T-cell therapy in solid tumours: a perspective from a CAR-T-cell perspective of Ivan Horak, CEO at Tessa Therapeutics

Improvements are coming in a number of different directions. Researchers are discovering new targets that could lead to safer, more-effective therapies. Further genetic circuitries will help the cells persist longer and stay active. And they are finding ways to subvert tumours’ ability to suppress immune responses.

Ivan Horak, chief medical officer and chief scientific officer at Tessa Therapeutics, a CAR-T-cell therapy developer based in Singapore, predicts that the industry will eventually dedicate more effort to childhood cancers of the brain, bone and other organ systems — but only after scientists first solve many of the biological challenges that have precluded the success of CAR-T-cell strategies in solid tumours of any kind. “We have to see some light at the end of tunnel for solid tumours in adults before we aggressively move to children,” he says.

T cells patrol the body in order to find foreign particles on the surface of cells. Such cells could be infected with a virus, for example, or they could be tumour cells that are producing abnormal, cancer-associated proteins. A class of T cells called killer T cells can then destroy the abnormal cells.

Controlling T-cell activity using CAR-T cells wired with the immune system: A case study in relapsed neuroblastoma

The approach has been approved to treat some diseases. But researchers have been pursuing ways to make the treatments safer and more effective, and to expand their use to other diseases.

In one of the new studies, Ahmad Khalil, a synthetic biologist at Boston University in Massachusetts, and his colleagues wired a complex system of 11 DNA sequences into CAR T cells. The resulting genetic circuits can be switched on and off using already-approved drugs, which allows researchers to control when and where the hacked T cells are active, as well as their production of a protein called IL-2 which stimulates immune responses.

The ability to turn the T cells on and off could also help to reduce a phenomenon called T-cell exhaustion, in which T cells become inactive after a prolonged period of stimulation, says Evan Weber, a cancer immunologist at the Children’s Hospital of Philadelphia in Pennsylvania. Some studies have found that giving T cells a ‘rest period’ can reduce T cell exhaustion and boost their overall effectiveness against tumours3.

Sharon Hood states that Emily was motivated by the quest to advance medical progress towards new treatments for the disease. She was always trying to give others a chance to have a chance, even if it was just for herself.

Emily decided to volunteer for an experimental cell therapy that harnesses the power of the immune system when she was 18 years old.

Few CAR-T-cell developers outside of academia have devoted substantial resources to childhood tumors, and no similar products have been approved for under-18s. Most companies focus on adult cancers that are more common and present more lucrative market opportunities.

It makes sense that this finding echoes the findings of others. In the United Kingdom2 and China3, for example, investigators have evaluated anti-GD2 CAR-T cells in small cohorts of people with relapsed neuroblastoma, a paediatric cancer of the nerve tissue. The therapies passed safety tests, but no child experienced tumour shrinkage in either study.

In addition to the CAR construct, the T cells in all three of these trials will get one additional genetic tweak: they will carry an extra protein that mops up growth factors that normally block the ability of T cells to strike their target. These growthfactor-hoovering proteins are designed to turn the usually repressive signal into one that will increase T-cell activity. It’s making a negative into a positive.

Michael Verneris is an associate professor at the University of Colorado School of Medicine in Aurora, Colo., where he has improved the mobility of CAR-T cells. A study of childhood sarcomas5 found that after radiation treatment, cancer cells begin to release signalling molecule interleukin-8. T cells don’t express the IL-8 on their surface, but this molecule is known to attract some immune cells.

Umoja Biopharma in Seattle is an exception. The company’s first clinical-stage candidate is the CAR-T-cell platform developed in the lab of one of the co- founder, chemist Phillip Low at the University of West Lafayette in Indiana. Teenagers and young adults are being studied for a trial. “It’s a technological leap that is playing out for the first time in kids,” says Michael Jensen at Seattle Children’s Hospital and co-founder of Umoja Biopharma.