Werner Sunderland, Mariana;
(2019)
Gene editing of tumour infiltrating lymphocytes for the generation of adoptive cellular therapeutics against cancer.
Doctoral thesis (Ph.D), UCL (University College London).
Preview |
Text
Thesis Final Draft FINAL with corrections.pdf Download (19MB) | Preview |
Abstract
Cancer treatments that are based on the reactivation, expansion, or mobilisation of the immune system, such as adoptive cellular therapies and immune-checkpoint blockade, have achieved long-lasting anti-tumour responses in cancer patients. However, there is still a high proportion of patients that do not benefit from these treatments. This highlights the need for more effective therapies. Based on the notion that adoptive cell therapies do work and are likely limited in vivo by the activation of immune modulatory pathways, this project focused on ablating negative regulation and increasing the intra-tumoural effector activity of tumour-reactive T cells. Specifically, my project aimed to genetically modify tumour infiltrating T cells by knocking-out the expression of immune- checkpoints on their surface so as to render them resistant to checkpoint inhibition, thus generating potent and long-lasting anti-tumour immunity. For this purpose, the CRISPR/Cas9 technology was used to genome edit tumour-reactive T cells using primary human tumour-infiltrating lymphocytes (TILs) obtained from melanoma and non-small-cell lung carcinoma (NSCLC) patients. The project initially focused on the generation of PD1-deficient tumour- reactive T cells as a proof of concept, as targeting this pathway with antibodies has shown clear efficacy in the clinic. Following the generation of PD1-deficient gene edited T cells, we developed LAG3-deficient and TIGIT-deficient tumour-reactive T cells, as well as T cells that were deficient for both PD1 and LAG3 expression. In sum, the overall purpose of this project was to utilise cutting edge gene editing tools to engineer tumour-reactive lymphocytes and render them resistant to checkpoint inhibition. The results from this work have established a clinically relevant pipeline for the generation of potent adoptive cell therapy products for the treatment of cancer.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Gene editing of tumour infiltrating lymphocytes for the generation of adoptive cellular therapeutics against cancer |
| Event: | UCL |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10086039 |
Archive Staff Only
 |
View Item |
