What is the role of cytokine and growth factor therapy in immunotherapeutic targeting in pediatric oncology?

Updated: Mar 20, 2018
  • Author: Crystal L Mackall, MD; Chief Editor: Jennifer Reikes Willert, MD  more...
  • Print
Answer

Answer

Future studies will seek to combine T-cell–based vaccination protocols with other modalities to amplify the magnitude of the immune response. For instance, various adjuvants, such as granulocyte-monocyte colony-stimulating factor (GM-CSF) and toll-like receptors (TLRs), can be used to better activate antigen-presenting cells (APCs); these can potentially result in more effectively activated or expanded T cells.

Alternatively, cytokines, growth factors, and costimulatory molecules that help in the expansion and activation of T cells are also under investigation. For instance, both interleukin (IL)-7 and IL-15 are γ-c signaling cytokines that substantially augment T-cell response to vaccination and have been shown to improve antitumor effects in animal models. [88, 89] Costimulatory molecules include 4-1BB ligands, OX40 ligands, and CD28 ligands, all of which can enhance T-cell expansion after activation. Anti-4-1BB antibodies have been shown to have potent antitumor effects in vivo.

Finally, inhibition of regulatory pathways remains a major area of study because suppressive mediators released by tumors play a central role in limiting antitumor immunity. Among these are blocking antibodies to CTLA4, anti-CD25 to deplete regulatory T cells, and blockers of PD-1 and its ligand, PD-L1. The combination of these strategies that will ultimately be most promising in augmenting antitumor immunity remains to be seen.

IL-2 is active against renal cell carcinoma and malignant melanoma; however, for pediatric tumors, several trials of IL-2 have been performed with no antitumor effects observed. [90, 91, 92] Even in neuroblastoma, a potentially immunoresponsive solid tumor, [93, 94, 95] systemic administration of IL-2 as a single agent has shown no benefit. [91]

Moreover, recent studies have clearly demonstrated that in addition to activating natural killer (NK) cells (the presumed mechanism responsible for the antitumor effects), IL-2 also substantially expands and activates CD25+ CD4+ regulatory T cells. [96] This subset is a significant mediator of tumor-induced immune suppression; therefore, the administration of IL-2 in the context of cancer is likely to amplify this already suppressive subset.

Few other cytokines have been administered as single agents in children with cancer. Interferon alfa (IFN-α) is probably the most well-studied cytokine and has been documented in the treatment of patients with chronic myelogenous leukemia (CML), hairy cell leukemia, some B-cell and T-cell lymphomas, and solid tumors, such as melanoma, renal carcinoma, and Kaposi sarcoma, all of which are very rare in pediatric patients.

IFN-α is approved by the US Food and Drug Administration (FDA) for the adjuvant therapy of adults with stage III melanoma. An ongoing clinical trial is examining the use of IFN-α in children with melanoma. [97] Ongoing phase I trials are also exploring the role of pegylated IFN-α for plexiform neurofibromas and brain tumors in children (see Clinicaltrials.gov). How IFN-α mediates antitumor effects remains unclear.

Regional therapy with tumor necrosis factor alpha (TNF-α) has been performed in patients with sarcoma, and some antitumor responses were observed in Ewing sarcoma and Wilms tumor, although this approach is limited by the development of systemic toxicity. [98]

Recombinant GM-CSF (sargramostim) is a growth factor that may act on cancer cells through a role in cytokine priming. When given before and during induction chemotherapy, it may make leukemic blast cells more susceptible to the cytotoxic effects of chemotherapy. This growth factor causes upregulation of costimulatory molecule expression on leukemia blasts in vitro and, in combination with INF-α, can induce antitumor immune responses in relapsed acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) after allogeneic stem cell transplantation. [99]

Tumor cells engineered to secrete GM-CSF are particularly effective as antitumor vaccines, and the addition of GM-CSF to standard vaccines may increase their effectiveness by recruiting dendritic cells (DCs) to the site of vaccination. [100] GM-CSF is also commonly administered locally at the site of administration of tumor vaccines, where it presumably enhances antigen presentation via recruitment of antigen presenting cells to the site where the immunogen is deposited.

A novel application of inhaled GM-CSF may be for children with pulmonary metastases from sarcomas, with 1 child with Ewing sarcoma demonstrating a complete response. [101, 102] Of 40 patients treated with pulmonary metastases, 24 had disease stabilization or partial regression for a mean duration of 10 months. [102] This included 8 of 13 patients with sarcoma who responded.


Did this answer your question?
Additional feedback? (Optional)
Thank you for your feedback!