Nanoformulation of CCL21 greatly increases its effectiveness as an immunotherapy for neuroblastoma.

Neuroblastoma is the most commonly diagnosed extracranial solid tumor in children. The patients with aggressive metastatic disease or refractory/relapsed neuroblastoma currently face a dismally low chance of survival. Thus, there is a great need for more effective therapies for this illness. In previous studies, we, as well as others, showed that the immune cell chemoattractant C-C motif chemokine ligand 21 (CCL21) is effective as an intratumoral therapy able to slow the growth of cancers. In this current study, we developed and tested an injectable, slow-release, uniform, and optimally loaded alginate nanoformulation of CCL21 as a means to provide prolonged intratumoral treatment. The alginate-nanoformulated CCL21, when injected intratumorally into mice bearing neuroblastoma lesions, significantly prolonged survival and decreased the tumor growth rate compared to CCL21 alone, empty nanoparticles, or buffer. Notably, we also observed complete tumor clearance and subsequent full protection against tumor rechallenge in 33% of nanoformulated CCL21-treated mice. Greater intratumoral presence of nanoformulated CCL21, compared to free CCL21, at days 1 and 2 after treatment ended was confirmed through fluorescent labeling and tracking. Nanoformulated CCL21-treated tumors exhibited a general pattern of prolonged increases in anti-tumor cytokines and relatively lower levels of pro-tumor cytokines in comparison to tumors treated with CCL21 alone or buffer only. Thus, this novel nanoformulation of CCL21 is an effective treatment for neuroblastoma, and may have potential for the delivery of CCL21 to other types of solid tumors in the future and as a slow-release delivery modality for other immunotherapies.

Insights into CCL21's roles in immunosurveillance and immunotherapy for gliomas.

Chemokine (C-C) motif ligand 21 (CCL21) is involved in immunosurveillance and has recently garnered the attention of neuro-oncologists and neuroscientists. CCL21 contains an extended C-terminus, which increases binding to lymphatic glycosaminoglycans and provides a mechanism for cell trafficking by forming a stationary chemokine concentration gradient that allows cell migration via haptotaxis. CCL21 is expressed by endothelial cells of the blood-brain barrier in physiologic and pathologic conditions. CCL21 has also been implicated in leukocyte extravasation into the central nervous system. In this review, we summarize the role of CCL21 in immunosurveillance and explore its potential as an immunotherapeutic agent for the treatment of gliomas.

CCL21 is an effective surgical neoadjuvant for treatment of mammary tumors.

In previous studies, the chemokine CCL21 has shown biological activities that include T cell, natural killer (NK) cell, and dendritic cell (DC) chemoattraction. The goal of this study was to determine the effects of administering CCL21 to orthotopic mammary tumors in terms of impact on tumor growth rate, immune cell infiltration of the primary tumor and survival. We found that a single intratumoral administration of CCL21 slowed the growth of orthotopic mammary tumors and increased intratumoral infiltration by T cells, NK cells and DCs. CCL21 intratumoral administration also prolonged the survival of tumor-earing mice. Furthermore, mice that received intratumoral neoadjuvant CCL21 ior to surgical resection of tumors survived significantly longer than control mice. The urviving neoadjuvant CCL21-reated mice, when challenged again with cl-6, had significantly slower rate of tumor growth than challenged control mice. Thus, our ata indicate that CCL21 treatment prior to mammary tumor resection can significantly rolong survival and increase resistance to subsequent tumor challenge. Overall, our indings suggest that intratumoral administration of CCL21 has potential as a neoadjuvant mmunotherapy for breast cancer.