Personalized Vaccine Demonstrates Promising Responses in Patients With Glioblastoma

David A. Reardon, MD

David A. Reardon, MD

The use of personalized neoantigen vaccines demonstrated promising results in a recent phase I/Ib trial of patients with glioblastoma.

Newly diagnosed patients typically undergo surgical resection, followed by a radiation therapy. In this small study, presented at the 2018 AACR Annual Meeting, researchers at Dana-Farber Cancer Institute created personalized vaccines for 8 patients based on their individual tumor types following standard of care treatment.

While only a small number of patients were enrolled on this trial, investigators found evidence of neoepitope-specific T cell responses to the vaccine in a subset of patients, according to David A. Reardon, MD. There was also a correlation found between response to the vaccine and corticosteroids. Patients who received a corticosteroid to treat inflammation did not respond, while patients that did not require corticosteroid therapy showed promising responses to the vaccine.

In a disease that is both deadly and difficult to treat, Reardon says these findings provide hope for the feasibility of immunotherapy approaches in this patient population.

In an interview withTargeted Oncology, Reardon, clinical director, Center for Neuro-Oncology at Dana-Farber Cancer Institute, discussed the results of this trial in further detail, and explained the impact these findings will have on future research for glioblastoma.

TARGETED ONCOLOGY: Can you provide an overview of your recent trial with personalized vaccines in glioblastoma?

Reardon: Our trial involved administration of a personalized, individualized vaccine for patients with newly diagnosed glioblastoma, the most common and deadliest cancer arising in the central nervous system in adult patients. This is a tumor that has proven refractory to therapy and our currently available best treatments are essentially palliative, unfortunately. We took a novel approach where we took advantage of next-generation sequencing technology to characterize the mutational burden or landscape in each individual patient's tumor, and then using established algorithms, we were able to predict the coding mutations that gave rise to mutant peptides that were most likely to be immunogenic for each individual patient, based on their individual human leukocyte antigen status. We then synthesized the top 20 of those coding neoepitope peptides predicted to be most immunogenic for that patient and administered those peptides back to the patient as an individualized, personalized vaccine for their tumor.

The standard of care for newly diagnosed patients is surgical resection. They have to heal for 3-4 weeks, then they undergo radiation therapy, typically with chemotherapy, and that phase takes about 6 weeks. Then patients have a 4-week break typically built into the standard of care therapy. This standard of care really lent itself to this approach. While they were recovering from their initial surgery, undergoing radiation therapy for 6 weeks, and then having a few weeks recovery, we took advantage of that time period to generate their individual vaccine, because as you can imagine, this is a labor-intensive effort and done on an individualized basis. It does take time, even with the new technology that is now routinely available for patients. The timing of being able to incorporate this into a standard of care approach for these patients really works well in this particular indication.

After they finish their radiation therapy, their vaccine would be prepared. We would have it ready, and then they would undergo a series of priming vaccine injections of up to 20 tumor specific neoepitope peptides. We gave 5 doses over 4 weeks as the timing phase, which was then followed by separate booster doses of these same 20 neoepitope peptides, spaced out at 8-week intervals. That was the treatment approach basically: 5 priming vaccines followed by 2 booster intervals at separate 8-week intervals.

We treated 8 patients on this initial experience. In 5 of the patients, we were able to collect blood for in-depth immunologic analyses, comparing prior-to-vaccination to post-vaccination, and we were able to interrogate how well the vaccine worked in generating effective immune responses.

Unfortunately, in 3 of the patients enrolled, they progressed before we could really get to the point where we could collect blood after their priming to do the analysis of the vaccine's effects. I think that underscores the difficulty of the indication we are dealing with here. Nonetheless, in 5 patients, we were able to analyze the pre- and post-vaccination responses and, interestingly, in those 5 patients, in addition to peripheral blood, we also had tumor samples at the time of radiographic progression so that we could not only compare the peripheral blood and the systemic immune responses pre-and post-vaccination, but the tumor samples. Of course we had tumor samples from prior to therapy, as well as at the time of progression, so we were able to compare the those as well to see if the vaccine had worked.

TARGETED ONCOLOGY: What were the results of this study?

Reardon: We saw pretty striking evidence of multi-neoepitope responses to the vaccine that we generated in a subset of patients, including remarkable multiple neoepitope peptide responses and fully functional T-cells specific for the mutant peptide and not the wild-type. Even though there is typically only 1 amino acid difference between the wild-type and the mutant neoepitope peptide, it was sufficient enough to generate specific immune responses to that mutant neoepitope peptide.

We saw patients who didn't respond, and we saw a very important correlation of whether patients responded or not, based on whether they were receiving concurrent corticosteroids therapy.

With brain cancer patients, there's often a lot of swelling in the brain associated with the tumor, which can be exacerbated by surgery and radiation therapy. If that swelling causes symptoms, like headaches, functional deficits, difficultly seizures, we have to treat that swelling with anti-inflammatory medicines and the only anti-inflammatory medication that effectively improves symptoms related to cerebral edema is dexamethasone (Decadron). Decadron is a highly-potent corticosteroid. It's 5-10 times more potent than prednisone or Solu-Medrol and it does decrease the inflammatory reaction in the brain. Patients who developed symptomatic cerebral edema requiring corticosteroid dosing while they were getting their vaccine priming, unfortunately, didn't respond. So that potent anti-inflammatory effect also negated their immunological response to the vaccine, unfortunately. The patients who did not require corticosteroids, those are the ones who responded beautifully. Although we are dealing with small numbers of patients, it was a striking correlation. Any corticosteroids done in priming, no immunological responses. No corticosteroids, nice responses.

TARGETED ONCOLOGY: Were there any other significant discoveries you came across with these findings?

Reardon: Another important observation we made is that the glioblastoma type of tumor is one that is a characteristically and immunologically cold tumor with a microenvironment that has very few infiltrating immune-effector cells. We could look at the pre-vaccine immune landscape from the patient tumors and because we had tumor collected post-vaccination, we could look to see how the immune infiltrate in the microenvironment changed post-vaccination. In the patients who weren't getting the steroids, who had the nice immune responses to the vaccinated neoepitope peptides, we also saw a striking, statistically significant increase in various immune effector cells into the tumor microenvironment. With this personalized, individualized vaccine approach, we were able to convert a cold tumor microenvironment to at least a warm or inflamed one with a significant immune infiltrate.

The final important discovery observed was that we were able to do to T-cell receptor clonality analyses, where that analysis identified specific T-cell receptors (TCR) for the neoepitope peptides that we vaccinated against in the reactive T-cells in the peripheral blood. Because again, we had the tumor tissue from patients after vaccination. We were able to separate out the immune effector cells from those tumor samples and identify identical TCR clones in the brain, in the tumor, as opposed to the same ones that were identified in the blood, so we had identical TCR clones in the peripheral blood, and in the brain after vaccination.

This is the first documentation that a systemically-induced tumor-specific immune response can effectively traffic into the brain and infiltrate into the tumor in the glioblastoma tumors. Although it's a fairly obvious expectation that we would like to see the vaccine-generating tumor-specific immune responses systemically, we also really have to confirm that they are getting to where they need to go to have their anti-tumor effect. This is the first evidence in this disease and indication where this has been able to be accomplished by an immunotherapy treatment approach. It's a small step with a small number of patients, but it is an important one to highlight the ability of a personalized vaccine approach utilizing tumor-specific mutations to generate tumor-specific antitumor T-cells for them to potentially impact this disease in the tumor with a cold microenvironment.

Importantly, glioblastoma is also a tumor that has a relatively low mutational burden. Our group has also demonstrated that this neo-antigen vaccine approach is possible and successful in melanoma, but we know that's a tumor with a high mutational load. Being able to take advantage of those mutations and identify a personalized vaccine in a setting like that is important, but it's one that is more relevant or more feasible in that setting. When you have a tumor with a ten-fold lower tumor mutational burden, can you still pick out and identify the appropriate neoepitope or coding mutations and utilize this approach? Indeed, in our experience we were able to confirm and demonstrate that this type of approach is feasible in a tumor with a cold microenvironment and characterized by a relatively low mutational burden.

TARGETED ONCOLOGY: Are there any follow-up steps you plan to take with these results?

Reardon: Yes, our next step is ready to go. Next, we are going to combine this neoantigen vaccine with checkpoint blockade. We have a study that we are going to initiate with approximately 30 new patients who enrolled for this summer. We are anxious to see if the addition of a checkpoint blockade can potentially expand the number of responding neoepitope peptides —T-cells responding to the number of vaccinated neoepitope peptides – and hopefully we can block some of these suppressive factors in the microenvironment, particularly those mediated by checkpoint blockade, to allow the T-cells to have a more significant impact.

TARGETED ONCOLOGY: What do you think is the takehome message from this study for community oncologists?

Reardon: I think the take home message is that for glioblastoma, a very deadly and challenging disease, this study provides some hope that immunotherapy approaches are feasible and may be able to be successfully exploited for this disease. It's still very early with a long way to go, but what we've been able to demonstrate here is that we can successfully stimulate tumor-specific immune cells that could have a potentially meaningful impact. The takehome message for community oncologist is that our study helps to provide hope that immunotherapy can have a benefit in this very challenging group of patients.