In two related papers published in Science Translational Medicine, researchers at UCSF have showcased how to engineer immune cells that are effective against solid tumours.
CAR T cell therapies
The ability to genetically modify T cells armed with chimeric antigen receptors (CARs) has shown unprecedented clinical efficacy in treating certain haematological malignancies. However, the development of effective CAR T therapies for solid cancers remains a challenge. This has largely been due to the lack of high-quality antigen targets as well as poor tumour infiltration and activity. Most antigens that have been targeted by CAR T cells are tumour-associated, rather than tumour-specific. In other words, they are not only highly expressed on the tumour but also expressed at low levels on normal tissues. This in turn can lead to severe on-target/off-tumour toxicities. As a result, there is a clear need for new tumour recognition strategies that can overcome existing challenges of specificity and heterogeneity to increase therapeutic benefit of these therapies in solid cancers.
To address these challenges, researchers previously developed synthetic Notch (synNotch) CAR T cells targeting solid tumour antigens. These circuits require the recognition of both priming and killing antigens. They can be thought of as “if-then” circuits as they will only execute CAR-directed killing if they are first primed by the synNotch ligand. In these recent studies, researchers used these circuits, carefully choosing the priming and killing antigens, to improve therapy specificity.
Cell therapies for solid cancers
In the first paper by Chloe et al, researchers tested the system in glioblastoma – the most aggressive form of brain cancer. To date, researchers have yet to successfully treat this cancer with immunotherapies due to the complexity of the tumours. Using this new system, the researchers were able to completely clear patient tumours from the brains of mice. Most importantly, they found no dangerous side effects or high risk of recurrence.
In the second paper by Hyrenius-Wittsten et al, the team were able to show that various components of this system could be switched out to target other cancers in the body. They specifically identified ALPPL1 as a tumour-specific antigen that researchers could use to target a spectrum of solid tumours, including mesothelioma and ovarian cancer. This molecule is rarely found in healthy tissue. The team found during tests of a synNotch circuit targeting ALPPL1 that CAR T cells were able to recognise and kill mesothelioma and ovarian cancer cells with precision.
In addition, both papers, found that these T cells maintained a long-lived memory and non-exhausted phenotype. In other words, the CAR T cells maintained stable levels of activity throughout the cancer killing process. The researchers found that synNotch CAR T cells remained in standby mode, conserving energy, until they identified the cancer.
Hideho Okada, Director of the Brain Tumor Immunotherapy Center at UCSF, stated:
“These findings address all critical challenges that have been in the way of developing immunotherapies for patients who suffer from these cancers.
This science is ready to move towards clinical trials.”
Image credit: By Science Photo Library – canva