Novel Nano-Photo-Immunotherapy Against Ovarian Cancer
Abstract
In the United States in 2018, it is estimated by the American Cancer Society that 22,240 women will develop ovarian cancer and 14,070 will die from the disease. Most epithelial ovarian cancers are diagnosed at an advanced stage where the tumor has seeded the abdominal cavity (Stage III). The current therapeutic treatments for epithelial ovarian cancer include the use of combination chemotherapy with a platinum-based drug and paclitaxel. If the patient has had an optimal cytoreductive surgery (removal of all visible peritoneal tumor >1 centimeter), then the current gold standard of treatment involves intravenous (IV) paclitaxel on day 1, intraperitoneal (IP) delivery of cisplatin on day 2, and IP paclitaxel on day 8, repeated every 3 weeks for a total of six cycles. Many patients are unable to complete six cycles due to the debilitating side effects of the chemotherapy. It is clear that a more efficacious and less toxic therapeutic approach against ovarian cancer is needed. In the last few years, there has been great excitement regarding the use of checkpoint blockade immunotherapy, such as anti-PD-1 antibody therapy, for clinical cancer treatment. Although such treatments are working quite well for melanoma and non-small cell lung cancer, response rates for many other cancers, including ovarian cancer, remain unacceptably low. In the last 10 years, we have developed several telodendrimer-based nanoplatforms for cancer imaging and therapy. Our latest generation of nanoplatform includes indocyanine green derivative and cysteine in the telodendrimers, which can self-assemble to form stable crosslinked nanocarriers. Because of the indocyanine green component, it can generate heat to destroy a tumor when illuminated with light. Such nanocarriers loaded with imiquimod, an immunostimulant, were found to be highly effective against a 4T1 mouse breast cancer model, particularly when the photo-immunotherapy was given in combination with the anti-PD-1 checkpoint blockade antibody currently used in the clinic. Such triple therapy not only eradicated the light-illuminated primary tumors, but also dramatically inhibited the light-untreated distant tumors via systemic activation of anti-tumor immune response. We believe such novel photo-immunotherapy can be applied to ovarian cancer patients, even with tumors widely distributed in the abdominal cavity (Stage III) or metastasized beyond the abdominal cavity, such as in the lung (Stage IV). In this project, we will prepare and characterize nano-imiquimod and evaluate its biodistribution and therapeutic efficacy in an ID8 mouse ovarian cancer model. This versatile multifunctional photothermal nanoplatform has great potential for clinical translation and can be applied to ovarian cancer patients at multiple levels. For example, when encapsulated with low-dose doxorubicin or paclitaxel and given 24 hours prior to exploratory laparotomy, the nanoplatform can be used for image-guided surgery followed by intraoperative-photochemotherapy to eradicate the residual tumor at the surgical sites. When encapsulated with imiquimod, it can stimulate anti-tumor immune response at all tumor sites, particularly when some of the tumor sites are illuminated with light, e.g., during surgery. When given in conjunction with checkpoint blockage antibodies, it can cause systemic tumor response in the remaining non-illuminated tumors. This entire treatment scenario with this novel nanoplatform is practical and readily translatable in the clinic. In this proposal, we will limit our research scope to the immunotherapeutic aspect of the nanoplatform. The proposed nanoplatform, once optimized, is expected to have great impact in the treatment of Stage II, III, and IV ovarian cancer, as well as many other solid tumors. Ovarian cancer can potentially affect all women. We believe the knowledge gained and novel therapeutics developed from this proposed project will greatly benefit the health and we
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910159
Entities
People
- Kit Lam
Organizations
- United States Army
- University of California, Davis