AB-12

Deficiency in costimulatory molecule expression has been implicated in the ability of tumors to escape immune effectors. The activity of the intratumoral administration of recombinant fowlpox vectors expressing a triad of costimulatory molecules (rF‐TRICOM) was evaluated in the asbestos‐induced AB12 and AC29 mouse models of mesothelioma. Mesothelioma cell infected with rF‐TRICOM expressed high levels of the costimulatory molecules. Prolongation of survival was observed in mice receiving rF‐TRICOM in AB12 and AC29 intraperitoneal models. Complete tumor regressions were observed in mice receiving intratumoral rF‐TRICOM in the AB12 subcutaneous tumor model. Tumor regressions were associated with the development of serum IgG reactivities to mesothelioma‐associated determinants and specific systemic cytolytic activity, and responding mice were capable of rejecting tumors upon re‐challenge. Antitumor activity was also observed in mice with established AB12 tumor vaccinated with irradiated rF‐TRICOM‐infected AB12 cells. The antitumor activity of intratumoral rF‐TRICOM was superior to that of the intratumoral injection of a fowlpox vector expressing granulocyte‐macrophage colony stimulating factor (rF‐GM‐CSF). AB12 and AC29 tumors were found to produce GM‐CSF and to have substantial macrophage infiltration. Production of GM‐CSF decreased in vivo in tumors injected with rF‐TRICOM. rF‐TRICOM and wild‐type fowlpox inhibited the growth of AB12 and AC29 cells in vitro; less inhibition was observed with rF‐GM‐CSF. These results indicate that the intratumoral injection of rF‐TRICOM has significant activity in mouse models of mesothelioma and can elicit a systemic antitumor immune response. The results also suggest potential limitations to the intratumoral administration of cytokines, such as GM‐CSF, in mesothelioma.

Except for the SKOV3 cell line, which had only minimally increased FDG uptake (+10% +/- 26%; P > 0.3), all other tumor cell lines tested showed significantly increased FDG uptake over time (GM1500, +59% +/- 19%; B18F10, +81% +/- 15%; AB12, 93% +/- 21%; II45, +161% +/- 21%; REN, +198% +/- 48%; P < 0.01 for all). By contrast, FDG uptake in mononuclear cells was decreased in 7 of 8 donors. Animal studies: SUVs of tumors from 90-min images were significantly higher than those from 45-min images (+18% +/- 8%; P < 0.01), whereas the SUVs of inflammatory lesions decreased over time (-17% +/- 13% of the early images; P < 0.05).

The SUVs of delayed images from the known malignant lesions compared with those of earlier scans increased over time (+19.18% +/- 9.58%; n = 31; P < 0.001; 95% confidence interval, 15.8%-22.6%). By contrast, the SUVs of benign lung nodules decreased slightly over time (-6.3% +/- 8.1%; n = 12; P < 0.05; 95% confidence interval, -10.9% to -1.7%). The SUV of inflammatory lesions caused by radiation therapy (+1.16% +/- 7.23%; n = 8; P > 0.05; 95% confidence interval, -3.9%-6.2%) and the lesions of painful lower limb prostheses (+4.03% +/- 11.32%; n = 25; P > 0.05; 95% confidence interval, -0.4%-8.5%) remained stable over time.

These preliminary data show that dual time imaging appears to be useful in distinguishing malignant from benign lesions. Further research is necessary to confirm these results.