Our primary focus remains to bring NOX66 to market to make both chemotherapy and radiotherapy work better and at lower, safer dosages. However, we now can reveal a tantalizing opportunity that is being incorporated into our trials for minimal additional cost.
Last Friday’s announcement introduced that opportunity, as well as a new word for most people –
I suggest that you become familiar with it, because it has the potential to change the way radiotherapy is used.
The word derives from the Greek ab (away from) and scopus (target), coined in 1953 to describe the phenomenon where radiation of tumour cells in one part of the body results in death of tumour cells in a distant part of the body with no possibility of any radiation reaching those cells.
It’s an incredibly rare phenomenon with only about 8 individual case reports in the medical literature since 1953. These cases have involved melanoma and cancer of the lung, kidney and blood.
I very much doubt anyone reading this would have heard of the word. And that’s because the biotechnology/pharmaceutical industries have regarded an abscopal response as so unachievable as to not warrant any effort being put into it. The result is that the general reaction whenever I mention the word is a glazing over of the eyes and mutterings of ‘blue sky’.
Well, you will be hearing a lot more about an abscopal response and it is far from ‘blue sky’.
The following is the sort of scenario where an abscopal response has been observed. A patient has late-stage cancer with a large number of tumours involving different parts of the body. The patient would have been through the usual rounds of surgery and chemotherapy and radiotherapy and now is in the palliative care stage. Treatment now is focused on relieving the symptoms of the disease with some of the larger tumours pressing on vital organs and nerves causing pain and loss of organ function. The decision is made to irradiate 1 or 2 of the larger and more troublesome tumours to try and shrink them. This is called palliative therapy because it’s only intended to provide temporary relief. In patients with multiple tumours, irradiating the whole lot isn’t an option because that would involve giving a total body dose of radiation that would likely do more harm than good. The aim is to shrink the targeted tumours enough to give some relief from pain.
An abscopal response describes an outcome where not only do the two irradiated tumours completely disappear, but so do all the other tumours in the body that did not receive any radition.
This is a very real effect….we know it exists. It is not the stuff of theory or wishful thinking. The problem is that we know so little about how it works that it has been a mountain just too high for scientists to climb. But that mountain is now starting to be climbed.
The climbing started about 20 years ago with studies in mice suggesting that the immune system played a role in the abscopal effect. The responses in the mice weren’t exactly dramatic, but they were good enough to hint at the involvement of an immune response.
This then led to the theory that killing a tumour cell by radiation somehow released tumour antigens previously shielded from the body’s immune system. Now freed, these antigens are picked by front-line immune cells called dendritic cells, resulting in an immune response that leads to the body being able to attack and kill the non-irradiated tumour cells. In essence, a vaccine-like effect, not dissimilar to CAR-T cell therapy or a bunch of experimental cancer cell vaccines all currently being tested in the clinic.
First deliberate abscopal study
In 2003, a group of radiation oncologists at Weill Cornell Medical School in New York decided to take the experience from mouse studies and see whether a combination of radiotherapy and immunotherapy would invoke an abscopal effect in humans. This was the first time that an abscopal response was being sought deliberately.
Their study involved 41 patients with late-stage cancers who each had at least 3 tumour lesions. The patients were treated with a combination of radiotherapy and a drug that stimulates the body’s dendritic cells, known as colony stimulating factor (CSF). Only 1-2 tumours were irradiated in each patient so that there at least 1 tumour that was not exposed to the radiotherapy beam. The key outcomes of that study were:
- 10 of the 41 patients showed an abscopal response as defined by at least a 30% reduction in the size of the tumours that did not reveive radiotherapy
- 2 of the patients showed a complete (100%) response
- an abscopal response was restricted to patients with fewer than 6 lesions.
As a pilot study that was treading into completely unchartered waters, this is an exciting outcome. Getting a complete response in just 2 out of 41 patients might seem disappointing, but this has to be seen in the context of only 8 reported such cases of complete response over 60 years out of countless millions of patients treated with radiotherapy. Plus, the mean survival of the 10 patients who showed any abscopal response was 21 months versus 8 months for those showing no response, so very much a worthwhile outcome. Still well short of scaling Everest, but an encouraging start.
Since this study was reported in 2015, numerous clinical trials have got underway in patients with late-stage cancer using various combinations of radiotherapy with some of the new immunotherapies that have come to market, and the data from these studies should start flowing over the next few years.
The Noxopharm clinical strategy
We are taking a different tack. The patients likely to be involved in other studies will have late-stage disease, which by its very nature means that many of the cancers will be highly resistant to the damaging effects of radiotherapy. It is open to speculation that that high level of resistance to radiotherapy will impede any abscopal effect.
Our approach is to seek to overcome that resistance by using idronoxil to make the bulk of cancer cells suffer damage at the hands of the radiotherapy.
We propose to run 2 clinical studies, each providing a two-shot approach. The first shot has nothing to do with an abscopal response. We simply will be testing whether we can radio-sensitise the 1-2 tumours that are exposed to radiotherapy. In this case we will be using a low dose of radiation that would not be expected to deliver anything more than partial shrinkage. We are expecting complete remission of those exposed tumours. If this is all we achieve, then we will have achieved something highly significant and highly relevant in the field of cancer management.
The second shot is the bonus shot and that is to see whether we get an abscopal response in all non-irradiated tumours.
It is important to understand the distinctions between our approach and that of others. As already noted, we are seeking to inflict greater damage on the cancer cells by sensitising them to the radiotherapy. But the idronoxil through its general anti-cancer function means that it also is inflicting damage on those cancer cells throughout the body not exposed to radiation. A unique dual action that we hope will enhance the likelihood of an abscopal effect.
But to that dual action we can add a third action. Idronoxil also unusually displays a stimulatory effect on the immune system, leading in mice bearing human cancers to the generation of immune cells known as natural killer cells and tumour-lytic cells. These are the foot soldiers that carry out the attack on cancer cells after the dendritic cells are activated.
We are hopeful that the unique combination of
- augmenting radiation damage in the cancer cells exposed to radiation
- plus inflicting damage on all non-exposed cancer cells in the body
- plus leading to the activation of cancer-killing immune cells
will provide idronoxil with the means to deliver a potent abscopal effect.
We will be conducting 2 clinical studies to enable us to look at different cancer types. The first ‘abscopal trial’ is within several weeks of commencing.
Olivia Newton-John Cancer Research Institute
The clinical program is being supplemented by a laboratory study being conducted in partnership with this institute. The objective is to better understand the mechanisms involved in idronoxil-induced abscopal response. The Institute was selected because of its highly respected radiobiology laboratory offering the necessary expertise and resources to conduct cell and animal studies.
From this we hope to refine the conditions under which an abscopal response can be invoked, as well as identifying those patients most likely to respond.
The appropriate steps to protect this potentially highly valuable intellectual property have been taken, with claims based on positive data in our possession.