A new way to treat cancer in patients who don’t respond to current targeted treatments has “tremendous potential to save lives’’ according to one of the authors of a study published in the journal, Cell, who is hopeful that significant business investment in developing a promising class of compounds could see it enter the USD 54 billion-dollar global immuno-oncology therapy market.

Immuno-oncology therapies, one of the newer classes of cancer drugs, are highly effective in up to 30% of patients, and generally have an acceptable side-effect profile. A contributing factor in tumours that respond poorly, or are resistant to targeted therapies, is the variation in drug-target availability on the surface of tumour cells.

Researchers from the University of Queensland’s (UQ)s Diamantina Institute and Institute for Molecular Bioscience, The Princess Alexandra Hospital, Children’s Medical Research Institute, The University of Newcastle, and The University of Sydney have discovered that another class of compounds, called endocytosis inhibitors (in particular, dynamin inhibitors), when used in combination with certain immuno-oncology therapies, dramatically increased the response rate to the cancer drugs in pre-clinical models, by promoting drug-target availability on the surface of tumour cells.

These results and data from a proof of concept study published in Cell on 5 March 2020, demonstrate for the first time that the approach of combining these two types of agents in patients with cancer is feasible. This holds great promise for advancing the combination therapy toward the clinic, with the aim of greatly increasing the pool of patients that may be effectively treated with immuno-oncology therapies.

“Results in pre-clinical models are impressive,” Professor Phil Robinson of Children’s Medical Research Institute said.

Immuno-oncology therapies work by binding to specific receptors on the surface of cancer cells, which activates the patient’s own immune response to recognise and selectively kill the tumour. However, if the majority of target receptors for the cancer drug are internalised and are not located on the cell surface when the cancer treatment is administered, the therapy is either ineffective or patients respond poorly. In pre-clinical models, the addition of an endocytosis inhibitor reduces/prevents this internalisation and increases the exposure of target receptors on the tumour cell surface for the immuno-oncology therapy to bind.

“Our collaborators at UQ have shown in the pre-clinical setting that dynamin inhibition improves immune cell mediated killing of tumour cells (Antibody-Dependent Cellular Cytotoxicity) for three separate immunotherapies, cetuximab (anti-EGFR), trastuzumab (anti-HER2), and avelumab (anti-PD-L1). The UQ data shows in pre-clinical models in vivo that the combination therapy reverses resistance to the immune-oncology drug (kills the tumour) and induces resistance to rechallenge with new tumours (i.e., provides long-term protection) without further therapy,” said Prof Robinson.

“The Cell data are also proof of principle that treatment of patients with a dynamin inhibitor can prevent internalisation of receptors on tumours in patients .We now know that there are existing endocytosis inhibitor drugs whose off-target effects can be used and tested in future trials. Our focus is to develop the next generation of these drugs, which will be more specific, more potent, with fewer side-effects—and which can reach more people.”

The current work was carried out using prochlorperazine, a well-known drug that has been on the market for many years, which has endocytosis inhibition properties (specifically through dynamin inhibition) and is currently licensed for other indications.
Drug development has advanced tremendously in the 40 years since prochlorperazine was licensed for medical use. Our drug development teams at CMRI and UoN have been working for over a decade on a new class of endocytosis inhibitor drugs which will be much more potent and specific than the drug used in the current study, with the aim of producing fewer side effects while still having the same potential impact on the efficacy of the immuno-oncology therapy. With safety having now been demonstrated for the mode of action of endocytosis inhibition, it is imperative to expedite the development of the existing and new drugs for use in combination with immune-oncology therapies to improve their success rate, including potentially in patients for whom immunotherapy has previously failed.

“Now, we just need to prove its efficacy in rigorous Phase II trials and get our new candidate dynamin inhibitor drugs into the clinical pipeline.”

Investment is being sought to advance both programs of work, i.e., the existing drug (prochlorperazine) and candidate new chemical entities (NCEs). The global immuno-oncology therapy market reached USD 54 billion in 2018 and is expected to reach USD 157 billion by 2027. The drugs we are developing have potential application across a broader market of indications for all receptor-mediated immunotherapies (beyond cancer), thus dramatically expanding the potential value of this approach.