Cytokines Synergize to Combat Metastatic Neuroblastoma

Picture shows how cytokines Il-2 and IL-27, when given together as therapy for neuroblastoma, can effectively shrink cancer metastases in as much as 90 percent of the mice, even after these metastases had spread to the liver, lungs, and bone marrow.  Either cytokine  alone could not do this.  The combination of the two cytokines given simultaneously to mice was very potent against metastatic neuroblastoma.

Picture shows how cytokines Il-2 and IL-27, when given together as therapy for neuroblastoma, can effectively shrink cancer metastases in as much as 90 percent of the mice, even after these metastases had spread to the liver, lungs, and bone marrow. Either cytokine alone could not do this. The combination of the two cytokines given simultaneously to mice was very potent against metastatic neuroblastoma.

Neuroblastoma is the most common extracranial solid tumor in children, and clinical outcomes of patients with this disease are quite variable. Prognosis is particularly poor for patients with high-risk tumors (classification based on patients’ age, extent of disease spread, and other biological features). Researchers are working to harness the immune system to fight many different types of cancer, including neuroblastoma. An ideal immunotherapy would activate a specific antitumor immune response and create immunological memory that would help patients stave off tumor recurrence.

Cytokines are signaling proteins that modulate the activity of the immune system. IL-27 is a cytokine that helps the immune system mount targeted attacks against foreign invaders or other unfamiliar cells in the body. IL-27 is capable of “curing” mice with localized neuroblastoma, but it is significantly less effective in mice whose neuroblastomas have spread to other parts of the body. These preclinical data coupled with modest results of clinical trials of single cytokines have prompted researchers to begin thinking about using combinations of cytokines to treat cancer. Rosalba Salcedo, Ph.D., a researcher in the CCR Cancer and Inflammation Program, and other NCI scientists recently evaluated IL-27 in combination with another cytokine—IL-2—in a mouse model of metastatic neuroblastoma. The results of their studies were published in a recent issue of The Journal of Immunology.

Dr. Salcedo and her colleagues injected mice with a neuroblastoma cell line that metastasizes to the liver, lung, and bone marrow. These tumors are normally fatal to their host within one month. Tumor-bearing mice were left untreated or exposed to IL-2 or IL-27 alone or in combination. IL 27 was effective as a single therapy in a subset of mice, but the most striking results were observed with the combination treatment—90 percent of mice injected with both IL-2 and IL-27 experienced complete tumor regression and long-term survival. Remarkably, both cytokines together were also able to induce regression of liver and bone marrow metastases.

The "cured" mice were then injected with a second round of tumor cells to see if and how their immune systems would respond. Only one of the nine mice involved in this experiment developed a tumor, indicating that the immune systems of eight of the IL-2/IL-27-treated mice had been successfully trained to recognize and quickly eliminate the neuroblastoma cells. By carefully depleting different types of immune cells, the researchers were able to determine that this protection was due to cytotoxic T cells capable of mounting a specific immune response against the neuroblastoma cells.

Additional experiments revealed that IL-27, traditionally thought to be involved only in the initial targeted immune attack, also plays a role in reawakening the immune system if a target is encountered a second time. IL-2 stimulated the proliferation of T regulatory cells, which enable the tumor cells to persist. IL-27 was also shown to hinder - this f the inhibitory effects of IL-2, thus strengthening the overall immune response.

These studies illustrate the potential of cytokines with complementary activities to combat cancer when used in combination. The remarkable regression of primary neuroblastoma tumors as well as liver and bone marrow metastases provides hope that harnessing the immune system may be an effective way to improve treatment of high-risk neuroblastoma and perhaps other tumor types.

Summary Posted: 05/2009

Reference

J Immunol. 2009 Apr 1;182(7):4328-38 PubMed Link