Hans J. Hammers, MD, PhD
As immunotherapy continues to show promise in renal cell carcinoma (RCC), different agents are being tested to find the most effective treatment. According to Hans J. Hammers, MD, PhD, vaccines should also be considered when studying combination immunotherapies.
In a small safety study of a novel allogeneic renal cell carcinoma vaccine, patients with metastatic renal cell cancer were treated with HyperAcute Renal (HAR) immunotherapy. This vaccine consists of two allogeneic renal cancer cell lines, which have been genetically modified to express alpha-1,3-galactosyltransferase, a carbohydrate that humans have an inherent pre-existing immunity to.
By targeting alpha-1,3-galactosyltransferase, the immune system can begin to identify antigens expressed by the patient’s own tumor cells, says Hammers.
“The idea is that cell-lines that have been modified in this particular manner can jumpstart an immune response,” he added.
In this phase I dose escalation study, patients received a weekly injection of HAR (150 x106
cells intradermally) for 4 weeks followed by biweekly injections for the next 10 weeks. Results showed tolerability and suggested that RCC is an appropriate tumor type regarding combination immunotherapy including HAR.
In an interview with OncLive
, Hammers, associate professor, UT Southwestern Medical Center, discussed the role of vaccines, potential next steps, and the future of immunotherapy in RCC.OncLive: Could you provide an overview of the phase I study on alpha-1,3-galactosyltransferase?Hammers:
The treatment is an allogeneic renal cell carcinoma vaccine, meaning these are cell lines derived from different patients than the patient being treated. They have been genetically altered to express a certain sugar molecule, alpha-1,3-galactosyltransferase, that we see, for example, in pigs. In fact, most of the antibodies that we have circulating in our blood, actually are formed against alpha-1,3-galactosyltransferase. So, if you either transplant an organ from a pig or inject cancer cells that have been spiked with alpha-1,3-galactosyltransferase, they would be rapidly destroyed, leading to active inflammation.
These were allogeneic cell lines, 2 different ones, and the patient got injected subcutaneously in essentially 2 different doses. Drug development for vaccines is much less complicated than it is for targeted agents. The trial was designed in a way that patients initially received injections once a week for 1 month and then every 2 weeks thereafter. It was also designed in a way that patients were not allowed to have any concurrent therapy for the first 2 months, but then could combine it with any standard of care therapy thereafter, such as tyrosine-kinase inhibitors, but also immune-checkpoint inhibitors as they became available.
What we presented at the GU Symposium are safety data on the 15 patients that we have more details on. And overall, there were no big surprises—it is very well tolerated, mostly local reactions and in the end, we have a dose that can move forward into phase II studies.Are there any next steps for future clinical trials?
We know it’s safe to do, but we still have to wait for some data—a subset of patients was actually treated with nivolumab (Opdivo) after 2 months. We stand to see what kind of impact it has—if there is some sort of clinical activity that might be enhanced. But I do think it deserves at least testing in combination with nivolumab (Opdivo), but to some degree it’s also a commercial decision by the company, if there is enough promising data. The goal of this phase I trial is achieved—we have a safe dose, now there are several other aspects that play into this.What do you want community oncologists to take away from this study?
I think the main message is that maybe it is time to revisit vaccines. We've spent a lot of time on the ridiculed recent trials that have been negative. There was a very large phase III trial that was negative, but vaccines have not really been tested in the context of immune checkpoint inhibition, and to some degree, that’s a natural marriage. We do know that vaccines will face challenges, in particular with what we've learned about immune checkpoints. So, combining vaccines with immune checkpoint makes a lot of sense.
There will be different approaches—allogeneic vaccines can be taken off the shelf very easily, but may not be as individualized as if you were to focus on analyzing a patient’s tumor and created tailor-made vaccines for the individual patients. But, that’s a more advanced approach. I think we will see several of these concepts tested in the clinic, I don't know if they are going to work, but I do think that vaccines need to be visited and that’s what we will see.What is the current role of immunotherapy in RCC, and where do you see it in the future?