Unbiased in vivo CRISPR screen to identify novel T-cell immune checkpoints for cancer immunotherapy (360G-Wellcome-210910_Z_18_Z)
Harnessing the anti-tumour potential of T-cells for cancer treatment has been successful for a number of malignancies. The blockade of immune checkpoints, such as the T-cell receptor PD-1, reduces tumour burden in patients and can lead to durable cures for some. Treatment efficiency is further improved when PD-1 is targeted simultaneously with other checkpoints such as CTLA4 or LAG3. Despite the potential of co-targeting multiple checkpoints, the combinatorial co-inhibition of all known as well as yet undiscovered immune checkpoints has not been systematically assessed. Furthermore, genome-wide screening to identify novel checkpoints as well as modifiers of such checkpoints has been technically challenging. The objective of this proposal is to map the combinatorial landscape of known checkpoints coupled with PD-1 blockade as well as discover potentially new targets for immune activation against cancer. We propose to use of transplanted hematopoietic stem cells with different combinations of disabled T-cell surface proteins to screen for combinations which enable T-cell infiltration and tumour reduction in a PD-1 suppressed mouse melanoma model. Initially combinations of known checkpoints will be assessed, subsequently the screen will be expanded to all T-cell membrane proteins to identify novel immune checkpoints.
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Grant Details
Amount Awarded | 250000 |
Applicant Surname | Tomberg |
Approval Committee | Basic Science Interview Committee |
Award Date | 2018-04-24T00:00:00+00:00 |
Financial Year | 2017/18 |
Grant Programme: Title | Sir Henry Wellcome Postdoctoral Fellowship |
Internal ID | 210910/Z/18/Z |
Lead Applicant | Dr Kärt Tomberg |
Partnership Value | 250000 |
Planned Dates: End Date | 2022-07-15T00:00:00+00:00 |
Planned Dates: Start Date | 2018-10-01T00:00:00+00:00 |
Recipient Org: Country | United Kingdom |
Region | East of England |
Sponsor(s) | Prof Allan Bradley |