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Tumor Immunotherapy
Studies suggest that tumors can be eradicated by stimulating the antigen-presenting cells” that capture tumor antigens and trigger tumor-specific CD8+ "killer" T cells. To test if the UltraLigands were capable of inducing anti-tumor immunity, tumors in mice were allowed to grow to > 4 mm in diameter and then treated with 5 injections of UltraLigand into the tumor. Despite these arbitrarily stringent conditions, treatments were found that cured mice of two standard but difficult tumors - A20 lymphoma and B16-F10 melanoma.
Cure of A20 lymphoma by UltraCD40L and UltraGITRL
A simple protocol of intratumoral injections of plasmid DNA encoding multimeric soluble UltraCD40L (SP-D-CD40L) led to tumor eradication and long-term, tumor-free survival in 80% of mice. Because these tumors are infiltrated with immunosuppressive CD4+ CD25+ regulatory T cells (“Tregs”) and because GITRL turns off Treg immunosuppression (published in Clinical and Vaccine Immunology 13:1223-1230, 2006), multimeric soluble UltraGITRL (SP-D-GITRL) is another effective treatment for this lymphoma.
Cure of B16F10 melanoma by a combination of UltraCD40L with other immunostimulants
B16F10 melanoma is a standard reference tumor for immunotherapy studies in mice. It is poorly immunogenic and rapidly metastasizing. Few effective treatments for B16F10 have been previously devised. The simple injection of plasmid DNA for multimeric soluble UltraCD40L (pSP-D-CD40L-NST, a 2nd generation version of this molecule) combined with two Toll-like receptor (TLR) agonists (CpG DNA for TLR9 and poly(I:C) for TLR3) plus extracellular ATP (ATPe) cured about 50% of mice without inducing autoimmunity (i.e., there was no loss of melanin pigment or "vitiligo"). When used without CD40L, CpG + poly(I:C) + ATPe did not cure any of the mice, demonstrating a requirement for MultimericBio's UltraCD40L in this combination. Clinical trials of both of these TLR agonists and ATPe have shown that they can be safely used in humans, setting the stage for a clinical trial of this immunostimulatory combination. In addtion, the delivery of pSP-D-CD40L UltraCD40L DNA via nanoparticles was recently shown to be a highly effective and feasible way to deliver this novel immunostimulatory agent (published in PLOS One 4(10): e7334, 2009).
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