A new combination molecule –iMyD88/CD40 – acts as a molecular "master switch" to turn on dendritic cells (immune system cells), improving the effectiveness of tumor vaccines, said a consortium of researchers led by Baylor College of Medicine in a report that appears in The Journal of Clinical Investigation.
To accomplish this improved antitumor response, Dr. David Spencer, vice chair of pathology and immunology at BCM, and his colleagues fused the "universal" adapter molecule, MyD88, to CD40, a molecule that further activates dendritic cells when they reach the lymph nodes. MyD88 triggers the initial "danger" alarm that tells the immune system an infection has occurred.
Safer, more potent immunological treatments To endow this chimeric protein with an on/off switch feature, Spencer and his colleagues fused this to a third human-derived protein domain (a part of the protein molecule that can develop a function of its own) called FKBP12. FKBP12 has a high affinity to the synthetic molecule AP1903 that dimerizes or connects two similar molecular subunits (e.g., MyD88/CD40) called monomers that are modified to contain the dimerizer-binding domain. Upon administration of AP1903, the two key signaling domains are multimerized or become a protein complex made of up similar molecules. This activity simulates normal activation mechanisms.
This development points the way to safer and more potent immunological treatments for a variety of cancers, Spencer said.
"We are just one step away from a vaccine that targets dendritic cells in living organisms," said Spencer, who is also a member of the Dan L. Duncan Cancer Center at BCM. "This work illuminates the path toward a truly "off-the-shelf" vaccine. This could lead to more effective cancer vaccines with fewer side effects."
Previous work used chemicals called adjuvants as a "danger signal" to alert the protective dendritic cells to the presence of tumors. However, to avoid systemic effects, these adjuvants need to be carefully removed prior to administration, said Spencer.
Result: Control of aggressive tumors in mice
MyD88 replaces the adjuvant signal and thus eliminates adjuvant toxicity. When activated by the drug AP1903, the "inducible" iMyD88/CD40 fusion protein leads to increased levels of the interleukin-12 and other factors secreted by the immune system.
This ultimately increases the number of killer T-cells while activating dendritic cells in lymph nodes.
"This resulted in the elimination or control of pre-established, aggressive tumors in mice," said Spencer. Tumor vaccines are promising cancer treatments that seek to arouse the body’s own immune defenses against cancer. However, they have not proven long lasting or potent enough to eliminate tumors in most studies. Spencer and his colleagues seek to correct those problems.
Others who took part in this work include Priyadharshini Narayanan, Dr. Natalia Lapteva, Mamatha Seethammagari and Dr. Jonathan M. Levitt, all of BCM, and Dr. Kevin M. Slawin with the Vanguard Urologic Institute and The University of Texas Health Science Center at Houston. Seethammagari is also with the Diana Helis Henry Medical Research Foundation in New Orleans. Spencer holds the Roger D. Rossen, M.D. Endowed Professorship.
Funding for this work came from the Diana Helis Henry Medical Research Foundation, the National Institutes of Health and the Vanguard Urologic Research Foundation. Clinical applications of this vaccine and other cell technologies are being developed by Bellicum Pharmaceuticals, a privately held biotherapeutics company co-founded by Slawin and Spencer.