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Adoptive chemoimmunotherapy of a syngeneic murine lymphoma with long-term lymphoid cell lines expanded in T cell growth factor

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Summary

Recently techniques have been developed for the long-term growth of cytotoxic T-lymphoid cells in vitro with T cell growth factor (TCGF). We have investigated the use of these in vitro-expanded T cells for the immunotherapy of a disseminated syngeneic murine FBL-3 lymphoma. In this model, mice with disseminated tumor were treated on day 5 with 180 mg cytoxan/kg and then 5 h later were given lymphoid cells IP. In vivo-immunized lymphocytes resulted in significantly improved survival in three of three experiments, curing 52% of 38 animals, compared with treatment with cytoxan alone (0 of 31 cured) or cytoxan plus unimmunized cells (0 of 40 cured) (P<0.0005). In vivo-immunized lymphocytes were re-exposed to FBL-3 tumor in vitro for 5 days in complete medium (CM) or lectin-free TCGF (LF-TCGF). Both groups showed significantly improved survival in six of six experiments. Cytoxan cured 17% of 66 animals, while cytoxan plus normal lymphocytes after IVS cured 6% of 47 animals. In vivo-immunized cells resensitized in vitro to FBL-3 in CM or LF-TCGF cured 82% of 50 animals (P<0.001) and 72% of 61 animals (P<0.001), respectively. Cells from in vivo- and in vitro-sensitized lymphocytes exhibited no cytotoxicity in our in vitro 51Cr-release assay; expansion of these cells resulted in significant specific lysis of fresh FBL-3 targets. Adoptive transfer of immune lymphocytes resensitized to FBL-3 tumor in vitro and expanded in LF-TCGF conferred a significant survival benefit (P<0.001, curing 7 of 27 animals) compared with all controls. These expanded cells were then continuously grown in LF-TCGF for 2 1/2 months. Again, in vivo-immunized lymphocytes resensitized to FBL-3 tumor and expanded in LF-TCGF for 2 1/2 months cured 56% of the animals with disseminated tumor, significantly prolonging survival over that recorded in any control group (P<0.0002). Irradiation of these same cells totally abolished their efficacy. Clones were generated from IVS and continuously grown in LF-TCGF. Two of these clones were very cytotoxic for fresh FBL-3 (>4,000 lytic units/106 cells). When adoptively transferred to mice in this chemoimmunotherapy model these cytotoxic clones significantly enhanced survival over that recorded following treatment with cytoxan alone (P<0.00001), though prolongation of survival was small. Implications of these results for application of these techniques to other less antigenic tumors and human cancers are discussed.

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Authors and Affiliations

  1. Surgery Branch, National Institutes of Health, 20205, Bethesda, MD, USA

    Timothy J. Eberlein, Maury Rosenstein, Paul Spiess & Steven A. Rosenberg

  2. Biometric Research Branch, Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, 20205, Bethesda, MD, USA

    Robert Wesley & Steven A. Rosenberg

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  1. Timothy J. Eberlein
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  2. Maury Rosenstein
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  3. Paul Spiess
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  4. Robert Wesley
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  5. Steven A. Rosenberg
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Eberlein, T.J., Rosenstein, M., Spiess, P. et al. Adoptive chemoimmunotherapy of a syngeneic murine lymphoma with long-term lymphoid cell lines expanded in T cell growth factor. Cancer Immunol Immunother 13, 5–13 (1982). https://doi.org/10.1007/BF00200194

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  • DOI: https://doi.org/10.1007/BF00200194

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