The long-term objectives of this interactive R01 proposal are to develop new and effective treatment approaches for epithelial ovarian cancer (EOC) based upon the activation in vivo of tumor infiltrating lymphocytes (TIL) specific for autologous tumor. Notwithstanding recent advances in the chemotherapy of EOC the survival of these patients leaves much to be desired. The hypotheses to be tested in this grant application are that ovarian TIL-derived T-cell lines can be developed from peritoneal exudate cells (PEC) of EOC patients after intraperitoneal (IP) priming with interferon-lambda (rLFN-lambda) followed by low doses of IL-2. In particular, we will address the issues whether IP priming with these cytokines is correlated with (a) increased proportions of tumor cells that express MHC Class I and/or Class II surface antigens in vivo; (b) recovery of large numbers of CD3+TCRalphabeta+ lymphocytes from the peritoneal cavity (P.c.) that express either CD8+ or CD4+ phenotypes; (c) an ability to expand either CD8+ or CD4+ T-cell lines from PEC utilizing a T cell purification procedure and (d) that the T-cell lines obtained after IP priming with rIFN-lambda exhibit specificity in terms of (i_ autologous tumor cell cytolytic activity and/or (ii) cytokine production. All these hypotheses are focused on elucidating the mechanisms of action, in vivo, of these TILs and can be addressed only in conjunction with a clinical trial in which patients with EOC are treated with a strategy of adoptively transferred TIL developed from (PEC) obtained after in vivo priming with rIFN-lambda and IL-2. The clinical trial follows a basic design that we have used in IP adoptive immunotherapy trials of EOC patients. IP priming with rIFN-lambda is a novel feature of our trial design. (e) We will also test the hypothesis in a separate protocol that: ovarian TIL-derived T-cell lines concentrate at tumor sites after IP injection.
Our specific aims are to: Determine whether IP priming of EOC patients with rIFN-lambda followed by low dose rIL-2 correlates with (1) Increased expression of MHC Class I or Class II surface antigens on EOC cells in vivo, and (2) Production of ovarian TIL-derived T-cell lines from PEC that (a) express either the CD8+TCRalphabeta+ or CD4+TCRalphabeta+ phenotype, and (b) exhibit tumor specific activity in terms of (i) Autologous tumor cell cytotoxicity and/or (ii) cytokine production.
Other specific aims are to (3) Determine the frequency and intensity of toxic events and/or clinical responses that result from a treatment strategy that includes IP priming with cytokines and IP treatment with rIFN-lambda followed by cytokine primed T-cell lines and low dose rIL-2, and (4) Determine the ability of purified ovarian T-cell lines to concentrate at tumor sites.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA064943-02
Application #
2107695
Study Section
Special Emphasis Panel (SRC (72))
Project Start
1994-08-01
Project End
1998-05-31
Budget Start
1995-06-01
Budget End
1996-05-31
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Obstetrics & Gynecology
Type
Other Domestic Higher Education
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
Platsoucas, Chris D; Fincke, John E; Pappas, John et al. (2003) Immune responses to human tumors: development of tumor vaccines. Anticancer Res 23:1969-96
Melichar, B; Nash, M A; Lenzi, R et al. (2000) Expression of costimulatory molecules CD80 and CD86 and their receptors CD28, CTLA-4 on malignant ascites CD3+ tumour-infiltrating lymphocytes (TIL) from patients with ovarian and other types of peritoneal carcinomatosis. Clin Exp Immunol 119:19-27
Freedman, R S; Kudelka, A P; Kavanagh, J J et al. (2000) Clinical and biological effects of intraperitoneal injections of recombinant interferon-gamma and recombinant interleukin 2 with or without tumor-infiltrating lymphocytes in patients with ovarian or peritoneal carcinoma. Clin Cancer Res 6:2268-78
Loercher, A E; Nash, M A; Kavanagh, J J et al. (1999) Identification of an IL-10-producing HLA-DR-negative monocyte subset in the malignant ascites of patients with ovarian carcinoma that inhibits cytokine protein expression and proliferation of autologous T cells. J Immunol 163:6251-60
Gordinier, M E; Zhang, H Z; Patenia, R et al. (1999) Quantitative analysis of transforming growth factor beta 1 and 2 in ovarian carcinoma. Clin Cancer Res 5:2498-505
Freedman, R S; Lenzi, R; Kudelka, A P et al. (1998) Intraperitoneal immunotherapy of peritoneal carcinomatosis. Cytokines Cell Mol Ther 4:121-40
Nash, M A; Lenzi, R; Edwards, C L et al. (1998) Differential expression of cytokine transcripts in human epithelial ovarian carcinoma by solid tumour specimens, peritoneal exudate cells containing tumour, tumour-infiltrating lymphocyte (TIL)-derived T cell lines and established tumour cell lines. Clin Exp Immunol 112:172-80
Melichar, B; Savary, C; Kudelka, A P et al. (1998) Lineage-negative human leukocyte antigen-DR+ cells with the phenotype of undifferentiated dendritic cells in patients with carcinoma of the abdomen and pelvis. Clin Cancer Res 4:799-809
Melichar, B; Ferrandina, G; Verschraegen, C F et al. (1998) Growth inhibitory effects of aromatic fatty acids on ovarian tumor cell lines. Clin Cancer Res 4:3069-76
Ferrandina, G; Melichar, B; Loercher, A et al. (1997) Growth inhibitory effects of sodium phenylacetate (NSC 3039) on ovarian carcinoma cells in vitro. Cancer Res 57:4309-15

Showing the most recent 10 out of 13 publications