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.(ABSTRACT TRUNCATED AT 400 WORDS)