The theory of immunotherapy dates back to the 18th century but as a treatment for cancer only began taking off in recent decades.
But despite revolutionising oncology and having been developed into blockbuster drugs for several big pharma companies, immuno-oncology is still not able to successfully treat every patient.
Generally, the main point of immuno-oncology is to stop tumours evading the defensive cells of the body’s immune system so they can recognise and destroy the cancerous cells.
But most types of cancerous tumour do not respond to single-therapy treatments of this sort.
This is where Highlight Therapeutics comes in, as it aims to partner its potentially powerful treatment with existing immuno-oncology drugs to extend their benefits to patients that have not responded to treatment so far.
The company’s lead product, BO-112, is being tested in two main clinical trials, both of which are at the Phase II stage in collaboration with Merck & Co’s (MSD) Keytruda therapy.
BO-112 has been found to be very potent in making tumour cells visible to the immune system, using double-stranded messenger RNA.
Messenger RNA, or mRNA, plays a fundamental role in human biology by transferring the instructions stored in DNA to make the proteins required in every living cell. Medicines based on mRNA, like some of the new vaccines that have been developed to treat coronavirus, instruct a patient’s own cells to produce a specific protein.
“BO-112 turns ‘cold’ tumours ‘hot’ and so leads to the body’s immune cells attacking the tumour,” explains Highlight Therapeutics chief executive Marisol Quintero.
To do this, the mRNA activates a series of intracellular processes that stop the tumour cells from evading detection by increasing expression of the MHC-1 antigen, as well as activating the immune cells.
Highlight Therapeutics is confident that BO-112 can work in conjunction with most other types of cancer treatment, from radiology and chemotherapy to other immuno-oncology treatments such as checkpoint inhibitors and adoptive cell therapies.
Merck’s blockbuster Keytruda is one of those checkpoint inhibitors.
While some cancerous tumours evade the body’s immune system when they bind to proteins on the surface of immune cells called T cells, checkpoint inhibitors help to prevent this binding process, and so allow the T cells to destroy the cancer cells.
Keytruda, or pembrolizumab, is a checkpoint inhibitor that acts against a checkpoint protein called PD-1.
BO-112 has been shown to reactivate PDL1 and also enhance lymphocyte infiltration – so enables the checkpoint inhibitor regain their efficacy on tumours that had become resistant.
An initial study of BO-112, working with patients progressing to checkpoint inhibitors, showed the concept was feasible and proved safety and gave signals of efficacy.
This was then spun out into two Phase II clinical trials, both in combination with pembrolizumab.
One trial is in patients with melanoma in a second-line setting, so patients that receive a checkpoint inhibitor as part of their first-line treatment and are progressing will be eligible to receive Highlight’s drug in combination with pembrolizumab.
The other trial is in patients with select advanced stage solid tumors with liver metastases, that is the cancer has spread from another part of the body to their liver.
“This trial is more challenging”, says Quintero, “because it combines two aspects of this concept of resistance to checkpoint inhibitors.”
In this trial, the drug is being given to patients that present with liver metastases from colorectal or gastric/gastro-esophageal junction cancer.
Quintro says these indications have microsatellite stable (MSS) tumours – one of the most highly mutated tumour types – and known to be very “cold” and are both indicative of a poor response to immunotherapy.
“So we inject directly into the liver metastases to make these liver metastases visible to the immune system and combine that with pembrolizumab,” she says.
This typifies Quintero’s overall strategy.
“The idea of the liver metastases is something that can be applied outside gastrointestinal tumours, and we intend to do that very soon.”
The initial readouts from these two Phase II trials this will define the strategy for the board, in terms of how to reach regulatory approval.
Highlight Therapeutics is unlisted currently but has raised €45mln and Quintero says the board plans this year to properly assess a listing in London or elsewhere, which would be to finance the drug registration and trials.
The company is one of several focused on intratumoral therapy, including several pursuing melanoma, but as Quintero says, the only one that is working at two levels.
“On one side we are working to activating your system. But we are also modifying tumours to make them present more efficiently to the immune system and that’s unique from our mechanism of action.”