There are many experimentally proposed approaches on how to eliminate tumor-initiating or cancer stem cells (CSC). It seems like targeting CSC phenotypically by antibody against the overexpressed surface molecules or selectively activated signaling pathways by small molecules could not be a universal or even a very successful approach due to their high variability and complexity.
It is well know that tumor cells utilize many mechanisms to escape immune system surveillance. For some reasons such professional immune killers as antigen-specific cytotoxic CD8+ T-cells appear to be anergic and not able to function in cancer patients. One possible mechanism to explain this could be their increased replicative senescence. Can we play with immune cells in order to train them to kill cancer cells? Can we direct immune reactions such as phagocytosis or cytotoxicity precisely against CSC? Based on some significant recent advanced studies, the answer is Yes! Here I overview some approaches dedicated to activation of the host immune system against CSC.
Recently Irving Weissman’s group showed the possibility of increasing phagocytic activity of macrophages selectively directed against leukemic blasts or stem cells (LSC). They figured out that surface molecule CD47 is highly expressed on LSC and protects them from phagocytosis and therefore could potentially be a good target for it. Interestingly, CD47 expression increased on migrating normal hematopoietic stem cells (HSC) after mobilization or induced inflammation. Applying antibody against CD47, authors showed eradication of human LSC through activation of phagocytosis by macrophages in xeno- model of acute myelogenous leukemia (AML).
Dendritic cells (DC) as professional antigen-presenting cells can be primed by specific CSC-expressing molecule and used as a vaccine for stimulation of host cytotoxic T-cells. One of the first steps to utilize this approach was recently made on mouse glioma cell lines.
Cytotoxic CD8+ T-cells
The idea of direct stimulation of the cytotoxic CD8+ T-cells by CSC-specific antigen was utilized and commercialized by ImmunoCellular Therapeutics. Clinical data from phase I of trial of ImmunoCellular Therapeutics’ Cancer Vaccine ICT-107 was recently presented ASCO 2009 Annual Meeting.
ICT-121 is IMUC’s cancer stem cell (CSC) vaccine product candidate that consists of a peptide to stimulate a cytotoxic T-lymphocyte (CTL) response to CD133, which is generally overexpressed on the CSCs. It is designed as an “off-the-shelf” vaccine. IMUC will initially evaluate it in a Phase I clinical study for glioblastoma, which the company expects to file an Investigational New Drug application (IND) for in the fourth quarter of this year. While glioblastoma will be the initial target for ICT-121, CD133 is also overexpressed in colon cancer, breast cancer, liver cancer, prostate cancer, multiple myeloma and melanoma, providing many potential cancer targets for this CSC vaccine in the future.
Natural killer (NK) cells
NK cells – innate immunity lymphocytes are professional malignant cell killers. It was demonstrated before that human allogeneic NK cells can recognize and kill leukemic blast by graft-versus-leukemia effect. Now Ulrich Langenkamp showed that allogeneic (KIR-receptor mismatched) human NK cells are able to recognize and selectively kill leukemic stem cells but not normal HSC. Future studies will investigate the possibility of using allogeneic expanded NK in clinical trials for treatment of leukemia.
One of the things which worries me about these studies is that all of them were done based on isolation of CSC by surface markers (CD34+/CD38- for AML or CD133 for melanoma), validity of those was recently challenged.
- How the immune system signals to hematopoietic stem cells?
- Link between Immune System function and Hematopoietic Stem Cells – Journal Club Online v.1
- Lecture: A Delicate Balance: Stem Cells, Cancer and the Immune Response
- Lecture: Edgar Engleman – Using dendritic cells to create cancer vaccines
- Lecture: Robert Weinberg – Cancer stem cells and malignant progression