5T4-targeted immunotherapy promising in metastatic colorectal cancer

Last Updated: 2017-09-15

By Reuters Staff

NEW YORK (Reuters Health) - Immunotherapy with modified vaccinia Ankara-5T4 (MVA-5T4, TroVax) may improve survival in patients with metastatic colorectal cancer, researchers report.

Previous attempts at immunotherapy targeting upregulated tumor antigens like 5T4 have been largely unsuccessful.

Dr. Andrew Godkin from Cardiff University in Wales and colleagues sought to improve 5T4 immune responses in patients with metastatic colorectal cancer by vaccinating them with a nonreplicating modified vaccinia Ankara-5T4, which had shown efficacy in preclinical models.

Their randomized, open-label phase 1 and 2 trial in 52 patients with inoperable metastatic colorectal cancer assessed the effectiveness of cyclophosphamide, which depletes regulatory T cells (Tregs), in increasing the immunotherapeutic potential of MVA-5T4.

Cyclophosphamide-induced Foxp3+ Treg-cell depletion prolonged progression-free survival (PFS) in patients treated with MVA-5T4, although statistical significance was not reached, likely due to the small sample size, the team suggests.

Patients who experienced more than twofold increases in anti-5T4 T-cell and antibody responses had significantly longer PFS (5.7 months) and overall survival (20.0 months), compared with patients who didn't experience such increases (2.4 and 13.1 months, respectively), the researchers report in JAMA Oncology, online September 7.

The addition of cyclophosphamide did not appear to enhance the effectiveness of MVA-5T4 or to lessen the response to vaccination.

All three treatment groups (MVA-5T4 alone, cyclophosphamide alone, or the combination of MVA-5T4 and cyclophosphamide) had significantly better PFS (but not overall survival) than did the wait-and-see control group.

"Therefore," the researchers note, "receiving treatment with MVA-5T4 or low-dose cyclophosphamide was more effective than allowing a protracted break from chemotherapy."

No treatment-related grade 3 or 4 adverse events occurred.

"Although cyclophosphamide failed to enhance MVA-5T4 immunogenicity, survival benefits with minimal adverse effects were demonstrated, and further investigation is warranted," they conclude.

"Because of cyclophosphamide's ineffectiveness in sustained Treg cell depletion during MVA-5T4 vaccination," the researchers add, "we would propose the combination of MVA-5T4 with more potent blockade of tumor-derived immunosuppression for future development, for example, with anti-CTLA-4 to eliminate intratumoral Treg cells or with anti-LAG-3 checkpoint inhibitors, given the extent of infiltration of highly suppressive LAG-3+CD4+ tumor-infiltrating T cells."

Dr. Godkin did not respond to a request for comment.

The study had no commercial funding. Two of the authors are employees of Oxford Biomedica, PLC, which owns the rights to TroVax.

SOURCE: http://bit.ly/2h6qIFP

JAMA Oncol 2017.