Ovarian cancer (OC) is the fifth leading cause of death in women in the US and the most lethal gynecological malignancy worldwide. The available treatment modalities include conventional systemic chemotherapy and surgery, but nearly 80% of patients with high grade serous OC (HGSOC) relapse post-treatment. There is a significant need for innovative treatments and the addition of cellular immunotherapy may enhance conventional therapeutic strategies. Previous studies from our lab have shown that HGSOC cells secrete high concentrations of vascular endothelial growth factor alpha (VEGF-A) and the inhibitory lipid, ganglioside GD3. GD3 can block CD1d-mediated NKT cell activation. In addition, VEGF-A can directly inhibit iNKT activation and blockade of VEGF can reduce levels of GD3. Thus, we hypothesize that inhibition of VEGF in combination with GD3 targeting chimeric antigen receptors (CAR) can be used to restore iNKT cell responses to OC, by negating the negative signals, enhancing iNKT cell migration, and increasing NKT cell-mediated cytotoxicity of HGSOC cells. We have generated anti-GD3 CAR constructs featuring the costimulatory domains, CD28 and/or 41BB. We are evaluating the in vitro and in vivo efficacy of anti-GD3 CAR-iNKTs compared to traditional CAR-T cells. Collectively, these studies will determine the effectiveness of iNKT-based CAR strategies for the treatment of OC in combination with classic therapeutic regimens.
Funding: Travel support from Towson University Alumni Association and a fellowship award from the UM Ventures Baltimore to Yuyi Zhu. Research support for TJW was provided in part by NIH grants P30CA134274 and R01AI061061.