Flt3 ligand augments vaccine designed to prevent melanoma recurrence

Significance 

Cancer vaccines directed at tumor antigens have elicited immune responses, but responses are low, require multiple vaccinations and are generated in a minority of patients. Most randomized cancer vaccines trials have failed to show clinical efficacy.

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 cells called dendritic cells, according to phase 2 clinical trial results published in Nature Cancer.

These results are important because most cancer vaccine trials have failed to show clinical efficacy. These results show that adding two immune-boosting components can boost the immune response for not only melanoma patients but possibly also others whose cancers express a protein called the vaccine antigen, which is common in some cancers.

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, found that adding the small molecule Flt3L, which increases the number of dendritic cells, boosted the vaccine’s effectiveness at producing antibodies and T cells that can later fight melanoma. Adding a second component, called poly-ICLC, also strengthened the dendritic cells’ ability to promote antibodies as well as helper and killer T cells.

Sixty patients who had stage 2 or 3 melanoma, and whose cancer was successfully removed via surgery, received the vaccine. Half of the patients received the vaccine alone while the other half received the vaccine with Flt3L and poly-ICLC.

The vaccine is designed to target dendritic cells and is composed of an antigen found in melanoma bound to an antibody to increase the chances of binding with dendritic cells.

The cocktail of the vaccine, Flt3L, and poly-ICLC nearly doubled the vaccine’s efficacy, according to 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 to those who received only the vaccine. Researchers found antibodies were still present in blood samples tested 12 weeks after the last dose.

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.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.

These findings also provide a basis for adding immunotherapies called checkpoint inhibitors, which have been successful in treating metastatic melanoma, to vaccines in order to further increase the success in fending off melanoma recurrence. 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, 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.

Flt3 ligand augments vaccine designed to prevent melanoma recurrence - Medicine Innovates
Melanoma in skin biopsy with H&E stain — this case may represent superficial spreading melanoma.

About the author

Nina Bhardwaj, MD, PhD is Professor of Medicine (Hematology and Medical Oncology) and Urology. She is the Director of Immunotherapy, Medical Director of the Vaccine and Cell Therapy Laboratory, and Co-Director of the Cancer Immunology Program at The Tisch Cancer Institute. Dr. Bhardwaj holds the Ward Coleman Chair in Cancer Research.

Dr. Bhardwaj has made seminal contributions to human dendritic cell biology, specifically with respect to their isolation, subset discovery, immunobiology, antigen presenting function, and use of vaccine adjuvants in humans. She developed Toll Like Receptor agonist- and dendritic cell-based vaccines for the treatment of both cancer and infection in several investigator-initiated studies and has pioneered neoantigen vaccine studies at The Tisch Cancer Institute. Dr. Bhardwaj translates basic science advancements into clinically relevant patient trials.

Dr. Bhardwaj was named one of the Scientific American’s Top 50 Researchers, receiving the Award for Medical Research in 2004. She received the Fred W. Alt Award for new discoveries in Immunology in 2015 from the Cancer Research Institute. Dr. Bhardwaj is a senior editor for Cancer Immunology Research and Frontiers in Immunology. She has served on numerous NIH Study Sections and advisory councils, and was formerly chair of the Cancer Immunology Steering Committee of the American Association for Cancer Research. Dr. Bhardwaj has successfully secured multiple federal and foundation grants and has authored more than 200 publications.

About the author

Philip A Friedlander, MD is an oncologist in New York, New York and is affiliated with multiple hospitals in the area, including Mount Sinai Morningside and Mount Sinai West Hospitals and Mount Sinai Hospital. He received his medical degree from Columbia University College of Physicians & Surgeons and has been in practice between 11-20 years.

Oncologists diagnose and treat cancers of all types. They use diagnostic tools like biopsies, endoscopies, X-ray and other imaging, nuclear medicine, and blood tests. Cancer surgeons, or surgical oncologists, remove tumors, while medical oncologists treat cancers with chemotherapy. Radiation oncologists use multiple forms of radiation in an effort to eliminate tumors.

Reference

Nina Bhardwaj, Philip A. Friedlander, Steven P. Fling . Flt3 ligand augments immune responses to anti-DEC-205-NY-ESO-1 vaccine through expansion of dendritic cell subsets. Nature Cancer volume 1, pages1204–1217(2020)

Go To Nature Cancer

About Priti