ReviewAssessment of fusion cells from patient-derived ovarian carcinoma cells and dendritic cells as a vaccine for clinical use
Introduction
Despite recent advances in post-surgical chemotherapy, ovarian cancer (OVCA) remains the leading cause of death for patients with gynecologic malignancies [1]. The majority of patients with OVCA are diagnosed at an advanced stage of the disease and are treated with surgical debulking followed by platinum-based chemotherapy. Most patients who respond to such therapy ultimately die of relapse from residual and/or drug-resistant disease. A novel therapy that reduces the risk of relapse is urgently needed. In this context, targeted immunotherapy may represent a useful anti-OVCA strategy since such therapy may be effective against chemotherapy-resistant disease with minimal toxicity.
One of the requirements for this approach is the identification of antigens capable of mediating tumor rejection. Certain antigen targets for immunotherapy of ovarian cancer, such as MUC1 [2], [3], Her-2/neu [4], [5] and CA-125 [6], [7], are already known, and others, although they remain unidentified, are likely to exist. The majority of tumor antigens, however, are nonmutated self-antigens to which the immune system is tolerant. It is well documented that tumor cells do not express costimulatory molecules and seldom express MHC class II molecules both of which are essential for the induction of cellular immunity. As a result, tumor antigen may not be effectively presented to the immune system [8], [9], or worse, T cells responding to tumor antigens may be anergized [10], [11], [12]. Therefore, a strategy is needed to overcome these barriers that prevent the induction of effective antitumor immunity against antigens selective for, or overexpressed in, ovarian carcinomas.
One strategy in development is the fusion of dendritic cells (DC) and tumor cells. DC are bone-marrow-derived leukocytes that are critical in the initiation of T-cell-mediated immunity [13], [14]. These cells derive their potency from constitutive and inducible expression of essential costimulatory ligands on the cell surface, including CD80, CD86, CD56 and CD40 [15], [16]. DC have been fused to patient-derived ovarian carcinoma (OVCA) cells [17], [18]. The fusion cells have induced cytotoxic T cells against autologous OVCA cells. In the present study, using samples collected from 22 patients with OVCA, we have adopted a systematic approach to address the following issues: (i) development of a protocol that allowed the successful generation of DC and OVCA cells and subsequent fusion of these two cell types (DC/OVCA); (ii) assessment of the anti-OVCA immune responses induced by DC/OVCA fusion cells; (iii) conversion of such fused DC/OVCA cells into a vaccine that can be frozen, thawed, irradiated and administered to patients.
Section snippets
Patients
This study was conducted during the period of May, 2000 to December, 2001 in which 27 patients from Massachusetts General Hospital (MGH) and later three patients from Boston University Medical Center were entered with presumptive admission diagnosis of primary ovarian carcinoma for surgery or recurrent carcinoma for further treatment. These patients had either one or more of the following findings: pelvic or abdominal mass, ascites or pleural effusion. The protocol and consent form of the study
Generation and characterization of OVCA cells from patients
In 22 patients diagnosed with ovarian cancer, we obtained 11 solid tumor samples, 5 ascites samples and 6 solid tumor samples with malignant fluids (Table 1). Tumor cells were successfully isolated from both the solid samples and malignant fluids in all 22 cases. Among them, an average 36.8 g of tumor sample was obtained to yield 1 × 107 tumor cells. The cancer cells expressed MUC1, CA-125 and Her-2/neu tumor antigens. MUC1 and CA-125 were demonstrated in 19 and 20 samples, respectively, out of
Discussion
There is ample evidence that antitumor immune response exists in patients with ovarian cancer [19], [20]. The presence of intratumoral T cells correlates with improved clinical outcome in advanced ovarian carcinoma [21]. Such tumor-infiltrating T cells can recognize autologous ovarian tumor [19], [20] or peptide derived from OVCA tumor antigen [5]. In addition, adoptive transfer of tumor-infiltrating lymphocytes has resulted in prolonged disease-free periods in patients with advanced ovarian
Acknowledgments
This work has been supported by the US Department of Defense Breast and Ovarian Cancer Research programs, grant DAMA170010220, by National Cancer Institute Grant R01 CA87057.
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