Please can you give a brief introduction to metastatic renal cell carcinoma (mRCC)?
Metastatic renal cell carcinoma is a devastating disease. There are roughly 20-25,000 new cases per year in the United States and it is increasing for some reason. For patients who present with mRCC their median overall survival is only about 15 months and 90% of the patients won’t live 2 years. It is quite an aggressive disease.
Renal cell carcinoma comes in 3 different grades. There are patients that present with favourable risk, meaning that they have none of the 6 risk factors that physicians look at to determine the severity of disease. If you have favourable risk you have a reasonably good prognosis – the median overall survival is 43 months.
If you have 1 or 2 of the risk factors you are classified as intermediate risk and the survival drops down to only about 22.5 months.
If you are poor risk, meaning you have 3 or more of the 6 risk factors then the survival is only about 7.8 months.
Our population that we are treating is a mixture of intermediate and poor risk, with overall survival at about 15 months and only 10% last more than 2 years.
What therapies are currently available for mRCC?
It is very interesting because there are quite a few therapies that are available. They fall into different treatment categories. The first of these is surgery to remove the affected kidney. Patients that have a kidney removed can live fine with the remaining contralateral kidney. So you have that option to remove that entire affected kidney.
Beyond surgery though there are a few classes of drugs, including targeted therapeutics such as tyrosine kinase inhibitors. These are small molecule drugs that target the VEGF pathway which is a key molecular pathway in allowing the tumor to become vascularized so that it has the appropriate oxygen it needs to grow. There are 4 or 5 of these inhibitors that block VEGF currently available.
Later stage diseases can be treated with biologics. For example, there is a monoclonal antibody that is directed against VEGF called Avastin. That is used in combination with Interferon alpha. This brings me to the last class which is immunotherapy. Interferon alpha is an immune modulator. Interleukin 2 is approved as well in this indication.
Generally, all of these therapies come with significant side effects, so even though you have all of these treatment options, the actual treatment of the patient is still sequential monotherapy because of their toxicity, meaning these drugs cannot be combined with one another.
This is where Argos comes in. We’re putting our immunotherapy on top of these drugs and we can do this because we don’t have any significant side effects or toxicity. This is our niche – we can combine with standards of care that are generally too toxic to be combined with more classical chemo-type therapy.
Please can you explain what AGS-003 is and how it was developed?
AGS-003 is a fully personalized immunotherapy. We make it for each patient and it is perfectly matched to each patient’s disease. The way we make it is we take a tiny piece of the patient’s tumor and from that we can extract the RNA and amplify it using PCR. So from a very tiny piece of tissue we can generate large amounts of the RNA that was present in the tumor. That RNA encodes all of the proteins that were being expressed at the time that the tissue was harvested. That allows us to capture nearly all of the tumor antigens that we can target the immune system against.
The way we make use of that RNA is by putting it into a specialized type of white blood cell that we also harvest from the patient. This white blood cell is called a dendritic cell. Ralph Steinman from Rockefeller University just won the Nobel Prize for the discovery of the dendritic cell. He’s also a cofounder of Argos.
We basically need two things from the patient: a blood sample that we collect from the patient using a procedure called leukapheresis. That gives us large amounts of cells called monocytes. Those monocytes are what we differentiate in the laboratory into dendritic cells. Then we program those dendritic cells with the RNA from the patient’s own tumor. What you end up with is an immune-stimulating cell that we can deliver back to the patient that will train the immune system to target those proteins that were expressed in the tumor.
There’s a couple of distinguishing factors about what we do. We have what we call our immunophilosophy that differs from the way others have been thinking. That is we believe that only mutated antigens can mediate tumor rejection when you generate an immune response against them. What others are doing is using what people call tumor antigens – but they are really normal non-mutated antigens that happen to be overexpressed in certain tumor cells.
A good example is Dendreon’s product Provenge for prostate cancer where their target antigen is a protein called prostatic acid phosphatase which is clearly overexpressed in prostate tumors, but it is a normal antigen, or normal protein. Our thinking on why these normal antigens don’t work is that when your immune system is evolving as a child, the purpose of your thymus is to display all of your normal proteins to your immune system. Any immune cell that recognises any of those proteins strongly enough to do tissue damage is eliminated from the person’s repertoire. So if your strategy is to call on immune responses against normal proteins you are simply doomed to mediocrity in that setting.
We believe clearly, and this is borne out by work done over the past 25 years, the reason why no one has been able to correlate immune responses to normal antigens with clinical outcome is because those immune responses are too weak to contribute to the outcome. What we [Argos] observed for the first time is that the immune responses we measure to the tumor after we administer the product predict meaningful, clinical endpoints such as progression-free survival, overall survival and tumor response rates – the regression of the tumors.
For the first time we have something that makes complete sense. We see the immune response and we can measure this after as few as 5 doses, and that is a statistically significant predictor of long term outcome. I know now that our immunophilosphy is correct because we know our product contains mostly normal antigens and a handful of mutated antigens that resulted in the tumor.
When we started out, the big question was if we optimally provide that to the immune system of the patient, will the immune system target the mutated antigens? We’ve discovered the answer is yes. When we administer the product to these patients we see a big impact on the metastatic tumors – they either stop growing or regress in the majority of patients. But we never see an immune attack against the normal kidney that is still in the patient. This indicates that the immune system is ignoring all of those normal antigens and preferentially targeting ones that are mutated in the tumors.
We feel quite comfortable that we are thinking about this correctly and that those strategies that are using normal antigens will have very minimal impact if any at all. Aside from the mediocre outcome that Provenge was approved on, we just saw Merck’s Oncothyreon product Stimuvax fail in Phase III clinical trial, which uses an overexpressed non-mutated protein as the target. This was unsurprising to us.
There are two other aspects that we had to engineer into the product – even if you have the perfect antigen payload to deliver to the immune system, you have to realise that the immune system of these patients does not behave like a normal persons. Virtually all of our patients are immunosuppressed when they present at baseline – that’s how the tumor is able to persist and evade the immune system. We had to engineer a way for the product to actually work in that environment.
We also had to engineer the product to give rise to the proper type of immune response. We’ve known for a long time that a specific type of T cell response, called a memory response, is associated with good outcome. However, there was never a way to specifically expand those antitumor memory T cells. But now that’s exactly what our product does.
Our product can function in the immune suppressed environment, it has the perfectly matched antigen payload that includes mutated antigens and it exclusively gives rise to memory T cells. The antitumor memory T cell response is what we measure that correlates with clinical outcome.
What stage of development is AGS-003 currently at?
We have completed two Phase II studies of our fully personalized immunotherapy AGS-003. The first was as a single agent – so the patients only received our product. The outcome there was basically equivalent to the best standard of care available today. The patients in that study survived for approximately 15 or 16 months, which is what you get with the best care you can administer today. The difference was we had no toxicity.
In addition to that we had roughly double the percentage of patients that survived long term. Even with the best standard of care available today, if you look at all of the clinical trials conducted with the Pfizer targeted drug therapy Sutent for example, which is the dominant first line treatment for metastatic kidney cancer, only about 13% of the Sutent patients will live longer than 30 months. In our study it was about 25%.
The second study that we did was in combination with Sutent. In that study the outcome was quite striking because the median overall survival actually exceeded 30 months compared to the expected 15 months. So this was a doubling of survival – even with a higher percentage of poor risk patients, which drags down that median significantly. As we had observed previously in the long term survivors we had 52% of the patients surviving greater than 30 months. Right now approximately a third of those patients from that study are out to 4 years or more. What has been observed with the standard of care alone is only 13% of patients surviving 30 months or more.
So the outcome here was quite striking for a clinical study in modern oncology, where drugs are being approved on 2 or 3 month survival advantages. Here we have a 15 month improvement in survival.
Based on these data and the fact that our mechanism of action involving this memory T cell response correlated with the outcome in the patients, it was recommended by our clinical advisory board that we move directly into a Phase III pivotal study. That pivotal study just started. We opened the protocol at the end of last year. We now have the first patients in the study and there are several more being screened right now.
We will have approximately 70 clinical sites open in the United States by the end of the first quarter 2013 and another 30 or so sites in Western Europe. We will be able to manufacture and produce products from our facility in North Carolina for all of those geographic locations.
What are the aims of the ADAPT Phase III clinical study for AGS-003?
The primary endpoint is overall survival; however, we will also be looking at various other parameters including whether the immune response correlation continues to hold up, as well as tumor response rates. We will also be monitoring progression-free survival.
The study is actually open-label – there is no placebo. So it is just basically the standard of care versus our product on top of the standard of care. The first line standard of care in these patients will be administration of Sutent. After that first cycle of Sutent, physicians will be able to treat the patient however they normally would – transitioning to different drugs either due to toxicity reasons or progression. We will continue to combine with these other drugs as well.
Our expectation here is if we reproduce the outcome from our Phase II study there should be a very large survival advantage, however, the study is powered at 80% to detect just a 6 month improvement in survival. We think this is quite a low bar for success in the trial based on what we already know.
How is the study going so far?
Logistically everything is in place – patients are being screened; tumors are being collected. Our expectation is that we would meet our accrual target and have the complete study enrolled in the first half of 2014. We expect 50% of the deaths to have occurred by mid-2014 – that’s when we’ll be doing an interim data analysis. Our data safety monitoring board will be reviewing the data at that point for safety and futility.
If they give us the green light to continue the study, that will be a good indication that things are on track and that we have an opportunity to meet our primary endpoint. Of course, we don’t expect any issues with safety. We’ve never had anything greater than a grade 2 adverse event in any of the patients that have been treated with this product. So we are quite comfortable on the safety side.
We expect that if we meet the accrual estimates that we will hit the primary endpoint around October 2015 at which point we would file the BLA application with the FDA. We would expect approval in the first half of 2016.
What do you think the future holds for mRCC therapies and what are Argos Therapeutics’ plans for the future?
I think the future is developing non-toxic effective therapies such as AGS-003 that can combine with existing standards of care. The way things have been going, despite a plethora of effective drugs, none of them can be combined with one another. So we have a situation where the clinical oncologists that treat these patients have no choice but to administer say a first-line Pfizer drug, wait for the patient to fail or be intolerant of toxicity and then move on to the next drug. There’s really nothing out there that can be combined with these. So we are quite excited about what the future holds for our personalized immunotherapy and our ability to use this non-toxic technology on top of the standards of care used in other indications.
As you can imagine, for our technology we are completely agnostic as to what the tumor tissue is. It really doesn’t matter. So the same process can be applied to any other cancer indication. We have the ability to transition to new indications without having to reinvent anything. If you are Dendreon and you are trying to raise an immune response against the prostate cancer antigen, if you want to do that in breast cancer you have to go and discover or in-license a new antigen that’s relevant to that disease. I think we have a more desirable portability between indications.
On top of that, what we have done in parallel to our clinical development is we have developed machines that make the product from start to finish. It does the same exact process as the way we make it manually now, but it’s all automated. These machines will be undergoing validation procedures and be ready for product launch. The FDA has agreed to let us to conduct the entire Phase III trial with the manual process, but file our BLA with the machines without having to do an additional clinical study. We just need to show analytic comparability between what the machines make and the manual process.
We have the machines in our laboratory now and we are testing them. They do a beautiful job, they make the product as well as you could make by hand. We have a whole commercial plan that once we develop the machines for commercialization of the RCC product we can use those same machines to manufacture for other indications. The machines will also allow us to move into other geographies, for example Eastern Europe, where you wouldn’t need a lot of skilled labour to make the product – you would just need operatives for the machines.
In fact, while our Phase III trial is going on this year, we plan to initiate a few additional small Phase II trials to investigate the effects of AGS-003 in earlier stage RCC as well as in other solid tumors.
Where can readers find more information?
They can visit our website: www.argostherapeutics.com
We also have another website that is dedicated to our Phase III clinical trial which we call the ADAPT study: adaptkidneycancer.com/
Finally I think there is a great amount of information on Kidney Cancer Association website: http://www.kidneycancer.org/
Would you like to make any further comments?
It is disappointing that other immunotherapies are moving into late-stage clinical settings without any demonstrations that their MOA is working the way they planned. For example, there was never any demonstration with Stimuvax that the immune response against the antigen they were using had anything to do with clinical outcome. I think the failure to demonstrate the mechanism of action hurts the immunotherapy industry as a whole with these late-stage failures. Even Provenge, received FDA approval but had no correlation between immunity to their prostate cancer antigen and end stage clinical outcome. If you asked them how their product is working, I don’t think anyone really knows. It certainly doesn’t seem to be working by the mechanism that is advertised.
From the standpoint of having no biomarker to measure whether your product is working as intended, it makes it very difficult to develop the next generation of improved products because it is basically a black box.
So I think Argos has a significant advantage in that we stand alone with respect to our ability to show that our mechanism of action is a statistically significant predictor of outcome.
About Charles A. Nicolette, Ph.D.
Charles A. Nicolette is the Chief Scientific Officer and Vice President of Research and Development at Argos Therapeutics, Inc.
Charles Nicolette received his Ph.D. in biochemistry and cellular and developmental biology from the State University of New York at Stony Brook, completing his doctoral dissertation and post-doctoral fellowship at Cold Spring Harbor Laboratory.
Prior to joining Argos, Charles invented and personally financed a patent on SPHERE technology which he licensed to Genzyme Corporation. Genzyme hired him as Director of Antigen Discovery for cancer vaccine development where he directed pre-clinical, translational and clinical stage programs for the next 6 years.
He joined Argos Therapeutics in August 2003 and has overseen the development of all of Argos’ pipeline products from preclinical through Phase III clinical development. He is the inventor on dozens of patent applications primarily relating to vaccine development for malignant and infectious diseases.