Researchers have speculated that adding vaccines to standard-of-care checkpoint-inhibitor monotherapy for some cancers might make treatment more potent. Now, a clinical trial suggests that the investigational personalized neoantigen vaccine NEO-PV-01 (Neon Therapeutics) boosts the effectiveness of the PD-1 inhibitor nivolumab (Opdivo; Bristol-Myers Squibb). The patients showed improvement over historical results for nivolumab alone.
As genome sequencing has become faster and less expensive, researchers have begun developing custom vaccines that target neoantigens specific to each patient's tumor. Cancer vaccines have a poor record as single agents—only one is FDA approved. However, personalized vaccines that target tumor-specific antigens are immunogenic in patients with melanoma, so they could synergize with checkpoint inhibitors.
To test this hypothesis, researchers enrolled 82 patients—34 with melanoma, 27 with smoking-associated non–small cell lung cancer (NSCLC), and 21 with bladder cancer—in a phase Ib trial. All patients had metastatic disease and received nivolumab while their vaccine was being manufactured and then concurrently with the vaccine, for a total of 2 years of treatment.
To create the personalized vaccine, researchers performed next-generation sequencing on DNA and RNA from each patient's tumor to identify neoantigens. Next, they analyzed the neoantigens to predict which ones were likely to stimulate an immune response. The scientists then incorporated peptides from the most promising candidates into a vaccine.
Manufacturing each patient's vaccine takes about 10 to 12 weeks from “needle to needle,” or from biopsy to the first injection, says Patrick Ott, MD, PhD, of Dana-Farber Cancer Institute in Boston, MA, a lead investigator for the trial.
The most recent top-line results from the trial, which the company released in July, showed that the vaccine caused side effects such as pain at the injection site and flu-like symptoms for 88.3% of patients. Two patients had side effects of grade 3 or higher after vaccination.
Analysis of tumor and blood samples from 12 patients with melanoma showed CD4+ and CD8+ T-cell responses to the neoantigens in the vaccine and tumor infiltration by T cells. The researchers also detected epitope spreading, a phenomenon in which T cells begin targeting neoantigens that aren't in the vaccine but that may be released by dying tumor cells. That finding suggests that the vaccine triggers destruction of tumor cells not only via neoantigen-specific T cells, but also by stimulating a broader range of T cells.
After a median of 13.4 months, the patients with melanoma had not reached their median progression-free survival (PFS), and 47% of them showed a response. Median PFS for the patients with NSCLC was 5.6 months, with a 22% response rate, and 5.6 months with a 24% response rate in patients with bladder cancer.
“The median PFS in all three tumor types is better than in historical controls,” notes Ott. For instance, two trials of nivolumab for metastatic melanoma reported median PFS of 3.1 and 6.9 months. The increased PFS could be a sign that “the vaccine is helping to generate immune responses that the PD-1 inhibitor can enhance,” Ott says.
“I think it's highly important,” says Cornelis Melief, MD, PhD, of Leiden University Medical Center and ISA Pharmaceuticals in the Netherlands, who wasn't connected to the research. The results demonstrate that “one can increase levels of T cells with a completely nontoxic and highly specific vaccine developed against neoantigens.”
Next year, Neon Therapeutics plans to launch a trial in patients with metastatic melanoma comparing the vaccine plus a checkpoint inhibitor to the checkpoint inhibitor alone. Melief says that researchers could also assess the vaccine by determining whether it restores responses in patients who are resistant to PD-1 monotherapy. “That would be a spectacular demonstration of the added value” of the vaccine. –Mitch Leslie
- ©2019 American Association for Cancer Research.
Volume 9, Issue 9
