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Imaging PD-L1 expression and tumour metabolism for stratification, treatment response and toxicity.

In this clinical PhD project the trainee will investigate novel imaging methods for stratification, response assessment and detecting toxicity to immunotherapeutics in NSCLC and melanoma.

Applications are now closed for the 2019 postgraduate training programme.

This project would be ideally suited to a clinical PhD student (oncologist, nuclear medicine physician or radiologist).

  • Primary Supervisor: Prof Gary Cook, Cancer Imaging, School of Biomedical Engineering and Imaging Sciences, King’s College London
  • Secondary Supervisor: Prof Peter Szlozarek, Centre for Molecular Oncology, Barts Cancer Institute, QMUL

Funding note: Non-EU candidates are not eligible to apply 

Background

Immune checkpoint blockade as a therapeutic strategy has had encouraging results e.g. in advanced NSCLC and melanoma [1]. However, there are significant adverse effects and only a subset of patients respond. For some drugs, immunohistochemical measurement of immune checkpoint molecule expression, e.g. PDL1, from biopsies is required to identify likely responders. This invasive approach does not account for the heterogeneity of expression between metastases and is not practical for serial measurements. There is therefore a strong rationale for developing non-invasive imaging methods as companion diagnostics for immunotherapy [2,3] e.g. 99mTc-PDL1 sdAb targeting PDL1 expression. Single-photon emission tomography (SPECT) and positron emission tomography (PET), combined with computed tomography (CT), are widely used in clinical oncological practice. Novel tracers, targeting specific tumour characteristics, may be valuable in predicting and monitoring response as well as assessing toxicity of novel cancer therapeutics.

The project will be divided into two components: 

Study 1:

PDL1 SPECT/CT imaging in NSCLC and melanoma

This study will measure PDL1 expression by 99mTc-PDL1 single domain antibody (99mTc-sdAb) single-photon emission computed tomography – computed tomography (SPECT/CT) imaging in melanoma and NSCLC treated with PD1/PDL1 immunotherapy. Imaging will be repeated at 12 weeks and comparisons made with immunohistochemical PDL1 expression and standard imaging (CT-NSCLC, FDG PET/CT-melanoma) response criteria.

The aims are to determine:
i) the correlation between 99mTc-PDL1 sdAb SPECT/CT and immunohistochemical measurement of PDL1 expression
ii) if 99mTc-PDL1 sdAb SPECT/CT can predict response
iii) to measure heterogeneity of PDL1 expression within and between tumours in the same patient.

Study 2:

A retrospective study of all patients (>100) with metastatic melanoma who have had clinical FDG PET/CT scans on ipilumumab therapy to document degree, timing and length of response and to determine the frequency of autoimmune adverse effects (e.g. sarcoid, colitis) visible on imaging [4,5].

Potential research placements:

  1. Thoracic medical oncology, supervised by Prof Szlosarek, Barts Cancer Institute, QMUL.
  2. Melanoma and phase 1 medical oncology supervised by Dr Harries and Dr Spicer at GSTT Hospitals, Medical Oncology.
  3. Cancer Imaging supervised by Prof Cook and Prof Goh at, School of Biomedical Engineering and Imaging Sciences, King’s College London

References

  1. Gong J.et al. Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations. J Immunother Cancer. 2018; 6:8
  2. Mayer AT, Gambhir SS. The immunoimaging toolbox. J Nucl Med. 2018; 59:1174-82.
  3. Cho SY, Lipson EJ, Im HJ, et al. Prediction of response to immune checkpoint inhibitor therapy using early time-point FDG-PET/CT imaging in patients with advanced melanoma. J Nucl Med. 2017; 58:1421–28.
  4. Wong ANM, McArthur GA, Hofman MS, Hicks RJ. The advantages and challenges of using FDG PET/CT for response assessment in melanoma in the era of targeted agents and immunotherapy. Eur J Nucl Med Mol Imaging. 2017;44(Suppl 1):67-77.
  5. Blumenthal GM, Theoret MR and Pazdur R. Treatment beyond progression with immune checkpoint inhibitors-known unknowns. JAMA Oncol. 2017 https://doi.org/10.1001/jamaoncol.2017.