Immunotherapy for peritoneal ovarian carcinoma metastasis using ex vivo expanded tumor infiltrating lymphocytes

Abstract

Background to the standard treatment of ovarian cancer Cancer of the ovary is responsible for the highest proportion of the mortality in patients with gynecologic malignancies. The overall survival for these patients at 5 years is 39% [1]. Epithelial ovarian carcinoma (EOC) represents 90% of the histologies and is thus the most frequent histologic group. Primary peritoneal carcinoma, also called extraovarian mullerian carcinoma, has the same pattern of tumor spread and sensitivity to chemotherapy as EOC, although the ovaries arc not primarily involved in the pathologic process. Other malignancies that originate from the ovaries include those of germ cell and stromal cell origin. These are considered separately and have a different clinical presentation and a different response to treatment.The standard first-line treatment of EOC or peritoneal carcinomatosis includes an initial exploratory laparotomy. Abdominal surgery is performed to accomplish certain objectives: (1) to establish a histopathologic diagnosis, (2) to obtain intraoperative staging of the tumor, and (3) to achieve the maximum feasible removal of the tumor. Currently, surgical staging follows the 1985 recommendations of the Federation Internationale Gynecologie Obstetrique (FIGO). Surgical treatment is followed in most cases by platinum-based chemotherapy utilizing either carboplatinum or cisplatinum in combination with cyclophosphamide. Platinum-based chemotherapy is the treatment of choice in patients who have stage II-IV disease, which represents 90% of all patients with EOC. No single adjuvant treatment approach has been established for patients whose disease appears to be confined to the ovaries, although many of these patients will ultimately relapse, even after receiving chemotherapy. Combination chemotherapy regimens that include cisplatin or carboplatin produce overall response rates that are in the range of 60-80% [2,3]. The majority of these patients will ultimately progress, or will relapse after a complete pathologic response due to either primary or acquired drug resistance [4]. Recent phase II data have shown high response rates with taxoids, for example, taxol or taxotere [5,6], although there are few complete responses and treatment with these drugs may be both toxic and costly. In consideration of the overall low frequency

Anticancer immune reactivity and long-term survival after treatment of metastatic ovarian cancer with dendritic cells

“…Tumor antigen-specific T cells occur naturally in OVCA patients. Naturally occurring T cells that recognize tumor-associated antigens were found in 50% of OVCA patients (27). The presence of intratumoral T cells correlates with improved clinical outcome in advanced OVCA (24).…”

“…These tumor-infiltrating T cells are capable of identifying autologous ovarian tumor or peptides derived from OVCA tumor antigens (22,23). The tumor antigen-specific T cells may be expanded from OVCA patients in vitro (27) and may recognize similar epitopes in HER2/neu antigens of breast cancer (7). The adoptive transfer of these tumor-infiltrating lymphocytes has been found to prolong disease-free survival in patients with advanced OVCA (25).…”

Pathogenesis of Ovarian Serous Carcinoma as the Basis for Immunologic Directed Diagnosis and Treatment

“…A significant correlation was found between the presence of intratumoural T cells and the detection of peripheral blood T cells recognising tumour antigens in 10 consecutive patients with ovarian cancer studied (manuscript submitted). Relevant also is evidence that tumour-specific T cell lines can be generated from tumour-associated T cells in ∼ 50% of patients [180]. These findings suggest that the adoptive transfer of autologous lymphocytes may represent a powerful therapeutic tool in ovarian carcinoma.…”

Manipulation of MHC-I/TCR Interaction for Immune Therapy

“…The resident ER chaperone proteins GRP94 (gp96) and CRT can escort tumor-derived peptides into the endogenous antigen presentation pathway of APC (65,66). Heat shock proteins (HSPs) hsp70 and hsp90 have a similar property which they chaperone peptides in antigen presentation and are necessary for priming CTL responses (67-70).…”