Expansion of human tumor infiltrating lymphocytes for use in immunotherapy trials.

The potential utility of tumor-infiltrating lymphocytes (TIL) in the adoptive immunotherapy of human tumors has been suggested by murine experiments showing these cells to be 50-100 times more powerful than LAK cells in treating advanced metastatic disease. A method for the large-scale expansion of human TIL for the use of these cells in clinical trials is described in this report. TIL were successfully expanded on an experimental scale from 24 of 25 consecutive human tumors, including six melanomas, ten sarcomas, and eight adenocarcinomas. Tumors were digested enzymatically to yield single cell suspensions which were cultured in RPMI 1640 medium with 10% human serum and 1000 U/ml recombinant interleukin-2. Lymphocytes constituted from 3% to 74% of single cell tumor suspensions, and expanded from 2.9-fold to 9.1 X 10(8)-fold over a culture period ranging from 14 to 100 days. Nine of 24 TIL cultures lysed fresh autologous tumor targets in 4 h chromium release assays. Cell surface phenotyping identified cultured TIL as activated cytotoxic/suppressor T cells. Subsequently, large-scale expansion of TIL was successful in generating more than 10(10) lymphocytes in five of eight consecutive cases. Clinical trials employing the adoptive transfer of expanded TIL to patients with metastatic disease have begun.

[1]  S. Rosenberg,et al.  In vitro growth of murine T cells. V. The isolation and growth of lymphoid cells infiltrating syngeneic solid tumors. , 1980, Journal of immunology.

[2]  E. Klein,et al.  Separation and characteristics of tumor-infiltrating lymphocytes in man. , 1980, Contemporary topics in immunobiology.

[3]  S. Miescher,et al.  Functional properties of tumor-infiltrating and blood lymphocytes in patients with solid tumors: effects of tumor cells and their supernatants on proliferative responses of lymphocytes. , 1986, Journal of immunology.

[4]  S. Rosenberg,et al.  Identification of specific cytolytic immune responses against autologous tumor in humans bearing malignant melanoma. , 1987, Journal of immunology.

[5]  T. Fujisawa,et al.  Cytotoxicity of autologous and allogeneic lymphocytes against cultured human lung cancer cells: optimal conditions for the production of cytotoxic lymphocytes. , 1984, Gan.

[6]  S. Rosenberg,et al.  Large scale production of human lymphokine activated killer cells for use in adoptive immunotherapy. , 1986, Journal of immunological methods.

[7]  S. Rosenberg,et al.  Lymphokine‐activated killer (LAK) cells. Analysis of factors relevant to the immunotherapy of human cancer , 1985, Cancer.

[8]  R. Blumberg,et al.  Functional characterization of T lymphocytes propagated from human lung carcinomas. , 1986, Clinical immunology and immunopathology.

[9]  P. Schofield,et al.  Specific and non-specific lymphocyte cytotoxicity in colon carcinoma. , 1981, British Journal of Cancer.

[10]  A. Chang,et al.  Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. , 1985, The New England journal of medicine.

[11]  S. Rosenberg,et al.  Successful immunotherapy of murine experimental hepatic metastases with lymphokine-activated killer cells and recombinant interleukin 2. , 1985, Cancer research.

[12]  J. Werkmeister,et al.  Immunoreactivity by intrinsic lymphoid cells in colorectal carcinoma. , 1979, British Journal of Cancer.

[13]  S. Rosenberg,et al.  Adoptive immunotherapy of established pulmonary metastases with LAK cells and recombinant interleukin-2. , 1984, Science.

[14]  S. Rosenberg,et al.  A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. , 1986, Science.

[15]  C. Balch,et al.  Interleukin 2 activation of cytotoxic T-lymphocytes infiltrating into human metastatic melanomas. , 1986, Cancer research.

[16]  W. M. Linehan,et al.  Isolation and characterization of lymphocytes infiltrating human renal cell cancer: Possible application for therapeutic adoptive immunotherapy , 1986 .