Natural antioxidant helps improve immune-based therapies by modulating T-cells

Shikhar Mehrotra, Ph.D. and Xue-Zhong Yu, M.D., National Institutes of Health-funded researchers at the Medical University of South Carolina (MUSC), have discovered a way to improve immune-based treatments, such as adoptive T-cell therapy (ACT) and hematopoietic stem cell transplantation (HSCT), by modulating T-cells with thioredoxin, a powerful, naturally occurring antioxidant molecule.

ACT is a cancer immunotherapy in which the patient's own immune cells (T-cells) are engineered to recognize cancer cell-specific markers. First, the patient's blood is collected, then T-cells are removed and genetically modified to attack cancer cells. Finally, the modified T-cells are re-administered to the patient.

ACT is currently used for patients with leukemia and lymphoma. However, a major downside to the treatment is that the re-administered T cells do not live long, leading to relapse.

HSCT is a classic immune-based treatment that requires a donor to supply stem cells, which are then administered to the patient to help them produce more immune cells to fight blood-related diseases, including blood cancers. A severe side effect of HSCT is graft-versus-host disease (GVHD), which occurs when the donor T-cells attack the recipient's healthy tissues instead of diseased cells.

Though they study different models, Mehrotra and Yu are long-time collaborators. Both are dedicated to understanding T-cell function.

"Our collaboration is a common interest in the biology of T-cells and how to manipulate them to benefit different disease conditions," Yu explains.

Mehrotra is an associate professor in the College of Medicine and co-scientific director of the Center for Cellular Therapy at MUSC Hollings Cancer Center. He and his team recently published a study in the Journal of Biological Chemistry that showed that thioredoxin extends the life of adoptive T-cells by neutralizing toxic reactive oxygen molecules (ROS).

Tumor environments have high concentrations of ROS. Without antioxidants such as thioredoxin, ROS will damage the cell and eventually cause cell death.

"Treating anti-tumor T cells with recombinant thioredoxin before adoptive transfer not only imparted high anti-oxidant capacity," explained Mehrotra.

"It also metabolically programmed these cells to withstand nutrient competition with the tumor - which resulted in better tumor control."

The team at MUSC used a strain of mice that overexpress thioredoxin and performed a standard ACT procedure. They observed increased T-cell viability and antitumor activity from mice overexpressing thioredoxin.

They confirmed the findings by engineering human T-cells to overexpress thioredoxin and again observed prolonged T-cell lifespan at the site of the tumor. The results suggest that treating human T-cells with thioredoxin before administration will increase cell viability and improve the anti-tumor effect of ACT in patients.

Yu is a professor in the College of Medicine and S.C. SmartState Endowed Chair in Cancer Stem Cell Biology and Therapy. Yu and his team at MUSC study the development of graft-versus-host disease (GVHD) in recipients of HSCT.

Using a mouse model, Yu's lab tested the effect of thioredoxin on donor T-cells, and the results were published in the Journal of Clinical Investigation. Like Mehrotra's study with adoptive T-cells, Yu's study found that thioredoxin's antioxidant effect decreased toxic ROS in donor T-cells, made them less reactive to the patient's healthy tissues, and thereby prevented development of GVHD.

"Thioredoxin is a natural product with no toxicity. We can use it to fine tune T-cell activation in a way that will reduce graft-vs-host disease but maintain anti-tumor effect," Yu reports on the new finding.

Mehrotra and Yu plan to continue to work closely to develop this new advancement in T-cell immune therapy.

The next step for both projects is to induce human tumors into mice and test the effect of thioredoxin-treated T-cells in both ACT and HSCT models. This will determine if it can be moved to clinic to be tested on patients.

Sofi MH, Wu Y, Schutt SD, Dai M, Daenthanasanmak A, Heinrichs Voss J, Nguyen H, Bastian D, Iamsawat S, Selvam SP, Liu C, Maulik N, Ogretmen B, Jin J, Mehrotra S, Yu XZ.
Thioredoxin-1 confines T cell alloresponse and pathogenicity in graft-versus-host disease.
J Clin Invest. 2019 May 2;130:2760-2774. doi: 10.1172/JCI122899.

Most Popular Now

Regorafenib to be tested in brain cancer patients …

Bayer announced that the regorafenib arm of the platform trial "GBM AGILE" (Glioblastoma Adaptive Global Innovative Learning Environment) opened for enrollment in the US ...

Sanofi and Google to develop new healthcare Innova…

Sanofi and Google will establish a new virtual Innovation Lab with the ambition to radically transform how future medicines and health services are delivered by tapping i...

Bristol-Myers Squibb provides update on pending me…

Bristol-Myers Squibb Company (NYSE: BMY) today provided an update on the approval process and timeline for the Company’s pending merger with Celgene Corporation (NASDAQ: ...

Breztri Aerosphere (PT010) approved in Japan for p…

AstraZeneca announced that Breztri Aerosphere (budesonide/glycopyrronium/ formoterol fumarate), formerly PT010, has been approved in Japan as a triple-combination therapy...

Artificial DNA can control release of active ingre…

A drug with three active ingredients that are released in sequence at specific times: Thanks to the work of a team at the Technical University of Munich (TUM), what was o...

Human-on-a-chip model tests cancer drug efficacy a…

A reconfigurable "body-on-a-chip" model could transform drug development by simultaneously measuring compound efficacy and toxicity, for both target cells and other organ...

Pathogen engineered to self-destruct underlies can…

A team of investigators has developed a cancer vaccine technology using live, attenuated pathogens as vectors. A feature of the vaccine causes these bacteria to self-dest...

Novartis successfully completes acquisition of Xii…

Novartis today announced that it has completed its acquisition of Xiidra® (lifitegrast ophthalmic solution) 5%, the first and only prescription treatment approved to trea...

LEO Pharma completes the acquisition of Bayer’s pr…

LEO Pharma and Bayer announced today the achievement of the relevant closing conditions to allow the transfer of Bayer’s global prescription dermatology business to LEO P...

How gastric stem cells fight bacteria

Stem cells are not only key players in tissue regeneration, they are also capable of taking direct action against bacteria. This is the finding of a study conducted by re...

New study showing drug prolongs life for patients …

Women with ovarian cancer who have undergone four or more rounds of chemotherapy typically haven't had much hope that another treatment option will lengthen their lives i...

Pfizer completes acquisition of Therachon

Pfizer Inc. (NYSE: PFE) announced the successful completion of its acquisition of the privately held clinical-stage biotechnology company Therachon Holding AG. Under the ...