CpG-oligodeoxynucleotides exert remarkable antitumor activity against diffuse malignant peritoneal mesothelioma orthotopic xenografts

Our plain-English summary of CpG-oligodeoxynucleotides exert remarkable antitumor activity against diffuse malignant peritoneal mesothelioma orthotopic xenografts, by M. De Cesare, L. Sfondrini, M. Pennati, et al (Journal of Translational Medicine, 2016).

The study

• Authors: M. De Cesare, L. Sfondrini, M. Pennati, C. De Marco, V. Motta, E. Tagliabue, M. Deraco, A. Balsari, N. Zaffaroni
• Journal: Journal of Translational Medicine
• Published: 2016;14:25
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Diffuse malignant peritoneal mesothelioma (DMPM) is a rare and locally aggressive disease. DMPM prognosis is dismal, mainly due to the lack of effective treatment options and the development of new therapeutic strategies is urgently needed. In this context, novel immunotherapy approaches can be explored in an attempt to improve DMPM patients' survival.

Methods: We tested the efficacy of CpG-oligodeoxynucleotides (CpG-ODN), synthetic DNA sequences recognized by Toll-like receptor 9 and able to induce innate/adaptive immune response, in two DMPM orthotopic xenografts (MesoII and STO), which properly recapitulate the dissemination pattern of the disease in the peritoneal cavity. Severe combined immunodeficiency mice carrying DMPM xenografts were treated at different stages of tumor development with i.p. delivered CpG-ODN1826 for 4 weeks. CpG-ODN1826-induced modulation in the composition of peritoneal immune infiltrate was assessed by flow cytometry.

Results: When administered to early-stage tumors (i.e., 4 days after i.p. DMPM cell injection in mice), the agent exhibited impressive efficacy against MesoII by completely inhibiting tumor take and ascites development (no evidence of tumor masses and ascites in 6/6 mice at necropsy), and also impaired STO tumor take and growth (4/6 tumor-free mice; i.p. tumor masses reduced by 94 % in the 2 remaining mice, P = 0.00005). Interestingly, when tested against late-stage STO tumors (i.e., 11 days after i.p. DMPM cell injection in mice), CpG-ODN1826 was still able to reduce the growth of i.p. tumor masses by 66 % (P = 0.0009). Peritoneal washings of tumor-bearing mice revealed a strong increase of macrophage infiltration together with a decrease in the presence of B-1 cells and a reduced IgM concentration after CpG-ODN1826 treatment.

Conclusions: Our results indicate that locally administered CpG-ODN1826 is able to markedly affect the growth of both early- and late-stage DMPM orthotopic xenografts in the absence of severe side effects, and suggest a possible clinical role for the agent in the therapy of DMPM.

In plain English

In this mouse study, the authors tested whether CpG-ODN1826 could slow diffuse malignant peritoneal mesothelioma. CpG-ODN1826 is a synthetic DNA compound that stimulates immunity. Human tumor cells from two cell lines (MesoII and STO) were injected into the abdomens of female immunodeficient (SCID) mice. They received the compound or saline into the abdomen five days weekly for four weeks. The study did not examine asbestos exposure. With treatment from day 4, no treated MesoII mouse (0 of 6) developed tumors or ascites; all 6 controls did. Among STO mice, 4 of 6 treated mice were tumor-free, and tumor weight was 94% lower than in controls. With treatment from day 11, all STO mice had tumors, but treated mice had 66% less tumor weight. Treated mice had more macrophages, fewer B-1 cells and less IgM antibody in abdominal fluid. Treated mice lost at most 10% (early-stage MesoII) or 13% (early-stage STO) of body weight, with no toxic deaths. The authors concluded that the findings support a possible clinical role for this approach. The results come from mice, not patients.

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: animal experiment: human peritoneal mesothelioma cells grown in the abdomen of immunodeficient mice (orthotopic xenografts), randomized to treatment or saline
• Who was studied: 8–10-week-old female SCID mice, 6 to 10 per group, carrying tumors from two human diffuse malignant peritoneal mesothelioma cell lines (MesoII and STO) established from patients operated on at the Istituto Nazionale dei Tumori, Milan
• Exposure: No asbestos exposure was studied. The exposure was treatment with CpG-ODN1826 or saline injected into the abdomen at 20 µg per mouse, five days a week for four weeks. Treatment started 4 days (early-stage tumors) or 11 days (late-stage STO tumors) after tumor cell injection.
• Main results:
  • Early-stage MesoII tumors: all 6 control mice developed ascites (median 42.5 days) and tumor masses. No treated mouse had ascites 102 days after the last dose, and no tumor masses were found. The authors reported 6 of 6 treated mice cured (P = 0.0004 for ascites-free survival).
  • Early-stage STO tumors: 4 of 6 treated mice were macroscopically tumor-free. Mean tumor weight was 695 ± 206 mg in control mice and 43 ± 60 mg in treated mice, a 94% inhibition (P = 0.00005).
  • Late-stage STO tumors (10 mice per group): tumors were found in all control and all treated mice. Mean tumor weight was 1120 mg in controls and 381 ± 99 mg in treated mice, a 66% reduction (P = 0.0009).
  • In abdominal fluid from late-stage STO mice (4 per group), macrophages made up 69.1 ± 4.5% of immune cells in treated mice versus 20.1 ± 4.6% in untreated mice (P = 0.0003).
  • In an additional late-stage STO experiment, treated mice showed a marked reduction of B-1 cells. IgM concentration in abdominal fluid was 11 ± 2.6 µg/ml in treated mice versus 27.6 ± 3.1 µg/ml in controls (P = 0.015).
  • Toxicity: body weight loss in treated mice did not exceed 10% in the early-stage MesoII experiment and reached at most 13% in the early-stage STO experiment. No toxic deaths occurred in either experiment. No maximum weight-loss figure is given for the late-stage STO experiment.
• The authors' conclusion: The authors concluded that locally given CpG-ODN1826 showed significant antitumor activity against early- and late-stage peritoneal mesothelioma xenografts without severe toxicity. In their view, this supports the possible clinical relevance of a CpG-ODN1826-based immunotherapy approach.
• Limitations the authors state:
  • The authors stated they could not determine whether the treatment-induced changes in B-1 cells played any part in the tumor growth inhibition, because the role of B-1 cells in tumor growth has been poorly investigated.

Topics

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

Medical terms in this study, explained in our Lexicon: Peritoneal Mesothelioma, Prognosis, Immunotherapy, Peritoneal Cavity, Ascites, Autopsy, Macrophage.

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