Project ID CM-HD2023_24

ThemeCM-HD

Co Supervisor 1A Comprehensive Cancer Centre, School of MedicineWebsite

Co Supervisor 1B Comprehensive Cancer Centre, School of MedicineWebsite

Redirecting macrophages in head and neck squamous cell carcinoma (HNSCC) using antibody engineering to enhance tumour penetration and drug longevity

Tumour-associated macrophages (TAMs) correlate with poor prognosis in many solid cancers. Radiation therapy (RT) is used as primary, adjuvant as well as palliative treatment in patients with head and neck squamous cell carcinoma (HNSCC). The initial effects of radiotherapy involve tumour bulk reduction through inflammation. Long-term resolution of RT-induced inflammation often leads to a chronic inflammatory phase that drives monocyte infiltration (that mature to tumour-associated macrophages, TAMs) and development of a pro-tumour immunosuppressive tumour microenvironment (TME).

Aim: Combine RT and immunotherapy for a treatment that infiltrates the TME and redirect TAMs towards an anti-tumour phenotype.
1. Year1: Patient-derived organoids (PDOs) will be established from human HNSCC and adjacent normal tissues of the patients recruited from the ongoing SOTO study (“treatment Sensitivity of Organoids to predict Treatment Outcome”). The PDOs will be cocultured with matched monocytes enabling “tumour-education” during macrophage maturation. Cocultures will be irradiated and analysed by flow-cytometry and multiphoton imaging at several timepoints post-RT, allowing longitudinal analysis of macrophage populations and identification of key TAM targets.
2. Year2: Using a toolbox of immunotherapies available through collaboration with AstraZeneca we will select appropriate therapies based on the PDO post-RT biomarker profile and define the parameters of efficacious treatment by combining RT and immunotherapy. Aspects of combination therapy will involve optimising treatment sequence, optimisation of RT dose/fractionation and timing of using immunotherapeutic agents. Readout of anti-tumour efficacy will be measured through profiling temporal changes to the tumour microenvironment with the aim of achieving a long-term antitumour immune response. Therapeutic efficacy of the bispecific panel will be assessed in PDO co-cultures using flow-cytometry and multiphoton imaging.
3. Year3: We will move to preclinical HNSCC models (using syngeneic MOCL1 and MOCL2 models) allowing an assessment of treatment combination efficacy in vivo. A key aspect of successful immunotherapy is the extent of therapeutic penetration into the solid tumour. As part of a collaboration with Kalber group (UCL), selected therapeutics will be radiolabelled and uptake, distribution and longevity within the HNSCC TME assessed using in vivo PET/CT imaging. As well as measurement of the anti-tumour effect in the irradiated primary tumour, our use of in vivo preclinical models will allow assessment of a systemic anti-tumour response that could effectively treat non-irradiated metastatic tumours as part of the abscopal effect.

One representative publication from each co-supervisor:

• Evans R, Flores-Borja F, Nassiri S, Miranda E, Lawler K, Grigoriadis A, Monypenny J, Gillet C, Owen J, Gordon P, Male V, Cheung A, Noor F, Barber P, Marlow R, Francesch-Domenech E, Fruhwirth G, Squadrito M, Vojnovic B, Tutt A, Festy F, De Palma M, Ng T. Integrin-Mediated Macrophage Adhesion Promotes Lymphovascular Dissemination in Breast Cancer. Cell Rep. 2019 May 14;27(7):1967-1978.e4. doi: 10.1016/j.celrep.2019.04.076. PMID: 31091437; PMCID: PMC6527923.

• Harrington, K. J.*, Kong, A.*, Mach, N., Chesney, J. A., Fernandez, B. C., Rischin, D., Cohen, E. E. W., Radcliffe, H-S., Gumuscu, B., Cheng, J., Snyder, W. & Siu, L. L. Talimogene Laherparepvec and Pembrolizumab in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (MASTERKEY-232): A Multicenter, Phase 1b Study. Clinical cancer research published online 15 July 2020. (* joint first author)