New Immunotherapy May Be Possible Against Peritoneal Mesothelioma

Locally administered doses of CpG-oligodeoxynucleotides may be effective in treating diffuse malignant peritoneal mesothelioma, according to researchers from Italy.

The particular form of CpG-oligodeoxynucleotide at the core of this finding is synthetic DNA sequence CpG-ODN1826.

Toll-like receptor 9 — or simply TLR9, a gene-level protein — recognizes CpG-ODN1826. This recognition appears to induce both an innate and adaptive immune response, the researchers report.

The researchers say that the immune response they observed was sufficient to exert antitumor activity against both early- and late-stage diffuse malignant peritoneal mesothelioma.

However, the researchers caution that so far they have only tested CpG-ODN1826 in lab mice and do not yet know how well it would work in humans.

Still, based on what they’ve seen in the lab, the researchers think CpG-ODN1826 may represent a formidable immunotherapy against diffuse malignant peritoneal mesothelioma.

The next step will be to better understand how CpG-ODN1826 does what it does. The researchers indicate this will allow them to define biomarkers to permit selection of those patients most likely to benefit from treatment with CpG-ODN1826.

Boosts Effectiveness of Other Mesothelioma Treatments

The researchers are from Fondazione IRCCS Istituto Nazionale dei Tumori in Milan. Their findings were published as “CpG-oligodeoxynucleotides Exert Remarkable Antitumor Activity Against Diffuse Malignant Peritoneal Mesothelioma Orthotopic Xenografts” in a recent edition of Journal of Translational Medicine.

The researchers said they were inspired by a desire to do something positive about the poor prognosis that typically follows a diagnosis of diffuse malignant peritoneal mesothelioma.

“Standard therapy with palliative surgery and systemic or intra-peritoneal chemotherapy is associated with a median survival of about one year,” they wrote.

The researchers said better survival comes from the use of cytoreductive surgery paired with perioperative hyperthermic intraperitoneal chemotherapy.

But even though that combination procedure can extend mesothelioma survival into the five-year range, about half of the patients who undergo it suffer recurrence long before then.

What the researchers said they are hoping for here is to come up with a novel therapeutic strategy that will optimize the effectiveness of cytoreductive surgery and hyperthermic chemotherapy.

Not only that, but there are many patients for whom cytoreductive surgery and hyperthermic chemotherapy can’t be used at all because their mesothelioma is far too advanced.

Encouraged Increase of Macrophages

For this investigation, the researchers experimented with two mesothelioma cell lines that had earlier been obtained from surgery patients at the Fondazione IRCCS Istituto Nazionale dei Tumori.

The cell lines were placed within lab mice. After the implanted cells had sufficiently multiplied, the researchers then treated the mice with CpG-ODN1826.

They observed that the CpG-ODN1826 “completely abolished or markedly impaired” the mesothelioma. In addition to preventing it from growing, the CpG-ODN1826 lengthened the survival of the mice.

Flow cytometry analysis performed on the mice afterward showed there had been a “strong increase of macrophage infiltration” after treatment. Macrophages are immune cells that kill invader cells.

In particular, the administered CpG-ODN1826 appeared to encourage production of cytotoxic and anti-proliferative molecules. Among them were reactive oxygen and reactive nitrogen intermediates, they said.

CpG-ODN1826 also appeared to give a boost to tumor necrosis factor proteins. These are credited with bringing on apoptosis of mesothelioma cells, according to the researchers.

“The impressive efficacy displayed by CpGODN1826 in mice with low tumor burden suggests a possible clinical utility of the agent as local adjuvant therapy in diffuse malignant peritoneal mesothelioma patients,” they concluded.