A vaccine created to prevent the recurrence of the deadly skin cancer melanoma is about twice as effective when patients also receive two components that boost the number and effectiveness of immune system dendritic cells (DCs), according to the results of a Phase II clinical trial published in Nature Cancer.
Researchers at the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, working with colleagues at the National Cancer Institute-funded Cancer Immunotherapy Trials Network (CITN) based at the Fred Hutchinson Cancer Research Center, tested the approach in patients treated using CDX-1401, a vaccine that is designed to target dendritic cells, and which is composed of an antigen found in melanoma bound to an antibody to increase the chances of binding with dendritic cells.
They found that addition of the small molecule, Flt3L (fms-like tyrosine kinase 3 ligand), which increases the number of dendritic cells, boosted the vaccine’s effectiveness at triggering the production of antibodies and T cells that can later fight melanoma. Adding the second component, poly-ICLC (a TLR3 agonist that activates DCs), also strengthened the dendritic cells’ ability to promote antibodies as well as helper, and killer T cells.
The team said the results are important because most cancer vaccine trials have failed to show clinical efficacy. The finding that the addition of two immune-boosting components can improve the immune response to the melanoma vaccine may also be relevant for patients with other types of tumor that express a vaccine antigen, which is common in some cancers.
“This is the first randomized clinical trial to show that an immune response to a cancer vaccine can be potentiated by the addition of Flt3L,” said Nina Bhardwaj, MD, PhD, director of the immunotherapy program at the Tisch Cancer Institute, who is first, and a corresponding author on the study. “The response was achieved because Flt3L mobilized dendritic cells, which are the gold standard in promoting cancer immunity, and improved the overall immunogenicity of the vaccine. This may change the approach of increasing efficacy in other cancer vaccines in the future.” Bhardwaj and colleagues reported the trial findings in a paper titled, “Flt3 ligand augments immune responses to anti-DEC-205-NY-ESO-1 vaccine through expansion of dendritic cell subsets.”
While cancer vaccines directed at tumor antigens can elicit immune responses, such responses are typically low, require multiple vaccinations, and are only generated in a minority of patients, the authors wrote. “Most randomized cancer vaccine trials have failed to show clinical efficacy … Failure of cancer vaccines can be attributed to many features, most fundamentally failing to target antigen-presenting cells (APCs) such as dendritic cells to elicit potent T-cell immunity.” Prior studies have shown that exogenously administered hematopoietin Flt3L (fms-like tyrosine kinase 3 ligand), can safely increase APCs, including circulating and tissue DC subsets, which points to a potential approach to increasing circulating DCs and increasing vaccine-induced immune responses.
For their Phase II, open-label, randomized trial, 60 patients who had stage 2 or 3 melanoma, and whose cancer was successfully removed via surgery, were treated using the vaccine, which comprises anti-DEC-205-NY-ESO-1, a fusion antibody targeting CD205, linked to NY-ESO-1.
Half of the patients in the study received the vaccine alone, while the other half received the vaccine with Flt3L and poly-ICLC. “Patients were randomized to vaccine (CDX-1401 + poly-ICLC) with or without pretreatment with CDX-301,” the team stated. “The current trial (CITN-07) hypothesized that vaccine formulation with CDX-301 would increase DC-mediated antigen processing and presentation to T cells, thereby yielding more effective immune responses.”
The results showed that the cocktail of vaccine, Flt3L, and poly-ICLC nearly doubled the vaccine’s efficacy, according to an analysis of the T cells detected in patients’ blood samples after they received four doses over four months. That immune response was seen significantly earlier in the patients who received the cocktail, and at much higher levels in many more patients, compared with responses in patients who received only the vaccine. The researchers also found that antibodies were still present in blood samples tested 12 weeks after the last dose. “Long-term immunity was evident months after the vaccine regimen, including recall of both CD4+ and CD8+ T cells,” they stated. The team did acknowledge that the trial wasn’t powered to assess therapeutic outcome, but was rather designed specifically to test whether the addition of CDX-301 could improve the vaccine platform to increase immune responses to an antigen of interest.
The scientists said their findings “unequivocally” demonstrated in humans that the CDX-301 treatment regimen helped to rapidly prime the vaccine antigen, induced integrated immunity (humoral and cellular), yielded a higher level of T-cell immunity in greater numbers of individuals, and was durable over several months. As they concluded, “Altogether, our results indicate that a CDX-1401-based vaccine can be safely delivered in the adjuvant setting of melanoma and that combination with CDX-301 can effectively boost an integrated immune response. Application of this formulation is widely feasible as NY-ESO-1 is expressed in many advanced cancers besides melanoma.”
Co-corresponding and senior author Steven Fling, PhD, director of the CITN Laboratory and senior staff scientist in the vaccine and infectious disease division at the Fred Hutchinson Cancer Research Center, further commented, “These positive results are significant not only for improving cancer vaccines, but also potentially for application to other vaccine platforms … and we are extremely grateful and indebted to the patients whose unwavering participation made this demanding clinical protocol a success.”
The reported findings also provide a foundation for adding checkpoint inhibitor immunotherapies—which have been successful in treating metastatic melanoma—to vaccines, as a potential way of further increasing the ability to hold back melanoma recurrence. “Given that ipilimumab, pembrolizumab and nivolumab are approved as adjuvant therapy for high-risk stage III melanoma, vaccines incorporating CDX-301 and suitable antigen-containing platforms merit clinical investigation in the adjuvant setting in combination with immune checkpoint blockade,” the scientists stated. Researchers also plan to follow trial participants over time and measure how many have cancer recurrence to further study the vaccine’s efficacy in each group.
“Immunotherapy has already shown great promise for patients with metastatic melanoma who would normally have a difficult, sometimes grave, prognosis,” said trial site investigator Philip Friedlander, MD, PhD, director of the melanoma medical oncology program at the Tisch Cancer Institute at Mount Sinai. “It’s important to work toward developing effective cancer vaccines that can prevent cancer on their own or in addition to the drugs already available.”
