Dr. Duane Mitchell’s research includes pioneering clinical trials in medulloblastoma (Re-MATCH) and glioma (PEACH), which have confirmed the potential of this approach as a platform for cures. In the following interview, Dr. Mitchell shared with Dan Wilcock of Children’s National Hospital (Washington DC) his excitement about the three clinical trials that will soon begin thanks to MBI’s support.
Can you describe the three clinical trials that are currently being planned?
DM: The first study focuses on personalized treatment with immunotherapy.
The personalized adoptive cell therapy approach uses a patient’s genetic material—RNA derived from their own tumor—in dendritic cells, which are the de facto generals of the immune system and instruct T cells on what to attack. We use dendritic cells both as a vaccine and as a platform to grow large numbers of activated T cells against the patient’s tumor.
In addition to injecting these cells as a vaccine, we also grow billions of these personalized T cells outside the patient in a clinical lab using growth factors. This produces much larger numbers of cells than are possible inside the body. These additional cells are then injected into the patient, who continues to receive the vaccines. After that, these T cells circulate throughout the body—they travel to the brain and attack brain tumor cells wherever they find them. That’s the goal.
We are the only lab in the world that is taking this specific approach.
This first study in Group 4 medulloblastoma will also include what is called immune checkpoint blockade. We learned from our previous studies that we need to help the activated T cells to remain active in the long term. Checkpoint blockade prevents the T cells we are infusing from becoming exhausted or deactivated once they reach the tumor. This allows them to persist, expand, and remain in a much stronger activated state, leading to better tumor elimination.
The second study is an RNA nanoparticle vaccine. This is a newer strategy that we’ve developed in our research program. As we’ve looked at our platform of using tumor-derived RNA to load dendritic cells and stimulate the immune system, we asked ourselves if we could package the RNA into a carrier that could deliver that RNA to dendritic cells in the body. We want to test whether we can deliver the RNA directly, like a vaccine.
We’re pretty familiar with RNA vaccines these days because of COVID-19. These vaccines use mRNA packaged into a carrier we call a liposome to stimulate the immune response. In fact, we started working on this years before the pandemic. The approach involves using a custom RNA extracted from the patient’s own tumor, but this time, the liposome can deliver the RNA directly to the immune cells in the body. It’s injected intravenously. We’ve shown that this can stimulate a very potent immune response. We think this is a very novel and exciting strategy for Group 4 medulloblastoma.
It’s an RNA nanoparticle vaccine. This is a newer strategy that we’ve developed in our research program. As we’ve looked at our platform of using tumor-derived RNA to load dendritic cells and stimulate the immune system, we asked ourselves if we could package the RNA into a carrier that could deliver that RNA to dendritic cells in the body. We want to test whether we can deliver the RNA directly, like a vaccine.
The third study combines elements of the first two studies. We call this third treatment strategy precision adoptive cell therapy. It uses a predictive computer algorithm that we developed — Open Reading Frame Antigen Analysis (ORAN). This allows us to study the patient’s unique immune system along with the specific genes expressed in the patient’s tumor, and compare that information to proteins normally expressed in the human body.
We believe that this will allow us to identify, in each tumor, what are the real, unique components that the patient’s immune system might recognize as foreign. Then we can develop an RNA-based vaccine that finely targets these tumor-specific antigens, whether they are mutations or uniquely expressed proteins.
Once we have profiled tens of thousands of genes, we can narrow those genes down to 50, 100, or maybe 300. Then we can create a very specific, personalized vaccine or T-cell therapy that targets these unique antigens in the patient.
We have also developed a process to identify which T cells are actually responding. Rather than expanding the capacity of a large number of T cells, we select very specific T cells that are responding well to specific antigens expressed on the patient’s own tumor. We believe that it will be possible to enrich hundreds or even thousands of times for the right T cells if we target the right antigens. This approach is much more powerful for both an RNA liposome vaccine and a T cell therapy. This will take us from personalized immunotherapy to precision immunotherapy.
What is the minimum time frame for these studies to start?
DM: The first two studies are using approaches that have either already been tested in the clinic or are just beginning to be tested in clinical trials. So I think we’re talking about a 6-12 month timeframe to start a clinical trial. For each of these studies, we’re proposing a pilot trial with about 6-9 patients. That’s enough to understand the safety profile, the immune response, and whether there were clinical responses in any of the patients treated. And we think that’s the right amount of information to then proceed with a much larger trial, if these initial results generate enthusiasm to move forward.
The third study needs to go through what’s called an Investigational New Drug (IND) application. The first two studies will be conducted with existing INDs. For the third, we need to submit a data set to the FDA in the US. That’s probably going to take 12-18 months.
How close do you think we are to saving the lives of patients with relapsed Group 4 tumors?
DM:
As a scientist, I know the current reality that we do not have a standard treatment that provides long-term cure in this relapse setting. Being cautiously optimistic, I believe that in the next 5 years we will see different outcomes for patients with recurrent Group 4 medulloblastoma. I am hopeful that the day is not far off when we will be able to tell a parent that we are going to treat their child with high-risk medulloblastoma differently. We will be able to say, based on the risk assessment, that we have a very, very high probability of beating this disease at the time of diagnosis. For those who do have a relapse, we will have effective treatments that we believe have a high probability of controlling the disease.
I have never seen a field advance and change as dramatically as immunotherapy has in the last 10 years. I know that we have not yet made significant advances in brain cancer because we are not yet curing 100% of patients. But I do believe that there are advances, and the field is gaining a lot of momentum toward positive outcomes.
To read the full interview, download the MBI August 2023 Report.
