Drug profiling and gene scissors open new avenues in immunotherapy

Researchers have discovered ways to boost CAR T-cell therapy.

According to a study published in the Blood journal, drug profiling and the CRISPR-Cas9 gene editing method have opened new avenues in the development of CAR T-cell therapy, used to treat leukaemia and lymphoma.

The study, carried out collaboratively by the University of Helsinki and the Finnish Red Cross Blood Service, surveyed the effect of more than 500 cancer drugs on the function of CAR T cells.

CAR T-cell therapy has yielded excellent results in the case of certain blood cancers and lymphomas resistant to other forms of treatment. In CAR T-cell therapy, patient’s own T cells (immune cells) are extracted from blood stream, after which they are engineered to express chimeric antigen receptors (CAR), which activate the cells to destroy cancer cells after identification.

“In spite of good treatment outcomes, the therapy is not effective in all patients. CAR T-cell therapy can also have adverse effects,” says Professor Satu Mustjoki from the University of Helsinki.

The drug profiling highlighted a class of drugs known as SMAC mimetics, which in laboratory tests sensitised cancer cells to CAR T cells. At the same time, drugs that inhibit the function of CAR T cells were found, which have potential in the treatment of adverse effects.

By employing the CRISPR gene editing method, the researchers investigated which mechanisms impact the sensitivity of cancer cells to CAR T cells. A process known as death receptor signalling and the FADD gene required to initiate this process were found to be vital for CAR T-cell function. The CRISPR method also revealed that the mechanism of SMAC mimetics is based on the initiation of death receptor signalling.

Based on the test results, SMAC mimetics could potentially be used to further sensitise cancer cells to cell death caused by CAR T cells. If the promise of the drugs identified in the preliminary profiling is upheld by further research, SMAC mimetics could be utilised in improving the outcome of CAR T-cell therapy.

“The study provides an extensive dataset on the effect of cancer drugs on the function of T cells, which are essential to immunotherapies. This data can be put to use when planning the combination of cancer drugs with therapies activating the immune system,” says doctoral candidate Olli Dufva from the University of Helsinki.

The study received funding from the Cancer Foundation, the Sigrid Jusélius Foundation and the Relander Foundation. The study was carried out under the iCAN Digital Precision Cancer Medicine flagship platform funded by the Academy of Finland.

Further information:

Olli Dufva, BM, University of Helsinki
Phone: +358 50 328 5692
Email: olli.dufva@helsinki.fi
Twitter: @ollidufva

Satu Mustjoki, professor, University of Helsinki
Phone: +358 40 552 1606
Email: satu.mustjoki@helsinki.fi

Twitter: @hruh_research

Reference: Olli Dufva, Jan Koski, Pilvi Maliniemi, Aleksandr Ianevski, Jay Klievink, Judith Leitner, Petri Pölönen, Helena Hohtari, Khalid Saeed, Tiina Hannunen, Pekka Ellonen, Peter Steinberger, Matti Kankainen, Tero Aittokallio, Mikko A. I. Keränen, Matti Korhonen, Satu Mustjoki. Integrated drug profiling and CRISPR screening identify essential pathways for CAR T cell cytotoxicity. Blood, December 12, 2019. https://doi.org/10.1182/blood.2019002121