Oncology Times, September 17, 2019 – By Rebecca Hepp
Researchers on the hunt for a cure for melanoma are one step closer with positive phase IIb results for a personalized cancer vaccine that shows a 50 percent reduction in recurrence for patients who completed the majority of the vaccination series. The prospective, randomized, double-blind, placebo-controlled clinical trial met its primary endpoints at 24 months without any significant safety concerns—and researchers are forging ahead to the next 36 month benchmark with high hopes.
“We know these patients have a very high risk of recurrence—at least a 50 percent chance, and it’s probably closer to 80 or 90 percent,” noted one of the study’s lead investigators, Adam C. Berger, MD, who is now Chief of Melanoma and Soft Tissue Surgical Oncology at Rutgers Cancer Institute of New Jersey. The data shows the personalized approach can cut that number in half, all without any serious side effects.
The TLPLDC (tumor lysate, particle-loaded, dendritic cell) vaccine is created using the patient’s own blood and tumor cells to capitalize on the body’s natural defenses. Samples are harvested at resection, frozen, and shipped to the lab where they are used to create autologous tumor lysate, which is loaded into pre-prepared yeast cell wall particles (YCWP). This combination is then introduced to the patient’s dendritic cells for phagocytosis, finally creating the TLPLDC vaccine.
“It was quite easy to create the vaccine; the amount of tumor needed to make the vaccine was quite small, and the turnaround time was such that patients could have their tumors removed and then be able to start the vaccine within [3-4] weeks,” according to Berger.
The 6-month vaccination regimen, which delivers the patient’s own unique blend of tumor antigens to the immune system, kick-starts an innate and adaptive response.
“In the past, researchers have used generic vaccines that contain proteins that are common in a lot of melanomas, but they aren’t specific to that particular patient,” Berger explained. “This is a much more personalized approach designed to retrain the immune system to recognize that these cells or proteins shouldn’t be there and to go find all of those abnormal cells and kill them.”
The added bonus of this approach is the ease of patient education, Berger added.
“Sometimes other treatments such as chemotherapy or immunotherapy have many side effects and it can be complicated,” he noted. “Some patients are turned off by that, but when you talk to them about having a vaccine, they can understand that you are making a vaccine that is really specific to their tumor, and patients tend to like that idea.”
To test the safety and efficacy of the novel vaccine, the research team at Thomas Jefferson University, led by Berger, who was the Chief of Surgical Oncology at Thomas Jefferson University at the time, substantially contributed to enrolling 144 patients with resected stage III and IV melanoma. Within 3 months of completing standard-of-care checkpoint inhibitor therapy for their melanoma, the study participants were given either the TLPLDC vaccine or an unloaded YCWP + autologous dendritic cell placebo in six doses over an 18-month span.
Because of the high risk of recurrence and because the vaccine requires time to activate the immune response, the researchers chose to vaccinate and analyze both the intent-to-treat (ITT) and the per treatment (PT) populations. (The study is also designed to offer an active vaccine for patients who experience recurrence in a crossover study fashion, as well as vaccination for control patients who did not experience recurrence at the completion of the trial).
Interim results, released last year at the 2018 ASCO Annual Meeting, showed a 32 percent relative reduction of recurrence at a median 12 months of follow-up, with no difference in the recurrence rate between the ITT and PT patients (Abstract 9525).
The 24-month co-analysis of the ITT and PT populations is a different story. These data show an overall recurrence rate of 54 percent in the vaccine group—which included those who were never or incompletely vaccinated—compared with 66 percent in the placebo group. While this represents a clinically relevant 18 percent relative risk reduction in recurrence, it’s not statistically significant, the researchers noted.
When they looked at the PT patients specifically, all of whom completed at least four of the six vaccine series, they found far more promising results. Only 29 percent of the vaccine group experienced disease recurrence compared with 56 percent in the placebo group—a 50 percent, highly statistically significant reduction in the relative risk of recurrence.
“The first three vaccines are given in the first 3 months, and for patients who have a high risk of developing recurrence, sometimes that’s not enough time for the immune system to mount the response to help prevent recurrence,” Berger explained. “So, we looked at those who received at least four vaccinations, and those were the patients who clearly did much better than the placebo group.”
Added to these promising results, the vaccine, perhaps because of it’s autologous nature, presented few adverse reactions. Only a third of the study patients had an adverse event related to the vaccine and most of them were grade 1 or 2, such as injection site reactions and flu-like symptoms, according to Berger.
“Chemotherapy and immunotherapy hit the whole body, so they can cause side effects, and for immunotherapy there can be immune side effects that are fairly serious,” Berger noted. “With this treatment we have something really targeted to the melanoma cells with low toxicity—it’s very safe.” The approach may prove particularly helpful for patients who can’t handle immunotherapy or who have had unsuccessful immunotherapy, he added.
When the researchers estimated the preliminary 36-month data, they found the vaccine is showing continued benefit beyond the initial 24-month mark.
All of this data means the team is moving ahead with the study’s 36-month endpoint analysis of disease-free and overall survival. The team is also working toward a phase III trial based on the 24-month data to show that the vaccine, likely in combination with other immunotherapies, could be standard of care, Berger said.