Enhanced in vivo therapeutic response to interferon in mice with an in vitro interferon-resistant B-cell lymphoma.

A stable subline of 38C13 B-cell lymphoma (SIR-1) resistant to the antiproliferative effects of alpha-interferon (IFN) was isolated. In addition to defects in antiproliferative effects of IFN, SIR-1 is defective in IFN-mediated antiviral activity against both encephalomyocarditis virus and vesicularstomatitis virus. It is also defective in the induction of 2'-5'-oligoadenylate synthetase mRNA and enzyme activity, enhancement of H-2 antigen expression, and transient induction and subsequent repression of c-myc by IFN. SIR-1, although completely resistant to IFN in vitro, is more sensitive to IFN than the parental cell line in vivo. IFN treatment at 10(4) units, three times weekly, resulted in a 28% increase in mean survival time and a 1.4% long term survival rate in the IFN-sensitive 38C13 cell line but resulted in a 275% increase in mean survival rate and a 27% long term survival rate in the interferon-resistant SIR-1 mutant. Statistical analysis of 38C13 and SIR-1 with and without IFN treatment demonstrate that: a) the SIR-1 mutant remains sensitive to the cytotoxic effects of IFN in vivo (P less than 0.0001); and b) the mean survival and long term survival of animals with the SIR-1 mutant is significantly greater than for animals with the IFN-sensitive 38C13 cell line (P less than 0.0001). Two additional independently isolated IFN-resistant cell lines (SIR-111 and SIR-E102) also demonstrate significantly enhanced in vivo response to IFN compared to the interferon-sensitive parental (38C13) cells. These results indicate that, for this cell line, the antitumor effects of IFN are mediated by activation of host defenses and that resistance to the in vitro cytotoxic effects of IFN results in a tumor phenotype that is more readily recognized by host defenses and eliminated.

Synergistic antitumor activity with IFN and monoclonal anti-idiotype for murine B cell lymphoma. Mechanism of action.

Combination therapy with syngeneic anti-idiotype antibody and human hybrid rIFN-alpha A/D synergistically increase survival in C3H/HeN mice challenged with a lethal dose of tumor cells. C3H/HeJ mice, which have previously been described to be LPS hyporesponsive and have a defect in Fc gamma R function, did not respond to anti-idiotype therapy as well as C3H/HeN normal mice. This defect was completely corrected in animals treated simultaneously with IFN. Anti-idiotype mAb that was cleaved into F(ab')2 fragments no longer had any antitumor activity alone and could not be enhanced by IFN therapy. These results suggest that antibody is functioning through Fc gamma R-bearing effector cells that are enhanced by IFN therapy. Synergy between IFN and anti-idiotype mAb was maintained in nude mice lacking classical T cells but was reduced in C3H beige mice lacking classical NK/killer cells. IFN did not increase idiotype expression on the tumor cells but did increase H-2 expression. Although we have previously shown that rIFN-alpha A/D can directly kill 38C13 in vitro, an IFN-resistant subclone derived from 38C13, SIR-1, was equally or more responsive to human rIFN-alpha A/D in vivo and had a synergistic antitumor response to combination IFN and anti-idiotype therapy, indicating that IFN acts primarily through host mediated effects rather than direct effects.