Avoiding on-target off-tumour toxicity in cancer immunotherapy. (360G-Wellcome-110022_Z_15_Z)
Chimeric antigen receptors link MHC-unrestricted antigen specificity with T-cell signalling, facilitating potent and regulatable antigen-specific cancer recognition and killing. Clinical trials of CAR gene modified T-cells show unprecedented clinical responses, with the major limitation of on-target off-tumour toxicity due to expression of most cancer antigens on some normal tissues. In my Wellcome clinical training fellowship I identified a novel method of avoiding such toxicity by designing CA Rs for use in gdT-cells. These gdT-CAR cells combine innate killing limited to sites of cancer or injury with CARs providing co-stimulation to overcome the immunoinhibitory tumour microenvironment. I demonstrated proof of concept using two model antigens, GD2 and CD33, applicable to solid cancers (e.g. neuroblastoma) and myeloid leukaemias (e.g. AML) respectively. In my fellowship I will develop this by: 1) Identifying mechanism and relative efficacy of different co-stimulatory CAR endodomains in gdT cells 2) Investigate selectivity of co-stimulatory CARs in gdT against acute myeloid leukaemia compared with healthy blood cells bearing the same tissue antigen. 3) Investigate the use of mass cytometry for high-dimensional signalling analysis to inform CAR design. Efficacy, toxicity and mechanism will be assessed in a staged manner using cell lines and primary tissue.
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Grant Details
Amount Awarded | 275672 |
Applicant Surname | Fisher |
Approval Committee | Clinical Interview Committee |
Award Date | 2015-11-19T00:00:00+00:00 |
Financial Year | 2015/16 |
Grant Programme: Title | Postdoctoral Training Fellowship for Clinicians |
Internal ID | 110022/Z/15/Z |
Lead Applicant | Dr Jonathan Fisher |
Partnership Value | 275672 |
Planned Dates: End Date | 2019-08-31T00:00:00+00:00 |
Planned Dates: Start Date | 2016-09-01T00:00:00+00:00 |
Recipient Org: Country | United Kingdom |
Region | Greater London |
Sponsor(s) | Prof John Anderson |