Vaccination of Colorectal Cancer Patients with Modified Vaccinia Ankara Delivering the Tumor Antigen 5T4 (TroVax) Induces Immune Responses which Correlate with Disease Control: A Phase I/II Trial

Abstract

Purpose: The highly attenuated strain of vaccinia virus, modified vaccinia Ankara (MVA), encoding the tumor antigen 5T4 (termed TroVax), has been evaluated in an open-label phase I/II study in colorectal cancer patients. The primary objectives were to assess the safety and immunogenicity of ascending doses of TroVax and to determine the biodistribution of the vector. Experimental Design: TroVax was given to 22 patients with metastatic colorectal cancer. Seventeen patients received doses of TroVax ranging from 5 Â 10 7 up to 5 Â 10 8 plaque-forming units at 0, 4, and 8 weeks and were considered to be evaluable for assessment of immunologic responses. Both antibody and cellular responses specific for the tumor antigen 5T4 and the viral vector were monitored throughout the study. Results: TroVax was well tolerated in all patients with no serious adverse events attributed to vaccination. Of 17 evaluable patients, 16 showed 5T4-specific cellular responses whereas 14 had detectable antibody levels following vaccination. TroVax was able to boost 5T4-specific immune responses in the presence of MVA neutralizing antibodies. Periods of disease stabilization ranging from 3 to 18 months were observed in five patients, all of whom mounted 5T4-specific immune responses. Furthermore, statistical analysis showed a positive association between the development of a 5T4 (but not MVA) antibody response and patient survival or time to disease progression. Conclusion: These data indicate that vaccination with TroVax is safe and well tolerated and that immune responses to 5T4 can be induced without any evidence of autoimmune toxicity. Furthermore, 5T4-specific antibody responses correlate with evidence of disease control.

Vaccination of Metastatic Renal Cancer Patients with MVA-5T4: A Randomized, Double-Blind, Placebo-Controlled Phase III Study

“…Results from phase I and II clinical studies of MVA-5T4 in renal, colorectal, and prostate cancer patients were encouraging and showed that immune responses were induced in almost all treated patients, and associations between 5T4-specific cellular or humoral responses and clinical benefit were reported in seven of nine studies (8)(9)(10)(11)(12)(13)(14)(15)(16). In particular, studies in RCC and colorectal cancer patients have detected an association between 5T4-specific (but not MVA) antibody responses and enhanced survival (9,12,16).…”

“…These studies showed MVA-5T4 to be well tolerated and able to induce 5T4-specific immune responses in most patients. Furthermore, associations between 5T4-specific cellular or humoral responses and clinical benefit were reported in seven of the nine studies (8)(9)(10)(11)(12)(13)(14)(15)(16).…”

Long-term Tumor Regression Induced by an Antibody–Drug Conjugate That Targets 5T4, an Oncofetal Antigen Expressed on Tumor-Initiating Cells

“…There are currently 2 5T4-targeting agents in clinical development for oncology indications: a vaccine consisting of 5T4-expressing vaccinia virus (26)(27)(28) and an anti-5T4 antibody fragment conjugated to superantigen from Staphylococcal enterotoxin A (29,30). Both of these agents engage the host immune system to attack the 5T4-expressing cells.…”

Identification of Vaccine-Altered Circulating B Cell Phenotypes Using Mass Cytometry and a Two-Step Clustering Analysis

“…11), also elicits robust nAb responses and confers protection against lethal monkeypox viral challenge via various routes (12,13), yet it has a much improved safety profile as compared with vaccinia virus (14)(15)(16)(17). Importantly, MVA is also being developed as a vaccine vector for many infectious and noncommunicable diseases (18)(19)(20)(21).…”