Paul E. Oberstein, MD, discusses autogene cevumeran, a personalized mRNA vaccine, being evaluated in pancreatic ductal adenocarcinoma.
Promising early data coupled with a highly anticipated phase 2 trial has set the stage for a personalized, novel mRNA vaccine–based regimen with autogene cevumeran (BNT122; RO7198457) to answer questions about achieving longer-term disease control for patients with pancreatic ductal adenocarcinoma (PDAC), according to Paul E. Oberstein, MD.1,2
“[Autogene cevumeran] excites people to look at vaccines again and more closely. The challenge with vaccines, [whether they are] off-the-shelf or customized, is always being able to predict who it's going to benefit. There are certainly hints that vaccines help specific individuals by getting immune response and preventing tumor recurrence,” Oberstein said in an exclusive interview with OncLive®.
In the interview, Oberstein broke down the vaccine and its mechanism of action, in addition to highlighting
Oberstein is an associate professor in the Department of Medicine, service chief of the Gastrointestinal Medical Oncology Program, and assistant director of the Pancreatic Cancer Center at Perlmutter Cancer Center of New York University Langone Health in New York.
Oberstein: This is an exciting time for pancreatic cancer, and one of the exciting developments is the possibility of having a cancer vaccine that would prevent recurrence of pancreatic cancer. The rationale behind cancer vaccines, in general, is that there are people who are found to have long-term disease control, meaning they get surgery or treatment for their pancreatic cancer, and their disease never comes back. [Patients who experience long-term disease control represent] a small number of people currently with pancreatic cancer. There are differences [in] the immune system [of] patients whose [are able] to fight or prevent the cancer from coming back. The pursuit of a vaccine is [to see whether] we get more of that. Could we stimulate the immune system to recognize the cancer cells as being foreign and therefore prevent them from growing to prolong survival?
One of the challenges of vaccines, [not only] in cancer but in many areas, is to convince the body's immune system that something is different and that needs to be targeted. If it's a cancer, cancer [cells] come from normal cells, and part what has been done in some of the work that led to this vaccine was identifying specific neoantigens—antigens that are tumor specific and the body's immune system can recognize and target. This vaccine takes a person's individual tumor, [and it undergoes] sequencing and other analytics to identify specific epitopes or specific areas in the tumor that might make the body's immune system effective in killing that cancer cell. [This mechanism] is an important part of [the vaccine]: it's a huge discovery [comprising] tremendous computational and other science.
The other innovative part of the mRNA vaccine is that it can be designed very quickly. Since this is customized based on the individual's tumor, you can't make an off-the-shelf vaccine and give it to everyone. It has to be done for that person, and the technology to do that didn't exist a decade or two ago. It's really new technology that's being refined and implemented in this vaccine to go from taking a person's tumor, analyzing it, and several weeks later, having a vaccine that you're ready to give to that person.
A phase 1 trial [showed] that it's feasible. The phase 1 trial ultimately included 16 patients, and all of them were able to get a vaccine and chemotherapy. What the earlier results had shown was that half of the patients had a strong sign that their body had recognized this vaccine. There were parts in the immune system that were present, served as memory, and were fighting tumors, or at least around to fight tumors after administration of the vaccine.
When they looked at these patients, they split them into 2 groups: those who showed a significant response in their blood and those who didn't. What was found earlier is that those who had a real robust response to the vaccine had much better outcomes than those who did not. [These data suggest] that something about what the immune system and the vaccine are doing is contributing to those better outcomes. Data presented at the
You also have to think about all the people who got the vaccine. Sixteen patients were treated, and ultimately, [with] long term follow-up, 9 of the 16 were still alive, which is over 50%. That [survival rate] compares with a historical control somewhere in the 30% to 40% range. [Therefore, these survival rates are] somewhat better than what you'd expect. Obviously, in the group that had an immune response, [survival] was dramatically better, but in the overall group, [overall survival rates were] also better.
Ultimately this is the big question: Does it make sense to give this vaccine to everyone if you don’t know who's going to have an immune response?
[Regarding] risks, it is a vaccine, and you can have a reaction in the body to it. You also give something called immune checkpoint blockade to stimulate the immune system with the vaccine, and that has a low risk of immune reactions and immune-mediated adverse effects. All in all, the [safety] risk of the vaccine is generally low.
The T-cell responses are quite robust, at least in those who respond to the vaccine [by developing] these cells that are memory cells that can rechallenge and be present in the tumor microenvironment. [Among patients in the trial], there were isolated cases where a tumor grew [following receipt of the vaccine], and then it seemed like there was a response again in the tumor. There are strong signals that the immune system is stimulated by this vaccine and that it's done in a way that persists for many years.
The next step, which is ongoing and important, is to look at this in a larger patient population to do a couple of things. One is to understand: Can we do better with the vaccine? Meaning, will all patients who get the vaccine—not just those who have an immune response—do better than those who don't get the vaccine? [Determining this] takes a randomized trial. [The IMCODE003 trial is enrolling approximately] 260 patients, and half of them would get the vaccine and half would not, then we can see which regimen does better in the long run.3
The larger trial will also give us a sense as to whether there's any downside of the vaccine and if there is anything that we weren't anticipating that might happen by delaying chemotherapy or by activating the immune system this way. We don't know that from a 16-patient trial, but a larger trial will help. That trial is ongoing and almost completed [enrollment].
It is a very important trial and will answer a lot of questions about if the vaccine is helpful for everyone or for certain people, how to predict who will benefit from the vaccine, and how to make the vaccine better so that we can keep using it for more people with more benefit.
