A pan-checkpoint inhibition strategy programmed into CAR T-cells.
Autolus Limited, a clinical-stage biopharmaceutical company focused on the development and commercialisation of next-generation engineered T-cell therapies, announced that data were presented today for its pan-checkpoint blocking technology at the American Society of Hematology (ASH) 59th Annual Meeting in Atlanta.*
Checkpoint inhibition is a common defence mechanism used by cancer cells to evade killing by Tcells. The presentation by Dr Martin Pulé, CSO and founder of Autolus, shows that CAR T-cells expressing an engineered adapter protein designed to block the PD1 and related pathways renders CAR T-cells resistant to this cancer defence mechanism.
The engineered adaptor protein is a dominant negative SHP2 protein that restores CAR T-cell activation by cancer cells expressing PD-L1, triggering cancer cell killing, and normal T-cell proliferation and cytokine release.
As opposed to systemic monoclonal antibody based checkpoint inhibition therapies with their well described safety signals, this strategy is confined to the engineered CAR T-cells, potentially leading to less systemic toxicity. In addition it has the potential to block a range of inhibitory signals as the adaptor proteins SHP1 and SHP2 are common to many inhibitory receptor pathways.
Dr Christian Itin, Chairman and CEO of Autolus, commented:
“This pan-checkpoint block is an example of the technologies Autolus is working on to address the layers of defence cancers are deploying to avoid killing by T-cells. Use of this and additional technologies will be important for the application of CAR T therapy; not only in blood cancers, but also for the treatment of patients with solid tumours.”
Further information
JW Communications +44 (0)7818 430877
Julia Wilson juliawilsonuk@gmail.com
About Autolus
Autolus is a private, clinical-stage, biopharmaceutical company, focused on the development and commercialisation of engineered T-cell immunotherapy products to combat cancer. Utilising its advanced cell programming and manufacturing technologies, Autolus has a pipeline of products in development for the treatment of both haematological malignancies and solid tumours. For further information please visit the Company’s website at: www.autolus.com
About Dominant Negative SHP2
Upregulation of inhibitory ligands on tumour tissue surface is one of the main cancer immune evasion mechanisms. The binding of the inhibitory ligand to its cognate receptor expressed on Tcell surface, impedes the function of the T-cells. Several of these receptors, such as PD-1, signal through SH1 and SH2 phosphatases. Monoclonal antibodies against cytotoxic T lymphocyte antigen 4 (CTLA-4) and PD-1, used as a monotherapy or as a combinational regimen, have been shown to significantly enhance anti-tumour effect by overcoming inhibitory signals from the tumour microenvironment. The immune-inhibitory pathway blockade is integrated into the CAR T-cells and it consists in converting inhibitory signal into activating ones by blocking SHP-1 and SHP-2 proteins with dominant negative SHP-2 (dnSHP2) proteins.
*Abstract: #3190 https://ash.confex.com/ash/2017/webprogram/Paper106896.html