Projects we fund

Overview

For many neuroblastoma patients, treatments use high amounts of different chemotherapies which do not result in a cure. For these patients treatments that work in a different way are needed. T-cells are special immune cells which can discriminate infected cells from healthy cells. They patrol the body looking for infected cells. Once they spot infected cells, they kill them. In addition, once they have even when the infection is cleared, they constantly remain on guard to stop the infection from returning.

T-cells usually ignore cancer cells: the cancer cells are not usually noticed by T-cells as they look similar to healthy cells. We can tackle this problem by ‘re-programming” T-cells so they can recognize and kill cancer cells. These re-programmed T-cells are called chimeric antigen receptor T-cells (CAR T-cells) and work very well against blood cancers. However, from clinical studies, we see that neuroblastoma cancers shield themselves from CAR T-cells. We need to equip CAR T-cells with additional abilities (a bit like a power-up in a video game) to overcome this immune shield.

Dr Karin Straathof and her team will develop these ‘powered-up’ CAR T-cells by further re-programming of CAR T-cells making them secrete IL-12, a powerful immune hormone. IL-12 causes inflammation and changes the tumour ecosystem: it converts the cells in the tumour from blockers of CAR-T cells to helpers of CAR-T cells. However, since IL-12 is very powerful, if a lot of it leaks outside the tumour where it can easily send immune cells everywhere into overdrive and make patients very sick. The challenge is to find a sweet spot: make CAR T-cells secrete just enough IL-12 to reset the tumour ecosystem while not enough leaks out so the patient does not get sick. The team have made modified versions of IL-12 which are tuned down. In early experiments, the team have shown that even the most tuned-down versions of IL-12 still have powerful anti-tumour effects but do not cause side-effects. In this project, Dr Straathof and her team will continue to study these new IL-12s and pick the one that will work best in patients. The project will use mouse models who spontaneously develop tumours very similar to neuroblastoma found in patients. In addition, the project will directly test CAR T-cells on intact pieces of neuroblastoma tumour from patients kept alive in a culture system for a few days outside the body. This work will allow the introduction of IL-12 into next-generation CAR T-cell clinical studies for neuroblastoma and other children’s cancers.

What difference will this project make?

Clinical trial data shows the potential of CAR T-cells to seek out and eliminate neuroblastoma tumours cells. The overall goal is to now develop ‘powered-up’ CAR T-cells which are able to achieve complete and durable responses in patients with neuroblastoma. Here, the team plan to develop such a powered-up CAR T-cell design and generate the required data set to incorporate the IL-12 power-up in a clinical trial they are developing for patients with neuroblastoma. Moreover, Dr Straathof and her team will use the best available and novel testing platforms to predict safety and ability to induce responses in patients. While used here for neuroblastoma, both this testing approach and the concept of using tuned-down IL-12 to power-up CAR T-cells may also be applied to other childhood cancers.