While our immune system is effective at detecting and fighting abnormal cancer cells and infections, tumours have developed evasive tactics, for example by producing signal molecules to suppress immune responses. The Marie Skłodowska-Curie Actions supported BITCAT project developed a proof-of-principle for drugs which overcome immune suppression, especially in cases of solid tumours. The team harnessed the underlying genetics responsible for regulating the immune system, using genetically engineered, artificial immune receptors called chimeric antigen receptors (CARs). “CARs were introduced into immune cells, mostly T-cells, and showed promise as a first step towards a treatment for solid tumour diseases, especially malignant glioblastoma,” says principle investigator Jana Burkhardt from McMaster University, which hosted the bulk of the project. Three publications are currently in development for peer review.
In contrast to classic treatments for cancer such as radio- or chemotherapy, immunotherapeutic methods promise drugs which target only molecules associated with particular tumours. While some tumours are more readily recognised by the immune system, such as melanomas, other tumours are not. Malignant glioblastoma, a common and devastating brain tumour, is known for its resistance to classic and novel therapeutic interventions. One reason for this is a lack of knowledge about tumour-specific proteins called antigens. Antigens can act as signals for immune systems to recognise and attack and so can be targeted by therapeutic drugs. Cells communicate by sending signalling molecules called ligands which are read by other cells with appropriate receptors, but cancer can use ligands to inhibit immune responses. For example, increasing the production of the PD-L1 ligand for the PD1-receptor (on T-cells) inhibits the T-cell-mediated immune response. BITCAT set out to counter this with CARs – artificially manufactured genetic elements in ligands that introduce activating signals into T-cells, boosting their immune response. While widely used clinically, obstacles remain to using CARs with solid tumours, such as malignant glioblastoma. "Selecting suitable, target tumour antigens is still problematic as they need to be distinguishable from healthy cells,” explains Burkhardt. Using genetic data from bioinformatic databases, BITCAT identified a number of target antigens on the surface of malignant glioblastoma cells. Two suitable ligands, which bind those antigens, were chosen to have their genetic sequence engineered, forming the basis of the CAR therapy. Glioblastoma tumour cells were exposed to these CAR T-cells resulting in the highly efficient killing of tumour cells, with minimum impact on healthy tissue. “We also confirmed the therapeutic effect in ovarian and breast cancer cells, suggesting a more general relevance for the selected target molecules or ligands,” adds Burkhardt.
Towards targeted cancer therapy
The CAR therapy was applied to human cells transplanted into animal models with depleted immune systems. Two groups of eight tumour-bearing animals were treated with CAR T-cells engineered with either ligand. Survival was increased by 50 % and 63 %, respectively, over at least 100 days, compared to control groups given either treatment with unmodified T-cells or T-cells modified with a CAR sequence but missing the ligand sequences. About half of the treated animals showed nearly complete remission – very rare with glioblastoma. “We are very happy about these results. Glioblastoma tops the list of cancer-related causes of death in children, and survival rates of 12-16 months following diagnosis have hardly improved since the 1970s. We are hopeful of our results making a real clinical difference,” says Burkhardt. The project results have already piqued the interest of several potential users, such as University Hospital Leipzig’s Neurosurgery Department.
BITCAT, glioblastoma, cancer, immune system, tumour, molecules, genetic, ligands, receptors, T-cells, antigens