In Vivo Safety And Efficacy Of A Novel Dendritic Cell Based Ad-Gmcaix Vaccine With Activity Against Renal Cell Carcinoma

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Carbonic anhydrase IX (CAIX) expression is constitutively up-regulated in clear cell renal cell carcinoma (ccRCC) due to loss of the VHL gene. Its up-regulation in ccRCC and low expression levels in normal tissues led us to develop an immunotherapeutic approach targeting the CAIX tumor antigen. We previously reported the successful generation and ex vivo priming of CAIX-specific, MHC restricted cytotoxic T lymphocytes (CTLs) by adenoviral (Ad) transduction of the GM-CAIX fusion protein in dendritic cells (DCs). Our current study tests, for the first time, the in vivo anti-tumor activity of DC-Ad-GMCAIX in preventing and intervening in the growth of RCC in immunocompetent mouse models. Tumor growth was studied in BALB/c mice transplanted s.c. with either the syngeneic CAIX-expressing RCC cell line RENCA-CAIX (PRCAIX) or the non-CAIX-expressing parental RENCA line. In the preventative model, cohorts of mice were s.c. immunized twice 6 days apart with either DC-Ad-GMCAIX, DC-Ad-null, or no DC transplantation, followed by s.c. challenge with PRCAIX or RENCA lines 12 days later. In the interventional model, tumors were first established and then immunotherapy was employed. At the end of each study, tumors were harvested, and partial necropsy, immunohistochemistry, and complete blood count were performed. DC-Ad-GMCAIX expressed in vivo the hCAIX protein that primed CTLs to specifically target hCAIX expressed by the PRCAIX line. In the preventative model, PRCAIX tumor growth was specifically and significantly inhibited by DC-Ad-GMCAIX for 15 days (all p<0.0001), reaching 79% median growth inhibition at termination (113 vs. 531 mm3). In the therapeutic cohort, time to 15% weight loss was significantly delayed (log-rank test p<0.001). Half of the mice in the treatment cohort did not develop tumors. The results were confirmed by a repeated study (inhibition for 15 days; all p<0.0001; 7/8 mice without tumor). In the interventional model, DC-Ad-GMCAIX-vaccinated mice demonstrated a specific and significant growth inhibition of PRCAIX-tumors for 8 days, with 60% median growth inhibition at termination (all p<0.0018; 487 vs. 1,205 mm3). In the therapeutic cohort, time to 15% weight loss was significantly delayed (log-rank test p<0.0167). No vaccine-related weight loss or organ toxicity was observed. hCAIX staining was absent or only minimally present in PRCAIX-tumors that grew despite therapy with DC-Ad-GMCAIX, compared to strong staining in the negative control groups. In conclusion, DC-Ad-GMCAIX therapy is capable of in vivo generation of CAIX specific CTLs in immunocompetent mice, leading to a significant inhibition of RCC tumor growth without systemic toxicity. Additional studies are being done to analyze the immune response, and the differential global gene and miRNA expression of tumor cells resistant to CAIX-based therapy. NCI RAID Initiative NSC 740833. § co-corresponding. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1563. doi:1538-7445.AM2012-1563