Investigating the therapeutic effects of CCL21 nanomedicine in neuroblastoma Brittany J. Poelaert1,2, Svetlana Romanova2,3, Kaitlin Smits1,2, Bailee H. Sliker1,2, Alexandra E. J. Moffitt1,2, Lynette Smith2,4, Tatiana K. Bronich2,3, Joyce C. Solheim1,2 1Eppley Institute for Research in Cancer and Allied Diseases, 2Fred and Pamela Buffett Cancer Center, 3Department of Pharmaceutical Sciences, 4Department of Biostatistics, University of Nebraska Medical Center, Omaha NE 68198
Neuroblastoma is the most commonly diagnosed extracranial solid tumor in children. Novel therapies capable of augmenting the patient's anti-tumor immune response, in a durable and concentrated fashion, are greatly needed. We hypothesized that therapeutic modalities utilizing the chemoattractant C-C motif chemokine ligand 21 (CCL21) in a novel alginate nanoformulation will provide prolonged release of CCL21, thus leading to the steady infiltration of immune cells into the tumor, delaying tumor growth, and halting disease progression significantly better than CCL21. Nanoformulations of CCL21 were first optimized for rates of release in vitro. We found that intratumoral administration of nanoformulation CCL21 significantly prolonged the survival of A/J mice with subcutaneous neuroblastoma tumors, compared to controls. Furthermore, we also determined that the tumor growth rate for nanoformulation CCL21-treated mice was significantly lower in comparison to those of mice treated with empty nanoparticles or CCL21 alone. Notably, in one trial using intratumoral injections of therapeutic agents into small, but clearly palpable tumors, complete tumor regression occurred in 44% of mice that received nanoformulation CCL21, whereas all control-treated mice failed to exhibit tumor regression. When rechallenged, the tumor-free, nanoformulation CCL21-treated mice failed to produce new tumors, therefore indicating that a protective memory immune response had been induced by the nanoformulation CCL21 treatment. These results suggest that nanoformulation CCL21 therapy may be clinically relevant for the treatment of children and adolescents diagnosed with neuroblastoma. In addition, this novel nanoformulation may also have potential for future development as a means for slow-release delivery of other immunotherapies besides CCL21, as well as for CCL21 delivery in combination with agents such as immune checkpoint inhibitors and standard of care treatments.
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