A combination of two immunotherapies — VIC-008 and Mozobil (plerixafor, or AMD3100) — suppresses mesothelioma growth and prolongs survival, suggesting a potential therapy for this type of cancer, a mouse study shows.
Findings were published in the study, “AMD3100 Augments the Efficacy of Mesothelin-Targeted, Immune-Activating VIC-008 in Mesothelioma by Modulating Intratumoral Immunosuppression,” in the journal Cancer Immunology Research.
Malignant mesothelioma is an aggressive cancer that occurs in the thin layer of tissue that covers most of our internal organs. There is currently no disease-modifying therapy that effectively increases the survival of these patients.
Mesothelin — a protein highly expressed in many human cancers, including malignant mesothelioma, and pancreatic and ovarian cancer — is an attractive target for cancer immunotherapy.
VIC-008, also called Jantibody, is a fusion protein that binds to mesothelin on the surface of cancer cells, tagging them with a foreign protein that activates immune cells against them.
VIC-008 was previously shown to significantly slow tumor growth and enhance survival in a mouse model of mesothelin-expressing ovarian cancer. VIC-008 increases anti-tumor responses, mediated by a special group of immune cells called CD8 T-cells, which are potent killers of tumor cells.
However, the immunosuppressive microenvironment within tumors, involving the presence of regulatory T-cells (Tregs) — immune cells that play a key role in reducing the immune system response — limits the effect of these immunotherapies.
Mozobil, developed by Sanofi, has several anti-tumor effects, such as increased tumor cell death and reduction of Treg numbers within the tumor, which prolonged survival in an ovarian cancer mouse model.
Mozobil is a small molecule known to block the interaction between CXCR4 and CXCL12 — two proteins highly present in several tumors and involved in tumor growth and metastasis. However, the mechanisms behind its effects on mesothelioma are still unknown.
Since high levels of CXCR4/CXCL12 are also found in most mesothelioma tumor tissues, and Mozobil reduces the presence of Treg cells, researchers from the Vaccine and Immunotherapy Center (VIC) at Massachusetts General Hospital evaluated the potential benefits of combining VIC-008 with Mozobil in two mouse models of mesothelioma.
The combo therapy significantly suppressed tumor growth and prolonged survival of both mesothelioma mouse models. These responses were associated with Mozobil-mediated reduction of the immunosuppressive microenvironment within the tumor.
Mozobil effects were based on the reduction of PD-1 levels in CD8 T-cells — reducing an important immune-evasive mechanism of cancer — and on a Treg shift from an immunosuppressive state to an anti-tumor state that could help fight cancer cells.
“The apparent ability to change immunosuppressive T cells within the tumor into T cell types that are more active and potentially helpful against cancer was a really exciting finding, and one that we’re continuing to investigate,” Mark Poznansky, MD, PhD, the study’s senior author and an associate professor of medicine at Harvard Medical School, said in a press release.
Researchers noted their findings emphasize that the anti-tumor effects of immunotherapies such as VIC-008 may be further improved if Tregs are reduced/impaired within the tumor.
“Our study may offer a therapeutic approach for significantly prolonging the survival of patients with malignant mesothelioma and expand the potential clinical efficacy of both novel and established … vaccines and immunotherapies for this difficult-to-treat disease,” the team concluded.