Antitumor activity of the intratumoral injection of fowlpox vectors expressing a triad of costimulatory molecules and granulocyte/macrophage colony stimulating factor in mesothelioma

Our plain-English summary of Antitumor activity of the intratumoral injection of fowlpox vectors expressing a triad of costimulatory molecules and granulocyte/macrophage colony stimulating factor in mesothelioma, by P.L. Triozzi, W. Aldrich, K.O. Allen, et al (International Journal of Cancer, 2005).

The study

• Authors: P.L. Triozzi, W. Aldrich, K.O. Allen, J. Lima, D.R. Shaw, T.V. Strong
• Journal: International Journal of Cancer
• Published: 2005;113(3):406-14
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

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.

In plain English

This was a laboratory study in mice at the University of Alabama at Birmingham testing an experimental immune treatment for mesothelioma. It did not study people or asbestos exposure directly. The mouse mesothelioma cell lines used, AB12 and AC29, had originally been made by implanting asbestos fibers into the abdomens of mice; the fiber type is not stated. The treatment, rF-TRICOM, was a non-replicating fowlpox virus carrying genes for three immune 'costimulatory' molecules. It was compared with a fowlpox virus carrying the immune signal GM-CSF (rF-GM-CSF), an unmodified virus, and salt solution. In mice with abdominal tumors, rF-TRICOM lengthened median survival: for AB12, 35 days versus 20 with the unmodified virus; for AC29, 45 versus 36 days. In mice with AB12 tumors under the skin, tumors disappeared completely in 4 of 10 mice after one rF-TRICOM injection and in 5 of 6 after two. After two rF-GM-CSF injections, this happened in 1 of 6. None of the 4 re-challenged mice whose tumors had disappeared regrew tumors over 50 days of observation. The tumor cells themselves produced GM-CSF. The authors concluded that the results support testing rF-TRICOM in patients with mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory animal and cell-culture experiments
• Who was studied: Female BALB/c and CBA/J mice, 4 to 8 weeks old, implanted with the mouse mesothelioma cell lines AB12 (in BALB/c mice) and AC29 (in CBA/J mice). Tumors were placed either in the abdomen (intraperitoneal) or under the skin (subcutaneous). Group sizes were 5, 6 or 10 mice depending on the experiment. The work was done at the University of Alabama at Birmingham. The cell lines had been made by implanting asbestos fibers (type not stated) into mice.
• Exposure: The exposure studied was the treatment, not asbestos. Tumors were injected with rF-TRICOM, a fowlpox virus carrying genes for B7-1, ICAM-1 and LFA-3. Comparison groups received rF-GM-CSF, unmodified wild-type fowlpox (rF-WT), or PBS salt solution. Asbestos appears only as the origin of the cell lines, which were made by intraperitoneal implantation of asbestos fibers; no fiber type is named.
• Main results:
  • Before treatment, neither AB12 nor AC29 cells expressed ICAM-1. B7-1 was found on 4.4% of AB12 cells and on no AC29 cells. After rF-TRICOM infection, most cells expressed both molecules; the exact percentage is printed with a damaged symbol before 96%.
  • In mice with AB12 tumors in the abdomen, the authors reported a significant increase in median survival with rF-TRICOM: 35 days, versus 20 days with the wild-type virus. There were 4 long-term survivors in the rF-TRICOM group. All rF-GM-CSF-treated mice died by Day 30.
  • In mice with AC29 tumors in the abdomen, median survival with rF-TRICOM was 45 days, versus 36 days with the wild-type virus. There were 2 long-term survivors with rF-TRICOM; the p-value for this comparison was printed as 0.237.
  • In mice with AB12 tumors under the skin, a single injection gave complete tumor regression in 4 of 10 rF-TRICOM-injected mice. All mice given rF-GM-CSF or wild-type virus developed progressive tumors.
  • With two injections 7 days apart, complete regression occurred in 5 of 6 rF-TRICOM mice (83%). It occurred in 1 mouse (17%) given rF-GM-CSF twice, and in 3 mice (50%) given rF-GM-CSF followed by rF-TRICOM.
  • Four mice whose AB12 tumors had completely regressed after rF-TRICOM were re-challenged with new AB12 cells. Tumors did not redevelop in any of them over 50 days of observation.
  • Spleen cells from mice that rejected AB12 tumors after rF-TRICOM killed AB12 cells in the laboratory. Spleen cells from untreated tumor-bearing mice did not.
  • Some mice with established AB12 tumors were given irradiated AB12 cells that had been infected with rF-TRICOM. Their mean survival was 44 days, compared with 26 days in controls given uninfected irradiated cells.
  • Untreated AB12 tumors contained substantial numbers of macrophages and high levels of GM-CSF messenger RNA. Six days after rF-TRICOM injection, GM-CSF messenger RNA fell by approximately 80%.
  • In culture, untreated AB12 cells produced significant levels of GM-CSF protein, and AC29 cells produced lower levels.
• The authors' conclusion: The authors concluded that their results support clinical testing of rF-TRICOM injected into mesothelioma tumors. They also said that mesothelioma tumors can produce cytokines such as GM-CSF, which may limit treatments based on injecting cytokines into tumors.
• Limitations the authors state:
  • The authors stated that a dose and schedule suitable for larger human tumors would still need to be developed.
  • The authors said it was unclear why rF-TRICOM injections worked in AB12 mesothelioma but not, in another group's study, in A20 lymphoma.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Macrophage, Mesothelioma, Cytokine.

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