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Investigational vaccine confers ‘striking’ benefit in glioblastoma
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The addition of an investigational vaccine to chemotherapy led to unexpectedly longer survival for patients with glioblastoma, according to results of a small study published in Clinical Cancer Research.
The combination also appeared well tolerated.
Glioblastoma is the most common primary malignant brain neoplasm, accounting for 15% of all intracranial tumors. It also is the most aggressive. Median survival is less than 15 months, and two-thirds of patients die within 2 years.
Kristen Batich, MD, PhD, research scientist at Duke Cancer Institute, and colleagues conducted a single-arm study to test the safety of a dose-intensified regimen of temozolomide plus a dendritic cell vaccine therapy that selectively targets a cytomegalovirus protein. Cytomegalovirus proteins are prevalent in glioblastoma tumors but not surrounding brain cells.
Batich and colleagues enrolled 11 patients with newly diagnosed glioblastoma. Patients first received a cycle of dose-intensified temozolomide (100 mg/m2 per day for the first 21 days of a 28-day cycle), followed by at least three vaccines with pp65 lysosome-associated membrane glycoprotein mRNA-pulsed dendritic cells mixed with granulocyte-macrophage colony–stimulating factor (GM-CSF). If tumors did not grow, patients continued to receive monthly 28-day dose-intensified temozolomide cycles with pp65 dendritic cells on day 23 of each cycle. HemOnc Today spoke with Batich about the study results and their potential implications.
Question: What prompted your study and what did you intend to assess?
Answer: Our group is investigating ways we can use the immune system to treat patients with glioblastoma. One of the key components of this approach is to identify appropriate targets, and educate and direct the immune system to fight tumor-specific targets in a very safe manner. These 11 patients were treated separately from a larger cohort of newly diagnosed patients who received dendritic cell vaccines that target the cytomegalovirus protein pp65 in conjunction with standard-dose regimens of temozolomide. In this separate cohort, we wanted to test if a dose-intensified regimented chemotherapy would enhance our dendritic cell vaccines that target cytomegalovirus. We wanted to know if it would be feasible and safe. We also established exploratory objectives that looked at efficacy and survival.
Q: Why did you think this regimen might be effective?
A: Using the immune system has the capacity to generate very profound immune responses if you can educate the body in the proper way, and it also has the further advantage of the capacity for memory. Thus, it’s a longer-lasting therapy. It is much more specific than chemotherapy regimens and other treatments. It’s also a very safe and highly specific premise for a therapy for patients with brain tumors. We would love to identify more tumor-specific targets that can be utilized to educate the immune system. However, right now, there aren’t many identifiable tumor-specific targets that every patient would carry or demonstrate.
Q: Which patient population did you include in your study?
A: Upon diagnosis, patients underwent a standard regimen that entailed total or near-total resection of the tumor, followed by a 6-week course of standard temozolomide in conjunction with radiation therapy. A posttreatment MRI scan evaluated changes in responses to that regimen. If the tumor hadn’t progressed, patients became eligible to participate in clinical trials such as this.
Q: Can you describe safety outcomes?
A: We observed no serious adverse events related to the cellular portion of the dendritic cell vaccine. We did observe side effects that corresponded to those we historically observe with temozolomide, such as nausea, vomiting, low platelet counts and low lymphocyte counts. One patient, after eight doses of the vaccine, developed a grade 3 allergic reaction to the GM-CSF. The patient had developed antibodies to the GM-CSF, so the GM-CSF was removed from this patient’s vaccine. This individual continued the study and received the vaccine with no subsequent problems.
Q: Did these results surprise you?
A: Prior to administration of each vaccine, we would perform a blood draw to analyze the functionality and activity of the T cells circulating in patients’ blood. After three vaccines, the functional response to pp65 increased in nearly every patient. All but one demonstrated a significant increase in their activity from the time prior to the first vaccine to after the third vaccine.
Q: What did you find in terms of efficacy?
A: Patients had profoundly striking outcomes compared with those who historically received standard of care. We observed median PFS of 25.3 months and median OS of 41.1 months. Control-matched patients treated with standard of care and additional therapies upon tumor recurrence had a median PFS of 8 months and median OS of 19.2 months. At the time of analysis, four patients had not experienced tumor growth. These data were taken 59 to 64 months after diagnosis, which is incredibly extended survival compared with what we typically see. We followed these four long-term survivors after the study ended. One died 77 months after diagnosis; however, three are still alive without any tumor growth at 85 to 88 months after diagnosis. This is pretty remarkable for a tumor like this, which has such a dismal prognosis.
Q: Did the efficacy results surprise you?
A: We were surprised by these long-term survivors. This is the second time we observed long-term survivorship among patients who received dendritic cell vaccines. Our study was part of a larger clinical trial in which patients received standard temozolomide with the same dendritic cell vaccine. This randomized study targeted pp65, although the vaccine did not contain the GM-CSF agent. Six patients received preconditioning with a control vaccine; the other six received the same therapy with a tetanus booster at the vaccine site. Three of six patients who received the tetanus booster achieved long-term survival. One patient is alive 10 years after diagnosis. These are small studies, but some patients have profound responses, way beyond what one might imagine. We are passionate about investigating why some patients have such strong immune responses.
Q: What is the next step in your research?
A: We will investigate the expression within the tumor of these cytomegalovirus proteins, looking at changes to first baseline expression upon diagnosis and evaluating changes in the tumor over time, should patients recur. We also plan a study in which we will compare the effects of dose-intensified temozolomide with a standard temozolomide regimen in conjunction with a vaccine that targets cytomegalovirus proteins.
Q: What is the potential impact of your research?
A: Glioblastoma is the most devastating primary malignant brain tumor in adults. Even with aggressive therapy, 50% of patients only survive 15 months. There is a tremendous need for safer, more effective therapies. We believe utilizing the immune system is a safer, more specific approach. With that comes the need to identify potential targets within tumors, and then evaluate if those targets are present in every patient. If not, we must determine how we can personalize this vaccine strategy in a feasible, scalable way. – by Kyle Doherty
Reference:
Batich KA, et al. Clin Cancer Res. 2017;doi:10.1158/1078-0432.CCR-16.2057.
For more information:
Kristen Batich, MD, PhD, can be reached at kristen.batich@duke.edu.
Disclosure: Batich reports being a co-inventor on a patent with two other researchers for an approach designed to improve the immunogenicity of dendritic cell vaccines. Please see the full study for a list of all other researchers’ relevant financial disclosures.