The DARRT Program
Part 2 introduced the concept of DARRT. It stands for Direct and Abscopal Response to RadioTherapy.
DARRT is the Company’s major focus. Our Veyonda® clinical program is deliberately broad-ranging and includes various chemotherapy and radiotherapy approaches with two overriding strategies in mind. The first is a de-risking strategy that ensures we have viable options should one program falter for any reason. The second is that once approved for one particular clinical indication, we intend to have Veyonda approved for other anti-cancer indications in a short time-frame.
But DARRT remains our major focus because we see it as a coming disruptive technology in cancer therapy.
DARRT is simple in its objectives – to use Veyonda to make radiotherapy more effective at shrinking tumours that are exposed directly to the radiation (that’s the direct or in-field effect), and at the same time leading to shrinkage of tumours that have not received any radiation (that’s the abscopal or out-of-field effect).
DARRT is simple in its execution – In DARRT-1, the patients were given Veyonda for about 2 weeks to load up as many cancer cells as possible with idronoxil. In the middle of that drug treatment, the patients received about 5 days of low-dose radiotherapy to 1-2 tumours that were causing symptoms such as pain.
DARRT is simple in its ambitions – to become a transformative treatment for prostate cancer, both late-stage and early-stage, delivering significant survival and quality of life benefits for the 1 in 40 men who are facing death from this cancer. In proving its benefit in prostate cancer, the aim is for it to go on to become a transformative treatment for many other forms of solid cancer.
It’s the rationale behind DARRT that is complex – in simplest terms, it is aiming to re-engage the body’s defence systems against cancer cells. It is part of the new wave of cancer therapies known as immuno-oncology. [For those wanting to dig deeper, there is a more detailed explanation at the end of this blog.]
A major attraction of DARRT is that it works by restoring the body’s own anti-cancer mechanisms. It isn’t seeking to kill everything in its path as most radiotherapy seeks to do. DARRT is intended to cause minimal damage, with that small amount of damage triggering inflammatory and immunological responses that put activated defence cells into the bloodstream, travelling throughout the body and destroying scattered tumours wherever they can be found – a form of vaccination against the cancer, if you like.
DARRT uses a form of radiotherapy known as external beam radiotherapy (EBRT), or radiation delivered as a narrow beam from a source outside of the body. EBRT is the most commonly used form of radiotherapy, is relatively inexpensive, and generally is readily available throughout the world.
DARRT involves delivering low dosages of radiation to a limited number of tumours. This radiation dose is killing some cancer cells, but mainly over 5 days; repeatedly damaging, not killing, cancer cells exposed to the radiation beam. That damage sets up an inflammatory response that in turn activates immune cells that attack the damaged cancer cells. This is the process now referred to as converting COLD (non-inflamed) tumours into HOT (inflamed) tumours.
In the vast majority of cases where radiotherapy is used on its own, this immune response remains limited to the irradiated tumour. In very rare cases, the immune response appears to spill over into the bloodstream to a sufficient degree to go on to attack and shrink tumours well outside the field of radiation, producing the so-called abscopal effect.
What we think is happening when Veyonda is used is that its presence in the irradiated tumours is augmenting the amount of DNA damage in cancer cells, thereby boosting the local inflammatory and immune responses. Instead of briefly ‘warming’ the tumour, we believe the tumour is becoming ‘hot’ , boosting the immune response to the point where it is far more likely to spill over into the bloodstream, reaching out to non-irradiated tumours where Veyonda is again waiting to help turn COLD tumours into HOT tumours, and so the process cascades and is repeated throughout the body.
The potential benefits of DARRT-1 are clear.
- The course of treatment is short
- The dose of radiation is low and the entire treatment is well-tolerated and
- DARRT doesn’t require hospitalisation as an in-patient
- The radiotherapy is relatively inexpensive and commonly available
- Veyonda can be administered by the patient at home and has shown minimal side-effects to date
- DARRT appears to be delivering a high rate of response in prostate cancer patients as indicated by reduced PSA (prostate specific antigen) and pain levels.
These are the reasons we see Veyonda having the potential to be a disruptive technology capable of transforming the treatment of late-stage prostate cancer.
But we don’t see Veyondaâ stopping there. We are already looking at taking it earlier in the management of prostate cancer, perhaps even as a first-line therapy for locally advanced disease..
And then beyond prostate cancer, as there is no reason to suppose that the rationale behind Veyondaâ will not apply to many other forms of cancer .
The critical next data release is the 24-week data on the 11 patients in the second arm of the DARRT-1 study in late-November. You can see a video on the latest interim results from the DARRT-1 study here. In the first half of 2020 we plan to share this data in independent peer-reviewed scientific forums such as medical journals and conferences.
DARRT science detail
This is for those who want to take the plunge and dive deeper into the science of DARRT. We are putting considerable effort into this because it will aid the registration of Veyonda and help guide ways to use Veyonda to best effect.
There are a number of reasons why cancer is triggered, but becoming established and growing freely represents a failure of the body’s immunosurveillance mechanism – this is a mechanism meant to detect the emergence of a cancer cell and then activate immune cells to attack and eliminate the abnormal cell, just as they do with a foreign cell such as a bacterium. A cancer cell is in effect a ‘foreign cell’ – an own cell that has turned into a feral, foreign cell.
Cancer cells don’t just avoid the surveillance system – they hijack it and manipulate it to prevent being attacked. Like all the various forms of immuno-oncology technologies, the aim is to reverse that hijacking and to restore the balance in favour of the immune system.
Radiotherapy can be another form of immuno-oncology, and DARRT is designed to use Veyonda to augment this effect.
Radiotherapy uses a form of radiation known as ionizing radiation (IR). Up to now, the overriding theory behind the use of IR has been to use its destructive force to kill as many cancer cells as possible. The problem with that approach is that it is very difficult to kill all cancer cells without causing serious damage to surrounding healthy tissues. Safe-to-use dosages of IR mean that some cancer cells (probably cancer stem cells) will likely survive because they are what is known as ‘radio-resistant’ (less sensitive to radiation). But in attempting to kill as many cancer cells as possible, the unintended consequence is that the immunosurveillance and immune cells in the irradiated tumours will have been wiped out too.
An emerging view of IR is that under certain circumstances it can be used to stimulate the immune system, clearly a preferential method of treating cancer. This effect comes from a lower, less destructive dose of IR that damages rather than kills cancer cells, with that damage triggering an inflammatory reaction with activation of dendritic cells, macrophages and natural killer (NK) cells, which in turn recruit CD4+ (helper) and CD8+ (cytotoxic) T cells that then attack the cancer cells. The paper by Carvahlo and Villar (2018) presents a good review of this effect.
We currently are working on better understanding the interaction between IR and idronoxil (IDX), the active ingredient in Veyonda, but this is what we suspect we will find:
- That IDX promotes the inflammatory response to radiation-induced damage
- That IDX adds to that effect by separately promoting the activity of both immunosurveillance cells (dendritic cells, macrophages and NK cells) and tumour infiltrating lymphocytes (CD8+ T cells) both in terms of cell number and with regard to their anti-cancer specificity
- These two effects combine to tip a local immune response within 1 or 2 irradiated tumours over into a general immune response that leads to an anti-cancer response in tumours throughout the body.
This understanding is a vital component of the drug development journey. Not only will much of this data be used in application for registration with bodies such as the FDA, but it will also help guide the work required to expand the indications of Veyonda so that we can target a wider group of cancers and benefit the people living with this often deadly condition.