Measles Virus-Based Immunovirotherapy in the Treatment of Metastatic Breast Cancer
Oncolytic viruses preferentially infect and kill cancer cells. MV-CEA and MV-NIS are modified strains of the measles (MV) Edmonston vaccine strain that express CEA and NIS as markers of MV infection.
Data derived from phase I clinical trials of the measles derivatives MV-CEA and MV-NIS in patients with multiple myeloma and ovarian cancer confirm the potential for anti-tumor efficacy and have demonstrated the development of anti-tumor immune responses in patients with ovarian cancer.
This project team in the Mayo Clinic Breast Cancer SPORE engineered a newer vaccine strain, MV-NAP, to express neutrophil activating protein (NAP), a Toll-like receptor agonist that stimulates the immune system to heighten a patient's tumor-specific systemic immune response.
Pilot toxicology studies of MV-NAP in mouse models support its safety. In addition, this strain demonstrated superior efficacy in preclinical breast cancer models compared with unmodified strains. In these models, patient response was independent of HER2 and hormone receptor status.
PD-1/PD-L1 blockade has already entered standard clinical practice with recent Food and Drug Administration approvals in melanoma, non-small cell lung cancer, kidney cancer and lymphoma.
A recent phase Ib trial of pembrolizumab in patients with heavily pre-treated, hormone receptor negative, HER2 negative, metastatic breast cancer provides early evidence of a role for PD-1/PD-L1 blockade in this malignancy. The follow-up phase II breast cancer trial is ongoing.
Hypothesis
This project in the Breast Cancer SPORE hypothesizes that PD-1/PD-L1 blockade will augment the immunostimulatory potential of MV-NIS and MV-NAP induced oncolytic cell death in breast cancer. Preclinical work in immunocompetent breast cancer models supports this hypothesis.
The project team is conducting two first-in-human phase I clinical trials of single agent MV-NIS and MV-NAP to determine safety, toxicity and the maximally tolerated dose of intratumoral MV administration in metastatic breast cancer. These studies are also exploring tissue and blood biomarkers as predictors of treatment benefit.
The project team is also conducting parallel preclinical studies to evaluate the optimal sequence and combination of MV and PD-1/PD-L1 blockade. This work is expected to culminate in a novel phase I study of MV administration in combination with PD-1/PD-L1 blockade to assess safety, toxicity and dose in addition to the potential efficacy and immunostimulatory potential of this novel drug combination.
Project aims
This project in the Breast Cancer SPORE has three aims:
- Conduct the first-in-human phase I clinical trial of single-agent intratumoral MV-s-NAP in metastatic breast cancer
- Evaluate the efficacy, optimal sequence and mechanism of action of MV virotherapy in conjunction with antibody blockade of the PD-1/PD-L1 axis in immunocompetent breast cancer models; and conduct preclinical toxicology studies to evaluate the safety of combination therapy in measles replication permissive transgenic models and assess biodistribution
- Conduct the first phase I clinical trial of intratumoral MV-s-NAP combined with PD-1 blockade in patients with metastatic breast cancer