- Development of a Novel Vaccine with Fusions of Dendritic and Ovarian Cancer Cells from Patients
- Blockade Of B7-H1 Improves Myeloid Dendritic Cells Mediated Antitumor Immunity In Ovarian Cancer
- The Use of the Sindbis Vector to Combat Ovarian Cancer
- The Effects of a Vitamin C Derivative on Ovarian Cancer
Current research has found that fusion cell technology may have the potential to produce a vaccine against a broad spectrum of cancers. Fusion cell technology fuses dendritic cells (DCs) - powerful immune stimulators- and cancer cells. The fused cells are injected back into the patient in order to stimulate an immune response against the patient's cancer. This technology eliminates the need to isolate specific tumor antigens (the proteins that can trigger an immune response) as the original tumor is utilized in the fusion. In addition, scientists have found it difficult to deliver tumor antigens into DCs. Dr. Jianlin Gong, an Ovarian Cancer Research Program award recipient, has developed a strategy to circumvent this problem. Dr. Gong has fused DCs and human ovarian tumor cells in order to create a hybrid cell that can initiate an antitumor response in humans. DCs were isolated from the blood of patients diagnosed with ovarian cancer and then fused with the cancerous cells from the same patients. In vitro experiments showed that these fusion cells were able to "kick-start" an immune response and when co-cultured with ovarian cancer cells, they were able to lyse or kill the ovarian cancer cells. Dr. Gong and her team has received FDA approval to conduct a phase I clinical trial of these "fusion cell" vaccines in women diagnosed with stage III/IV ovarian cancer.
Gong J., Nikrui N., Chen D., Koido S., Wu Z., Tanaka Y., Cannistra S., Avigan D. and Kufe D. 2000. Fusion of human ovarian carcinoma cell with autologous and allogenic dendritic cells induce anti-tumor immunity. J. Immunol. 165:1705-1711.
Koido S, Ohana M, Liu C, Nikrui N, Durfee J, Lerner A, Gong J. 2004. Dendritic cells fused with human cancer cells: morphology, antigen expression, and T-cell stimulation. Clinical Immunology (in press).
Koido S, Nikrui N, Ohana M, Xia J, Tanaka Y, Liu C, Durfee J, Lerner A, Gong J. Assessment of fusion cells from patient-derived ovarian carcinoma cells and dendritic cells as a vaccine for clinical use (In preparation).
Dr. Weiping Zou, an investigator at the Tulane University Health Science Center and recipient of an OCRP Idea Development Award, is studying the function of dendritic cells (DCs) in ovarian cancer. DCs are antigen-presenting cells in the immune system. The function of DCs is impaired in cancer patients but the mechanism of this impairment remains elusive. B7-H1, also called PD-L1, is a newly identified B7 family member. B7-H1 is now known to be present in human cancers including ovarian cancer. However, it was not known that this protein is present and upregulated on the surface of tumor associated dendritic cells until Dr. Zou's laboratory discovered that B7-H1 expression is increased in dendritic cells under tumor environment factors. These tumor environment factors are interleukin-10 (IL-10) and vascular endothelial growth factor (VEGF). Dr. Zou and his team demonstrated that tumor environmental factors impaired myeloid DC-mediated T cell activation by upregulating B7-H1 expression on myeloid DCs. Additionally, Dr. Zou and colleagues demonstrated that expression of myeloid DC-B7-H1 could be blocked with specific monoclonal antibody that could activate T-cell function and decrease the production of T cell IL-10. Furthermore, studies extended on immune deficient mice bearing human tumors also showed that blockade of myeloid DC-B7-H1 protein could activate a T-cell mediated immune response. Dr. Zou's research provides evidences that ovarian cancer growth can be slowed down significantly in the presence of B7-H1 blockade. This finding could ultimately help investigators develop new therapeutics for treating ovarian cancer.
Curiel TJ, Wei S, Dong H, et al. 2003. Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nature Medicine 9(5):562-567.
Curiel TJ, Coukos G, Zou L, et al. 2004. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature Medicine 10(9):942-9.
Curiel TJ, Cheng P, Mottram P, et al. 2004. Dendritic cell subsets differentially regulate angiogenesis in human ovarian cancer. Cancer Res. 64(16):5535-8.
Although cisplatinum chemotherapy can achieve a response rate of 80 percent in treating ovarian cancer, a majority of patients stricken with this disease will experience recurrence. The use of gene therapy to treat cancer has gained much attention over the past 10 years. A particular type of gene therapy utilizes vectors or specific DNA sequences that can be used to transport genetic material to the host cell. These vectors can be constructed to targeted diseased cells in the body. OCRP researcher Dr. Daniel Meruelo is determining whether a vector based upon the Sindbis virus can be used to kill ovarian cancer cells. Dr. Meruelo observed that administration of Sindbis in conjunction with interleukin 12 (a protein capable of producing an immune response) in ovarian cancer cells resulted in cell death. In a mouse model of ovarian cancer, treatment of Sindbis-interleukin 12 extended the life of mice by 2 weeks compared to untreated mice. Although clinical trials in humans still need to be conducted, preliminary results indicate that the Sindbis-interleukin 12 combination may be a valuable treatment avenue for ovarian cancer.
Meruelo D, Levin B, and Pampeno C. 2002. Generation of packaging cell lines for the continuous production of Sindbis vectors. In Vector Targeting for Therapeutic Gene Delivery, DT Curiel and JT Douglas eds. New York, New York: Wiley & Sons, Inc., pp 353-375.
Tseng J, Levin B, Hirano H, et al. 2002. Sindbis vectors mediate potent anti-tumor activity in vivo. JNCI 94:1790-1802.
Ishizu A, Tsuji T, Abe A, et al. 2003. Transduction of dominant negative ATF-1 suppresses the pX gene expression in joint fibroblastic cells derived from HTLV-I transgenic rats. Exp. Mol. Pathol. 74:309-313.
Tseng J-D, Levin B, Hurtado A, et al. 2003. Systemic tumor targeting and killing by sindbis viral vectors. Nature Biotech. Advance on-line publication, 1-8.
Compelling evidence indicates that certain cancers may be prevented with treatment of vitamin C and its derivatives. One such compound, ascorbyl stearate, has been shown to stop cell division and growth in brain tumor cells. Ascorbyl stearate is a promising treatment avenue as it is nontoxic and is able to easily cross biological barriers within the cell. Drs. Santo Nicosia and Domenico Coppola, who are currently funded by an FY01 OCRP Program Project award, are investigating the effects of this compound on cell division and cell death in ovarian cancer cells. Treatment of ovarian cancer cells with various concentrations of ascorbyl stearate resulted in a significant reduction in cell growth. Upon treatment, the ovarian cancer cells were "stuck" and could no longer divide. Additionally, these investigators found that ascorbyl stearate could induce cell death, as the cells could not complete the normal cell cycle. These results appear promising, as ascorbyl stearate may be a viable and nontoxic approach in combating ovarian cancer.
Nicosia SV, Bai W, Cheng JQ, et al. 2003. Oncogenic pathways implicated in ovarian epithelial cancer. Hematol. Oncol. Clin. North. Am. 17:927-943.
Naidu KAA, Naidu KA, Haiyan Z, et al. Ascorbyl stearate inhibits cell proliferation and survival in human ovarian carcinoma cells by targeting PI3/AKTT2 pathway (In preparation).