Abstract 2819: Efficacy and safety of the Ad-GM·CAIX dendritic cell-based vaccine in treating in vivo metastatic renal cell carcinoma compared to sunitinib monotherapy and simultaneous vaccine-sunitinib combination therapy

Abstract

Abstract Metastatic clear cell renal cell carcinoma (ccRCC) disease is responsible for significant morbidity and represents the main cause of death in patients with advanced ccRCC. We have developed a novel dendritic cell based vaccine targeting human carbonic anhydrase IX (hCAIX; DC-Ad-GM·CAIX) and compared it with the ccRCC standard-of-care drug, sunitinib as a monotherapy and in simultaneous vaccine-sunitinib combination therapy. Immunocompetent mice (Balb/c) were orthotopically-transplanted with syngeneic RCC-hCAIXpositive (NPR-IX) tumor cells, immunized, and/or treated with sunitinib at low-dose (5mg/kg/d), high-dose (40mg/kg/d) or untreated. At termination, primary tumor size (weight), lung metastatic burden, hCAIX and immune-markers expression levels were compared. Mono-immunotherapy with DC-Ad-GM·CAIX vaccine suppressed metastatic tumor growth: the total number of metastatic heterotypic foci (i.e., hCAIX positive and negative foci) following vaccination decreased 2.5 fold compared with untreated mice (P<0.05). When counting only the hCAIX positive metastatic tumor cells, the decrease in the metastatic tumor burden compared to untreated mice was even more pronounced (>10 fold). Vaccination alone resulted in reduced primary tumor burden of RCC-hCAIXpositive cells to <25% of the tumor cell population, with the remaining cells lacking hCAIX expression (hCAIXnegative); there was no significant overall primary tumor reduction compared to untreated mice. In contrast, sunitinib, whether given as high-dose monotherapy or in combination with the vaccine, inhibited the primary orthotopic tumors, achieving 35% (P=0.0001) and 51% (P=1.7e-7) tumor reduction, respectively. However, sunitinib monotherapy was less effective in reducing the metastatic tumor burden compared with the vaccine. In fact, simultaneous administration of vaccine and sunitinib increased the metastatic tumor burden in heterotypic tumors composed also of hCAIXnegative cells. In conclusion, this preclinical study demonstrates that (i) the DC-Ad-GM·CAIX vaccine effectively controls both primary and metastatic hCAIXpositive tumors and forms the basis for a phase I trial in metastatic ccRCC patients, which has been initiated at UCLA (http://clinicaltrials.gov number NCT01826877), (ii) Antigen editing with loss of hCAIX is an important immune escape mechanism, (iii) This in vivo study raises caution regarding the use of DC-Ad-GM·CAIX vaccine in simultaneous combination therapies with sunitinib. Co-corresponding Authors: ASB and JR Citation Format: Edward N. Rampersaud, Jonathan W. Said, Adrian Bot, Frédéric D. Birkhäuser, Nils Kroeger, Gang Zeng, Fairooz F. Kabbinavar, Antoni Ribas, Allan J. Pantuck, Arie S. Belldegrun, Joseph Riss. Efficacy and safety of the Ad-GM·CAIX dendritic cell-based vaccine in treating in vivo metastatic renal cell carcinoma compared to sunitinib monotherapy and simultaneous vaccine-sunitinib combination therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2819. doi:10.1158/1538-7445.AM2014-2819