What are the methods of innate immunity activation in pediatric cancer immunotherapy?
Dr. William Coley, who is considered the father of cancer immunotherapy, was the first to notice spontaneous tumor remission in certain sarcoma patients who developed bacterial infections. Dr. Coley pioneered the use of bacterial extractions, named ‘Coley toxins,’ which evoked antitumor immune response in some of his cancer patients.
Immunotherapy was eventually abandoned in favor of radiotherapy because of difficulty in standardizing the toxins. Newer knowledge now shows bacteria are potent in activating the innate immune system, which attacks the tumor cells as well.
The different methods of activating the innate immune system which are in various stages of research currently include:
Toll-like receptor activation
Toll-like receptors (TLR) are proteins in the membranes of immune cells, which recognize molecular patterns generally shared by pathogens, and activate the phagocytes. Toll-like receptors are activated by proteins in pathogens as well as proteins exposed by damaged self-tissue.
Many TLR-targeted therapies for adult cancer treatment are in clinical trials and two therapies have been effectively used:
- Bacillus Calmette-Guerin cell-wall skeleton (BCG-CWS): FDA-approved tuberculosis vaccine and has been used off-label for treatment of early stage bladder cancer.
- Imiquimod: FDA-approved for treatment of basal cell cancer.
Human papilloma virus (HPV) vaccine
HPV vaccine is a TLR-activator (agonist) that has FDA approval for use in children to prevent secondary cervical cancer. Animal studies have shown positive response to TLR-targeted therapies in pediatric cancers that include:
Research indicates that proteins released from cancer cells damaged by radiation therapy activate TLRs and immune response, and contribute to treatment efficacy.
Alarmins (danger signals)
Alarmins are inflammatory substances released when tumor cells die, which induce an innate immune response. Pediatric tumors such as rhabdomyosarcoma may under-express alarmins to avoid detection by the immune system. Enhancing the innate immune system resulting in better detection of alarmins is a target for immunotherapy research.
Muramyl tripeptide phosphatidylethanolamine (MTP-PE)
Muramyl tripeptide phosphatidylethanolamine (MTP-PE) is derived from muramyl dipeptide, which is a protein fragment found in cell walls of mycobacteria. MTP-PE activates the innate immune system.
Clinical trials of MTP-PE intravenous infusion along with chemotherapy in children with osteosarcoma, have shown improved survival rate. MTP-PE is not FDA-approved for osteosarcoma.
Natural killer cell activation
Natural killer (NK) cells are lymphocytes that are part of the innate immune system. They can identify and kill tumor cells directly, even in the absence of inflammatory signals. The activity of NK cells is regulated by killer immunoglobulin-like receptors (KIR) present in the cells. KIR in tissue native to the body inhibits NK cell activity, but KIR found in foreign tissue activates NK cells.
NK cells can be used to kill the tumor cells with an NK cell-KIR mismatched bone marrow transplant. Clinical trials are ongoing in both children and adult patients for treatment of acute myeloid leukemia, with NK cell-KIR mismatched bone marrow transplant, after self T-cell depletion.
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