Antitumor Efficacy of Lymphokine–activated Killer Cells and Recombinant Interleukin-2 in Vivo: Survival Benefit and Mechanisms of Tumor Escape in Mice Undergoing Lmmunotherapy

J. J. Mulé, S. E. Ettinghausen, P. J. Spiess, S. Shu, S. A. Rosenberg

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59 Scopus citations


The studies described in this paper showed that the combination of i.v.–transferred lymphokine–activated killer (LAK) cells and i.p. injections of recombinant interleukin-2 (RIL-2) was highly effective in vivo in reducing established pulmonary metastases of natural killer cell-resistant, MCA-105 sarcoma and B16 melanoma in mice. A 3-day in vitro incubation of normal C57BL/6 splenocytes in medium containing pure RIL-2 generated LAK cells that, when combined with RIL-2, reduced the mean number of established pulmonary micrometastases of the B16 melanoma and of the MCA-105 sarcoma from 179 and 140, respectively (in groups treated with Hanks’ balanced salt solution alone), to 12 (P = 0.01) and 6 (P = 0.01), respectively. This combined immunotherapy also consistently resulted in significant prolongation of survival in mice with established, 3-day or 10-day pulmonary metastases of the MCA-105 sarcoma. Mice autopsied at time of death revealed a massive involvement of tumor in the lungs and liver in the group receiving Hanks’ balanced salt solution alone compared to a small number of residual large lung or liver metastases in the group receiving LAK cells plus RIL-2. Experiments were designed to test whether variants existed in the original tumor cell inoculum that were resistant to killing by LAK cells and thus could account for the metastases that “escaped” the combined immunotherapy of LAK cells plus RIL-2 in vivo. Metastases of the MCA-105 sarcoma that escaped the combined therapy of LAK cells plus RIL-2 were dissected from the organs of mice upon autopsy and directly tested for susceptibility in vitro to lysis by LAK cells in 4-h and 18-h 51Cr release assays. Target cells derived from the metastases were lysed to an equivalent extent as those prepared from a fresh MCA-105 sarcoma that was growing s.c. In addition, successful reduction of pulmonary metastases established by the i.v. infusion of MCA-105 sarcoma cells obtained from metastases that escaped a prior round of therapy with LAK cells and RIL-2 could be achieved in vivo by the combined immunotherapy as well as by high doses of RIL-2 alone. Culture adapted, natural killer cell-resistant B16 melanoma cells surviving two successive treatments with LAK cells in vitro remained as susceptible to LAK cell lysis as untreated B16 melanoma cells in 18-h 51Cr release assays. Furthermore, an analysis comparing 24 clones derived from the LAK cell-treated B16 melanoma with 26 clones derived from untreated B16 melanoma failed to show any resistance to LAK cell lysis; all clones were highly sensitive to LAK cells in an 18-h terminal labeling assay of cytotoxicity. Thus, we found no evidence for LAK cell-resistant variants of the B16 melanoma. Taken together, our results show that prolonged survival of mice with established metastases is attained by the combined therapy of LAK cells and RIL-2 and that residual metastatic nodules that escape the therapy do not appear to be resistant to LAK cell killing in vitro or in vivo.

Original languageEnglish (US)
Pages (from-to)676-683
Number of pages8
JournalCancer Research
Issue number2
StatePublished - Feb 1 1986

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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