A pilot study demonstrating the feasibility of using intratumoral vaccinia injections as a vector for gene transfer

It has been hypothesized that the acquisition of tumor-specific immunity can be enhanced by enrichment of the cytokine milieu at the site of immunization. As a prelude to exploring the utility of intratumoral injection of vaccinia virus recombinants as in vivo insertion vectors for cytokine genes, we first demonstrated that three human melanoma cell lines could be infected in vitro with successful expression of the reporter gene product (influenza nuclear protein). In a subsequent pilot study, five patients with dermal, subcutaneous and/or lymph node metastases from cutaneous melanoma were revaccinated with wild-type vaccinia virus and, 4 days later, twice weekly intratumoral injections of the same virus were begun. Escalating doses of up to 10⁷ pock-forming units (PFU) were safely administered repeatedly with modest local (erythema and induration) and mild systemic (flu-like symptoms) reactions. Four of five patients developed antivaccinia virus antibody titers ≥ 1/3200. With rising antibody titers, local and systemic reactions waned. One patient with a large exophytic lesion experienced dramatic tumor regression with multiple injections of 10⁷ PFU of virus. Most importantly sequential biopsies of this lesion over a 2-month period demonstrated repeated infection with successful production of viral gene protein (E3L) despite antiviral antibody titers as high as 1/12,800. These data demonstrate that vaccinia virus can be safely administered repeatedly intralesionally and that viral gene function can be maintained for a protracted period even in the face of substantial antiviral antibody titers. We hypothesize that a passenger cytokine gene would function similarly and mediate an immunoadjuvant effect.