Chicago – A newly developed heat shock protein peptide vaccination appears to be safe and effective in treating patients with newly diagnosed glioblastoma (GBM), according to the results of a phase II single arm study.
In adding the vaccine to standard therapy for 46 patients with newly diagnosed GBM, median overall survival was 23.8 months, and there were no grade 3 or 4 adverse events associated with the vaccine, lead author Dr. Orin Bloch of Northwestern University, Chicago, reported at the annual meeting of the American Society of Clinical Oncology.
Standard therapy typically results in a median survival of 16 months, he said.
“There is a lot of information out there right now regarding CNS and other solid organ tumors particularly in the area of checkpoint modulation and its ability to stimulate an innate immune response against a tumor. I think in GBM we are facing a bit of a different scenario, however, because the tumor exists in a very privileged area behind the blood brain barrier and doesn’t regularly metastasize beyond the CNS,” Dr. Bloch said.
Therefore, only modulating checkpoints without stimulating and educating the immune system may not be the most effective approach. Adaptive immunity through vaccination or some other form of stimulation might be more successful, Dr. Bloch said.
“As a way of inducing immune stimulation and education using tumor-autologous peptides, one can capitalize on the native system of heat shock stimulation. Heat shock proteins are chaperone proteins that are ubiquitously expressed in cells and they’re bound to any number of intracellular peptides at any one time including, in tumor cells, neoantigens. If you extract these heat shock proteins with their bound antigens and deliver them in a naked form into the systemic circulation, their uptake into antigen-presenting cells through the CD91 receptor [will result in] the peptide [being] cleaved and presented on MHC class one and two for stimulation of CD8- and CD4-positive T cell response,” he said.
Heat shock proteins also interact with toll-like receptors and stimulate the secretion of pro-inflammatory cytokines, “acting as their own adjuvant,” Dr. Bloch further explained. Utilizing heat shock proteins activates both the innate and adaptive immune responses.
“This is an ideal platform for developing an immunotherapy for glioblastoma,” Dr. Bloch said.
In this phase II study, 46 adult patients with GBM underwent surgical resection of their tumors followed by chemoradiotherapy. At least four 25-microgram doses of vaccine were generated from tissue obtained during surgery. Within 5 weeks of completing radiotherapy, patients began receiving weekly vaccinations in combination with adjuvant temozolomide. Patients continued receiving vaccines until depletion or until tumor progression.
Median progression-free survival was 17.8 months (95% confidence interval, 11.3-21.6) and median overall survival was 23.8 months (95% CI, 19.8-30.2).
PD-L1 expression on circulating monocytes was also measured from peripheral blood samples obtained during surgery. Patients were classified as having either high PD-L1 expression (54.5% or more of monocytes) or low PD-L1 expression. Among patients classified as having high PD-L1 expression, the median overall survival was 18.0 months (95% CI, 10.0-23.3). Patients who had low PD-L1 expression had a significantly longer median overall survival time of 44.7 months with a confidence interval not calculable (hazard ratio, 3.35; 95% CI, 1.36-8.23; P = .003).
Finally, a multivariate proportional hazards model showed the MGMT methylation status and PD-L1 expression were the two greatest independent predictors of survival.
“Survival among patients who received the HSPPV-96 was greater than expected compared to historical controls... These results certainly, we feel, provide rationale for a phase III trial of vaccine plus standard of care versus standard of care alone,” Dr. Bloch said.
“PD-L1 expression on circulating myeloid cells is independently predictive of clinical response to vaccination, and it suggests that the low PD-L1 expressing population will most benefit from this anti-tumor vaccination scheme, but it also suggests that high PD-L1 expressing patients may benefit from combined checkpoint inhibition. Systemic immunosuppression driven by peripheral monocyte expression of PD-L1 is a previously unidentified factor that may mitigate vaccine efficacy,” Dr. Bloch further commented.
This study was funded by the National Cancer Institute, the National Institute of Neurological Disorders and Stroke, the National Brain Tumor Society, the American Brain Tumor Association, and Accelerated Brain Cancer Cure. Dr. Bloch reporting having no relevant disclosures.
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