Endocytosis inhibitors to improve anti-cancer monoclonal antibody immunotherapy responses

Many oncology patients receiving monoclonal antibody immunotherapy receive no therapeutic benefit, or rapidly develop resistance to therapy. Direct killing of tumour cells by antibodies (antibody dependent cell cytotoxicity, ADCC) requires strong engagement between antibodies bound to tumour cell surface receptors and NK cells. In studies with the anti-epidermal growth factor receptor (EGFR) antibody, cetuximab at the University of Queensland, head and neck cancer patients who have dysfunctional EGFR receptor internalisation (and hence have EGFR clustered on the tumour surface) respond to cetuximab treatment. However, those with normal EGFR receptor biology do not respond. Clustering of receptors on the tumour surface increases NK-antibody interactions, and hence ADCC, resulting in increased tumour cell killing.

Inhibition of dynamin (a key enzyme involved in internalisation of receptors such are EGFR, PD-L1, HER2 and VEGF) leads to receptor enrichment and clustering on the cell membrane. Specific dynamin inhibitors or the anti-nausea drug prochlorperazine (Stemetil),  a dopamine receptor antagonist with off target activity as a dynamin inhibitor, inhibit dynamin activity in vitro, leading to receptor clustering and in the presence of a therapeutic antibody (e.g. avelumab, cetuximab or trastuzumab), leading to enhanced NK-cell mediated antibody dependent cell cytotoxicity (ADCC). In mouse tumour models published in Cell (Mar 2020) prochlorperazine treatment in combination with either avelumab or cetuximab resulted in tumour clearance and reduced metastases. In addition, treated mice became resistant to the same tumour.

A clinical proof of mechanism study in head and neck cancer patients demonstrated that high dose i.v. prochlorperazine is able to cluster receptors on tumours. A phase 1b combination safety study of cetuximab and prochlorperazine is ongoing.

Key features

• Dynamin inhibition enhances the ability of anti-cancer antibodies that target tumour cell surface proteins to kill tumour cells by ADCC, increasing efficacy, reducing target heterogeneity and overcoming resistance.
• In vitro, in vivo and clinical data demonstrate that co-administration of prochlorperazine with a therapeutic mAb has the potential to be a transformative oncology treatment strategy.

Further information:

Cell:

• Boosting cytotoxic antibodies against cancer – Cell Preview, 5 March, 2020
• Endocytosis inhibition in humans to improve response to ADCC-mediating antibodies – Cell Article, 5 March 2020

Media release:

New drug combination could support better cancer treatments – The University of Queensland, 6 March, 2020

Media coverage:

Hopes one-two punch cancer treatment will prove knockout blow – Brisbane Times, 6 March 2020