CRTF project T Ng2020-11-17T09:33:05+00:00

Imaging therapy response and mechanisms of resistance in patient-derived organoids treated with anti-tumour targeted agents ± immune checkpoint therapeutics

Primary Supervisor: Professor Tony Ng, Comprehensive Cancer Centre, King’s College London

Secondary Supervisor: Dr Martin Forster UCL Cancer Institute

Linking anti-ErbB/HER therapies through stress-induced immune sensitisation via e.g.cGAS-STING

The main objective of this fellowship is to address the hypothesis that immunological recognition/sensitisation can be triggered by the stress response of cancer cells to anti-ErbB/HER therapies including osimertinib (a third generation anti-EGFR tyrosine kinase inhibitor), anti-EGFR antibodies (e.g. Cetuximab), as well as a new class of HER2-targeted therapies, which can impact on low/normal HER2 expressing tumours . We have recently discovered the immunogenic mechanisms of these HER targeted agents, in a variety of tumour types including breast and colorectal cancers. An example of anti-EGFR therapeutic induced immunogenicity pertains to our observed effect of osimertinib in activating the cGAS-STING pathway in M1 macrophages that interact with the treated lung cancer cells.

In the clinical trial setting, Ng’s lab has shown that the combined use of ErbB/HER dimer imaging (of tissue and blood exosome), deep immune monitoring (Helios and Hyperion, Fluidigm), CT imaging and conventional mutation analyses can allow more accurate prediction of the subgroup of patients who will have better survival, following chemotherapy/anti-ErbB/HER treatment of colorectal and head & neck cancers.

This clinical fellowship aims to extend these preclinical and clinical observations, and apply our state of the art multiphoton imaging methodologies to 3D patient derived models (including head and neck/colorectal organoids and live tumour slices that we have been collecting, as a longstanding collaboration with Martin Forster, Manuel Rodriguez-Justo, Sergio Quezada and Daniel Hochhauser); in order to further dissect the tumour cell non-autonomous mechanisms of this phenomenon of therapeutic stress-induced immunological sensitisation.

The imaging experiments will be supplemented by investigations that will focus on alteration of immune responses in peripheral blood mononuclear cells that will be cocultured with the treated 3D tumour organoids or in immune cells that are within live tumour slices. The clinical fellow will benefit from the ongoing work on macrophages and the cGAS-STING pathway. In addition, he/she will collaborate with Chris Tape’s group and employ his novel high-dimensional single cell analysis of signalling mechanisms in heterotypic single cells (e.g. tumour cells and macrophages) that interact within a 3D environment.

The longer term goal is to derive a stratification algorithm to drive the clinical development of anti-ErbB/HER ± immunotherapies, through biology-driven combinations and sequences,

for cancer patients in the trial setting. The clinical supervisor Dr Martin Forster is Clinical Investigator for several ErbB/HER and immune checkpoint trials (e.g. EACH, Cetuximab alone or followed by Avelumab in head and neck cancer) and the clinical fellow will be able to translate the preclinical findings in this proposal into mechanism-based biomarker assays that can be validated using the trial samples.

Potential placement opportunities

1. Multiphoton imaging analysis (with Dr Paul Barber, Computer Vision expert/ Principal Research Fellow at CRUK UCL Centre)

2. Training by Dr Valenti Gomez within the Imaging core (multiphoton imaging of the 3D human cancer tissue slice culture using SOPs and expertise that exist within the Tumour Microenvironment core at the CoL Centre).

3. Learning the use of Mass cytometry (cytometry time-of-flight or CyTOF) that employs heavy-metal-conjugated antibodies to study >35 (signalling) proteins in single cells, in Dr Chris Tape’s laboratory (UCL Cancer Institute).

The funding for this studentship covers students with home tuition fee status only. For more information on home tuition fee status please visit the UKCISA website. Please note that we will only be able to offer studentships to candidates that have home tuition fee status or provide evidence that they can fund the international portion of the tuition fee from external sources (i.e. not self-funded).

References

1. Li, B. T. et al., HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers. Cancer Discov 10, 674-687, doi:10.1158/2159-8290.CD-20-0215 (2020).

2. Barber, P. R. et al., HER2-HER3 heterodimer quantification by FRET-FLIM and patient subclass analysis of the COIN colorectal trial. J Natl Cancer Inst, doi:10.1093/jnci/djz231 (2019).

3. Ng, T. et al., in ASCO (Journal of Clinical Oncology) Vol. 36 Suppl 6043 (2018).

4. Evans, R. et al., Integrin-Mediated Macrophage Adhesion Promotes Lymphovascular Dissemination in Breast Cancer. Cell Rep 27, 1967-1978 e1964, doi:10.1016/j.celrep.2019.04.076 (2019).

For any informal enquiries on the project please contact Prof Tony Ng: tony.ng@kcl.ac.uk

For any enquiries on the CRUK CoL Centre programme please contact Annabelle Scott: annabelle.scott@ucl.ac.uk