Intranodal Immunization With a Vaccinia Virus Encoding Multiple Antigenic Epitopes and Costimulatory Molecules in Metastatic Melanoma

Abstract

Recombinant vaccinia virus (rVV) encoding tumor-associated antigens (TAAs) and adhesion or costimulatory molecules may represent important immunogenic reagents for cancer immunotherapy. Recently, intranodal (IN) antigen administration was suggested to be more immunogenic than intradermal (ID) vaccination. However, IN rVV administration has not been attempted so far. We used a rVV encoding gp100(280-288), Melan-A/MART-1(27-35) and tyrosinase(1-9) HLA-A0201 restricted epitopes and CD80 and CD86 costimulatory molecules in stage III and IV melanoma patients in a phase 1/2 trial. Of 15 patients initiating treatment, including two cycles of IN immunization, each comprising one rVV administration and three recall injections of the corresponding peptides, accompanied by subcutaneous granulocyte macrophage-colony stimulating factor supplementation, five withdrew due to progressing disease. Of 10 remaining patients seven showed evidence of induction of cytotoxic T lymphocytes (CTLs) directed against at least one epitope under investigation, as detectable by limiting dilution analysis (LDA) of specific precursors and multimer staining. Adverse reactions were mild (National Cancer Institute (NCI) grade 1-2) and mainly represented by fever, skin rashes, and pruritus. These data indicate that IN administration of rVV encoding melanoma-associated epitopes and costimulatory molecules is safe and immunogenic.

Tumor-Altered Dendritic Cell Function: Implications for Anti-Tumor Immunity

“…Finally, it is also possible to improve the efficacy of both exogenous and endogenous DC-based vaccines by transducing DC either ex vivo or in vivo with viral vectors that encode immunostimulatory molecules. A number of studies have reported improved anti-tumor immunity when this approach was used to drive expression of CD80/CD86 costimulatory molecules (165, 166) or IL-12 (167) by DC. Collectively, these strategies highlight the advances made in tumor immunotherapy as our understanding of tumor immune suppression and evasion has evolved over the last several years.…”

Recombinant viral vaccines for cancer

“…However, these responses translated poorly into survival benefit [20]. This agent was subsequently assessed after direct injection into the inguinal lymph nodes and, again, induction of epitopespecific CTL responses was observed, but these did not correlate with improved survival [21].…”

Parenteral Vaccine Administration: Tried and True

“…Intranodal injections of vaccines based on viral vectors have been studied in melanoma patients, who responded with strong cytotoxic and other immunological T-cell responses as well as some clinical benefi ts (Adamina et al 2010 ;Spaner et al 2006 ).…”