synNotch: Intelligent Cell Therapies against Glioblastoma and other Solid Cancers

Although I don’t normally publish articles related to pre-clinical research, this news seemed very interesting to me and I thought I’d share it immediately.
Immunotherapy has made great strides but is still not very effective against solid tumors such as glioblastoma multiforme. Now researchers from the University of California San Francisco (UCSF) have just published two related articles in Science Translational Medicine in which they demonstrate how to design intelligent immune cells effective against solid tumors. The approach could be ready for clinical trials in the near future.

The technique was tested on glioblastoma, the most aggressive form of brain cancer that affects adults and children and which has so far failed to respond to immunotherapies. The team showed that the new system, which uses a two-step process to hunt cancer cells, is able to completely eliminate human patient-derived glioblastomas implanted in the brains of mice without producing side effects and without risk of recurrence.

This technique is also able to overcome a problem known as “T-cell exhaustion”: the traditional CAR-T cells or the reprogrammed immune cells that attack the tumor tend to tire and lose their strength when engaged in a long fight against the tumor. These new cells, on the other hand, remain strong throughout the entire fight, conserving their energy.

Glioblastomas are a particularly tragic case in which patients have so far been unable to benefit from CAR-T lymphocytes. Until now, UCSF researchers had identified a molecule that is frequently found in glioblastoma cells. The CAR-T cells designed by the researchers targeted this molecule but since glioblastoma is multiform and not all glioblastoma cells have this molecule, some cancer cells are able to evade CAR-T therapy and eventually the glioblastoma returns. Furthermore, since some molecules are also found in other parts of the body, it is possible that the CAR-T molecules also damage healthy tissues.

The researchers then devised a new system called synNotch, a customizable molecular detector that allows scientists to program CAR-T cells to detect specific molecules found on the surface of cancer cells, ensuring that CAR-T’s only attack when they encounter molecules that they are programmed to attack. The team adopted a new two-step approach. The first uses synNotch to give CAR-T cells the ability to carefully judge whether they are in a tumor or elsewhere in the body. Once the CAR-T cells understand that they are in the tumor, the second set of sensors is activated, which allow the CAR-T cells to detect and kill the glioblastoma cells based on different molecules present in the brain tumor. This two-step process leads to more complete coverage and destruction of cancer cells while preventing cancer cells from accumulating simple mutations that would allow them to evade CAR-T.

The experiments described in the paper show that this strategy is effective. In mice with human patient-derived glioblastomas, CAR-T synNotch were able to completely eliminate the tumor. These same tumors were not defeated by normal T cells or traditional CAR-T cells. There were also no signs of side effects.

The second article describes how you apply the synNotch system to other now intractable diseases such as mesothelioma caused by asbestos and ovarian, pancreatic and testicular neoplasms. A surprising result of both studies is that the synNotch CAR-Ts maintained stable levels of activity throughout the entire cancer elimination process, avoiding the problems of “T-cell exhaustion” that hinders traditional CAR-T therapies.

Let us hope that clinical trials with CAR-T synNotch will start soon in order to understand if they will also be effective on humans. The for CUSP-ND for Emanuele fundraising campaign continues. Share the link in order to spread the word and raise awareness on as many people as possible!