emeritus and the Robert Andrews Millikan Professor of Biology. But before domain swapping, there was TCR gene therapy.

TCR gene therapy was implemented to take control over TCR recognition of antigens by manually inserting genes encoding a specially-designed target to a particular tumor cell type. This experimental therapy resulted in T cells that expressed two alpha chains and two beta chains, meaning four possible pairings, rather than natural T cells that express just one of each chain.

While this technique did provide scientists the capability to create an army of specialized T cells to target a specific type of cancer, certain risks also accompanied the new technology. Autoimmunity occurred as a serious side effect, after genetically-inserted TCR chains intertwined with the innate receptors already present in the T cell. This reaction caused T cells to attack healthy cells that were neither cancerous nor pathogenic.

"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," said lead author Michael Bethune, PhD. "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."

Bethune and his team fixed the failures of TCR gene therapy to create the domain swapping technique, which is void of the dangerous autoimmune reactions. Whereas 90 percent of mice given TCR-engineered T cells via TCR gene therapy exhibited autoimmune reactions, domain swapping proved to be a much safer, autoimmune-free treatment.

Domain swapping bypassed autoimmunity because of hybrid genes Bethune and his team manufactured in the lab. These genes encode TCR chains with alpha and beta constant domains already swapped in a “compensatory fashion.” The new domain swapping technique, Bethune said, “ensures that only the correctly paired domain-swapped TCRs function at the surface of the cell.”

With his findings, Bethune has created essentially the most error-free technique for genetically engineering top-notch T cells to target cancer. In the future, this technique could be personalized to individual cases of cancer, creating T cells specifically designed to fit a patient’s needs.

The present study was published in the journal eLife.
 


Source: California Institute of Technology
About the Author
  • I am a scientific journalist and enthusiast, especially in the realm of biomedicine. I am passionate about conveying the truth in scientific phenomena and subsequently improving health and public awareness. Sometimes scientific research needs a translator to effectively communicate the scientific jargon present in significant findings. I plan to be that translating communicator, and I hope to decrease the spread of misrepresented scientific phenomena! Check out my science blog: ScienceKara.com.
You May Also Like
DEC 15, 2019
Genetics & Genomics
DEC 15, 2019
A More Precise Version of CRISPR/Cas9 is Created
A more accurate version of Cas9 has been created, reducing the number of off-target effects. It may be better suited for use in gene therapy....
DEC 15, 2019
Genetics & Genomics
DEC 15, 2019
Gene-Editing Breakthrough for Cervical Cancer
Researchers at the The Menzies Health Institute Queensland have found a way to use gene therapy CRISPR-Cas9 to treat cervical cancer. The first treatment o...
DEC 15, 2019
Genetics & Genomics
DEC 15, 2019
Identifying the Origins of Modern Humans
New research reported in Nature has suggested that modern humans come from Southern Africa, where they lived for approximately 70,000 years....
DEC 15, 2019
Genetics & Genomics
DEC 15, 2019
Evaluating the Genetic Damage Caused by Cancer Treatments
Now that we know more about the impact of some cancer treatments, they can be applied optimally....
DEC 15, 2019
Genetics & Genomics
DEC 15, 2019
Mining 'Junk' DNA for New Cancer Therapeutics
There are vast portions of the genome that don't code for protein, but researchers are learning more about how important they are....
DEC 15, 2019
Genetics & Genomics
DEC 15, 2019
Promising New Treatment for Mitochondrial Disease Found in Fruit Flies
Researchers at the University of Cambridge have discovered a protein in fruit flies that can reverse the effects of harmful mutations in mitochondrial gene...
Loading Comments...