Nabil Ahmed, MD
Targeting cancer stem cells in glioblastoma.
Glioblastoma (GBM) is the most common brain cancer and remains largely incurable. The recent identification of chemotherapy and radiotherapy resistant stem cells in GBMs may help explain why conventional therapies are ineffective.
Immunotherapy may be able to kill GBM stem cells since immune-mediated killing does not rely on the conventional mechanisms of cell killing. HER2 is tumor protein is positive in >80% of GBMs, but not by the normal brain, making it an attractive target for immunotherapy.
We have shown that HER2-specific T cells from GBM patients kill GBM stem cells and induce remission of GBMs grown in mice. We now wish to evaluate our approach clinically and test if HER2-specific T cells can be safely given to patients with HER2-positive GBMs (Aim 1) and intend to study their will persistence and antitumor activity in the human body (Aim 2).
While our preclinical studies demonstrated the potent antitumor activity of HER2-specific T cells, tumors recurred in several treated animals. This limitation in T-cell efficacy is most likely due to the inhibitory tumor environment. GBMs (including GBM stem cells) contain high level of the STAT3, a protein which is not only necessary for GBM stem cell survival but also induces the expression of T cell suppressive factors. Thus, Aim 3 will test in preclinical models our hypothesis that combining STAT3 inhibition with HER2-specific T cells will more effectively eradicate GBMs than T cells alone.
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