Dr. Duane Mitchell's research includes pioneering clinical studies in medulloblastoma (Re-MATCH) and gliomas (PEACH), which have confirmed the potential of this approach as a platform for cure. In the following interview, Dr. Mitchell shared with Dan Wilcock of Children’s National Hospital (Washington DC) his excitement about the three clinical studies that will soon begin thanks to MBI’s support.
DM: The first trial is of a personalized immunotherapy treatment.
DM: O primeiro estudo tem foco no tratamento personalizado com imunoterapia.
The personalized adoptive cell therapy approach takes the patient’s genetic material — the RNA derived from their own tumor — to load dendritic cells, which are really the generals of the immune system that instruct the T cells what to attack. We use dendritic cells both as a vaccine and as a platform for expanding a large number of T cells that are activated 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 grade laboratory using growth factors. This produces much larger numbers of cells than can be achieved inside the body. These additional cells are injected into the patient, who we continue to boost with vaccines. These cells then circulate throughout the body – they traffic to the brain and attack the brain tumor cells wherever they see them. That is the goal.
We are the only lab in the world doing this particular approach.
This first trial for Group 4 medulloblastoma will also include what we call immune checkpoint blockade. We learned from our earlier studies that we need to help the activated T cells persist long term. The checkpoint blockade prevents the T cells that we’re infusing from becoming exhausted or deactivating when they reach the tumor. With it, they persist, expand and remain in a much stronger activated state, leading to better tumor clearance.
The second trial is an RNA nanoparticle vaccine. This is a newer strategy developed within our research program. When we looked at our platform for using tumor-derived RNA to load dendritic cells to stimulate the immune system, we asked whether we could package the RNA into a carrier that can deliver it to dendritic cells in the body. We want to test whether we can deliver the RNA directly as a vaccine.
Today, we’re all pretty familiar with RNA vaccines due to COVID-19. These vaccines use mRNA packaged into a courier which we call a liposome to stimulate the immune response. We actually began this work years before the pandemic. The approach is to use a personalized RNA extracted from the patient’s own tumor, but this time the liposome can deliver the RNA directly to the cells of the immune system in the body. It’s injected intravenously. We have shown that this can stimulate a very potent immune response. We consider this a very innovative and exciting strategy for Group 4 medulloblastoma
The third trial combines elements of the first two trials. We call it a precision adoptive cellular therapy treatment. It uses a computer algorithm and prediction capability that we have developed called Open Reading frame Antigen Analysis (ORAN). This can study the patient’s unique immune system alongside the specific genes being expressed in the patient’s tumor and compare it to information about every protein that is normally expressed in the human body.
We anticipate this will enable us to identify the real, unique components in each patient’s tumor that their immune system could recognize as foreign. We then can develop an RNA-based vaccine that exquisitely targets those tumor-specific antigens, whether they are mutations or uniquely expressed proteins.
Once we’ve profiled tens of thousands of genes, we may narrow it down to 50, 100 or even 300 genes. We then can make a very specific, very tailored vaccine or T cell therapy that homes in on those unique antigens of the patients
We have also worked on a process to identify which of the T cells are actually responding. Instead of expanding large numbers of T cells to great capacity, we can really select the very specific T cells that are responding well to the very specific antigens that are being expressed in the patient’s own tumor. We believe we’ll get hundreds, if not thousands-fold enrichment of the right T cells targeting the right antigens. This is a much more potent approach, either for an RNA liposome vaccine or for a T cell therapy approach. It will bring us from personalized to precision immunotherapy
How quickly can we launch these trials?
DM: DM: The first two trials take approaches that have been in the clinic or are already starting in clinical trials. We will likely need about 6 to 12 months to start clinical trials. For each of these trials, we are proposing a pilot clinical trial of between six and nine patients. That is enough to understand the safety profile, the immune response and whether we’ve seen clinical responses in any of the patients that were treated. We believe that’s the right amount of information to then go for a much larger trial, should those initial findings really generate the enthusiasm to go forward.
The third trial must go through what’s called an Investigational New Drug (IND) application. The first two trials will run under existing INDs. For the third, we need to apply to the U.S. Food and Drug Administration. This will likely take 12 to 18 months. How close do you think we may be to saving lives among patients with the relapsed Group 4 tumors?
DM: As a scientist, I know the reality that we currently don’t have a standard of care that can lead to long-term cures in that relapse setting. If I’m cautious but very optimistic, I believe in the next five years we’re going to see different outcomes for patients with recurrent Group 4 medulloblastoma. I’m hopeful that we’re not far from the day of being able to tell a parent with a high-risk medulloblastoma that we’re going to treat their child differently. We’ll be able to say, based on their risk assessment, that we have a very, very high probability of being
DM: As a scientist, I know the reality that we currently don’t have a standard of care that can lead to long-term cures in that relapse setting. If I’m cautious but very optimistic, I believe in the next five years we’re going to see different outcomes for patients with recurrent Group 4 medulloblastoma. I’m hopeful that we’re not far from the day of being able to tell a parent with a high-risk medulloblastoma that we’re going to treat their child differently. We’ll be able to say, based on their risk assessment, that we have a very, very high probability of being able to defeat this disease in the newly diagnosed setting. For those that do have a relapse, we’ll be able to say that we have effective treatments that we think have a high probability of controlling the disease.
To read the full interview, download the August 2023 MBI Report.