Scientists at the Cedars-Sinai Maxine Dunitz Neurosurgical Institute and department of neurosurgery say they have identified immune system targets on cancer stem cells from which malignant brain tumors are believed to originate and regenerate. The researchers add that they also created an experimental vaccine to attack them.
Results of laboratory and animal studies are published in the online edition of Stem Cells Translational Medicine. A Phase I safety study in human volunteers with recurrent glioblastoma multiforme, the most common and aggressive brain tumor in adults, is underway.
Like normal stem cells, cancer stem cells have the ability to self-renew and generate new cells, but instead of producing healthy cells, they create cancer cells. In theory, if the cancer stem cells can be destroyed, a tumor may not be able to sustain itself, but if the cancer originators are not removed or destroyed, a tumor will continue to return despite the use of existing cancer-killing therapies.
The researchers identified certain fragments of a protein (CD133) that is found on cancer stem cells of some brain tumors and other cancers. In the laboratory, they cultured the proteins with dendritic cells, the immune system's most powerful antigen-presenting cells, which are responsible for helping the immune system recognize and attack invaders.
“CD133 could serve as a potential target for cytotoxic T cells (CTLs) to target glioblastoma cancer stem cells. Two potential human leukocyte antigen (HLA)-A*0201-restricted CD133 epitopes, ILSAFSVYV (CD133-405) and YLQWIEFSI (CD133-753), showed strong binding to HLA-A*0201 molecules,” wrote the investigators in their online article entitled “Identification of Novel Human Leukocyte Antigen-A*0201-Restricted, Cytotoxic T Lymphocyte Epitopes on CD133 for Cancer Stem Cell Immunotherapy.” “In vitro immunogenicity studies generated peptide-specific CD8+ CTLs from normal donors. Autologous monocyte-derived dendritic cells pulsed with the CD133-405 or CD133-753 peptides generated CTLs that efficiently recognized the CD133 epitopes presented in T2 HLA-A*0201 cells and specifically lysed CD133+ HLA-A*0201+ GBM CSCs. These studies demonstrated natural processing and subsequent presentation of these epitopes in GBM CSCs and the ability of CTLs to kill CSCs bearing the antigen.”
The vaccine was able to stimulate an immune response against the CD133 proteins without causing side effects such as an autoimmune reaction against normal cells or organs, added the scientists.
“CD133 is one of several proteins made at high levels in the cancer stem cells of glioblastoma multiforme. Because this protein appears to be associated with resistance of the cancer stem cells to treatment with radiation or chemotherapy or both, we see it as an ideal target for immunotherapy. We have found at least two fragments of the protein that can be targeted to trigger an immune response to kill tumor cells. We don't know yet if the response would be strong enough to prevent a tumor from coming back, but we now have a human clinical trial underway to assess safety for further study,” explained John Yu, M.D., vice chair of the department of neurosurgery, director of surgical neuro-oncology, medical director of the Brain Tumor Center, and neurosurgical director of the Gamma Knife Program at Cedars-Sinai. He is senior author of the journal article.