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.
Ovarian cancer is one of the deadliest cancers, responsible for the deaths of ~15,000 Americans per year, even more than melanoma, AML or brain tumors. 5-year survival rates have improved little in the last 30 years, and still remain at 30% at best for patients with metastatic ovarian carcinoma, the stage at which most cases are diagnosed. Studies using pre-clinical models indicate that tumor-reactive T cells properly conditioned ex vivo have the capacity to induce significant therapeutic effects against established ovarian cancer, yet the activity of transplanted T cells was suboptimal.
Novel strategies for reprogramming adoptively transferred anti-tumor T cells, to allow better engraftment and thus superior therapeutic activity in the especially hostile microenvironment of ovarian cancer, are urgently needed. Forkhead box (FOX) proteins are a large family of transcription factors with diverse functions in development, cancer, and aging. Recently we have demonstrated that Foxp1 exerts a novel cell-intrinsic regulation of T cell quiescence.
In a mouse model of ovarian carcinoma, which recapitulates the microenvironment of solid human ovarian cancers, we find that tumor-associated T cells up-regulate Foxp1 as the tumor progresses. We also find that Foxp1 dampens T cell immune responses. Therefore, in this proposal, we hypothesize that the up-regulation of Foxp1 in ovarian cancer-infiltrating T cells negatively regulates the T cell responses; consequently, Foxp1-deficient tumor-reactive T cells will better resist tumor-induced immunosuppressive signals and elicit superior anti-tumor immunity.
While we aim to determine the role of Foxp1 in tumor-induced T cell unresponsiveness (Aim 1), we will also use pre-clinical ovarian carcinoma models to determine the therapeutic effectiveness of adoptively transferred T cells lacking Foxp1 (Aim 2). Our initial experiments show that ovarian tumor-bearing mice receiving in vitro-primed anti-tumor T cells deficient in Foxp1 have superior survival over control mice, providing a rationale for novel therapeutic interventions targeting Foxp1 in tumor-reactive T cells from ovarian cancer-bearing women.
In summary, our proposed work will have a profound effect on the field by defining a novel mechanism for the loss-of-function of anti-tumor T cells in ovarian cancer, which may be applicable to other lethal epithelial tumors. The accomplishment of the work will provide both a mechanistic rationale and proof-of-concept for new interventions aimed at maximizing the effectiveness of adoptively transferred tumor-reactive T cells. Our long-term goal is to develop improved treatment options for ovarian cancer in clinic through adoptive transfer of tumor-reactive T cells, which are genetically modified to overcome tumor-induced immune suppression.
