Transcutaneous Imiquimod Combined With Anti-Programmed Cell Death-1 Monoclonal Antibody Extends the Survival of Mice Bearing Renal Cell Carcinoma.

Purpose: Imiquimod (IQM), an imidazoquinoline derivative, is an immunomodulator that activates an adaptive immune response. IQM is applied topically for genital warts and actinic keratosis. Programmed cell death-1 (PD-1) suppresses activated T cells by binding to programmed cell death-ligand 1 and programmed cell death-ligand 2, braking antitumor immunity. Anti-PD-1 therapy has been used for various malignant neoplasms including renal cell carcinoma (RCC). Whether combination therapy with transcutaneous administration of IQM cream and intraperitoneal administration of anti-PD-1 monoclonal antibody (mAb) suppresses mouse RCC cells growing in subcutaneous tissue was investigated.

Methods: Female BALB/c mice were implanted subcutaneously with 2 × 10 RENCA mouse RCC cells and treated with a transcutaneously applied cream containing IQM and intraperitoneal administration of anti-PD-1 mAb beginning 5 days after cell implantation. Tumor burden and survival of the mice were determined. RENCA tumor-specific IgG production and a minor CD8 T cell subset derived from the spleen of the mice bearing RENCA tumor were detected by flow cytometry. The tumor and spleen weights of mice treated with IQM, anti-PD-1 mAb, and their combination were compared.

Results: Combination therapy with IQM and anti-PD-1 mAb significantly suppressed tumor growth compared to each monotherapy and prolonged the survival of the mice. The combination therapy produced more RENCA tumor-specific IgG than either IQM or anti-PD-1 mAb alone. The percentage of the CD44CD62L CD8 T cell subset (effector memory T cells) among splenocytes from mice treated with IQM therapy increased. The CD44CD62L CD8 T cell subset (pre-effector-like T cells) of mice treated with anti-PD-1 mAb increased. A negative correlation between tumor and spleen weights was suggested in mice treated with therapies containing IQM.

Conclusions: The present results show that combination therapy with IQM and anti-PD-1 mAb might be a promising novel therapeutic strategy for advanced RCC.