REACTIVATION OF MURINE TUMOR-INFILTRATING LYMPHOCYTES WITH SOLID-PHASE ANTI-CD3 ANTIBODY - IN-VITRO CYTOKINE PRODUCTION IS ASSOCIATED WITH IN-VIVO EFFICACY
Ps. Goedegebuure et al., REACTIVATION OF MURINE TUMOR-INFILTRATING LYMPHOCYTES WITH SOLID-PHASE ANTI-CD3 ANTIBODY - IN-VITRO CYTOKINE PRODUCTION IS ASSOCIATED WITH IN-VIVO EFFICACY, Surgical oncology, 3(2), 1994, pp. 79-89
Previously we described the use of solid-phase anti-CD3 monoclonal ant
ibody (mAb) to stimulate murine tumour-infiltrating lymphocytes (TIL)
and their subsequent expansion in recombinant interleukin 2 (rIL-2). I
n a pulmonary metastases model using the methylcholanthrene-induced sa
rcoma MCA-105 anti-CD3 activated TIL were capable of eradicating disea
se similar to TIL cultured in rIL-2 only. Here we extend these observa
tions by characterizing the biological effects of sequential solid-pha
se anti-CD3 activation. TIL from MCA-105 tumour activated with solid-p
hase anti-CD3 on day 1 were reactivated on day 14, or day 26, or both
and compared to TIL grown in rIL-2 only or TIL activated with anti-CD3
once on day 1. Reactivation enhanced in vitro proliferation 1.8- to 4
-fold compared to TIL activated once with anti-CD3 (P < 0.05). In addi
tion, the total lytic capacity of the cultures was enhanced after reac
tivation without changing the phenotype of the TIL cultures. Reactivat
ion resulted in a greater in vivo efficacy when the TIL were administe
red within 72 h of reactivation. In contrast, TIL activated with anti-
CD3 on day 1 and day 14 were least effective of all TIL cultures (P <
0.05). This correlated with in vitro cytokine production. The most eff
ective TIL cultures in vivo produced 4- to 100-fold higher amounts of
cytokines, especially interferon gamma (IFNgamma) and granulocyte macr
ophage colony stimulating factor (GM-CSF), than the other cultures. On
the other hand, the least effective in vivo TIL culture, TIL activate
d with anti-CD3 on day 1 and 14, produced little or no cytokines. Thes
e data suggest that in vitro production of cytokines is indicative of
in vivo efficacy of anti-CD3 activated TIL.