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
Acute urinary retention is a common emergency condition in elderly men. Transurethral and suprapubic catheterization are easy and safe procedures provided that a few simple rules are followed. ...Primarily, a transurethral catheter is placed if there is no urethral injury or stricture. Local anaesthesia of the urethra up to the sphincter region and a well-stretched penis warrant an atraumatic insertion of the catheter into the bladder. The use of a thick catheter with a round tip or of a catheter with a bended tip under rectal guidance facilitate the insertion of the catheter in difficult conditions. Alternatively, a suprapubic catheterization can be performed provided that no contraindication such as history or suspicion of transitional cell carcinoma is present. Optimal interventional conditions using ultrasound-guidance are mandatory in patients after abdominal surgery and with hemorrhagic diathesis in view of a safe and straight-forward placement of the suprapubic catheterization. In case of persistent bleeding after insertion of a suprapubic catheter, the suprapubic catheter should be replaced by one with a balloon blocked and kept under tension for several minutes.
Abstract only
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Background: We have previously reported the successful ex vivo generation of hCAIX-specific cytotoxic T lymphocytes (CTLs) by adenoviral (Ad) transduction of the GMCAIX fusion ...protein in dendritic cells (DC). We then produced GMP-grade material (NIH-RAID program, NSC 740833). Now we test, for the first time, the in vivo anti-tumor activity of DC-Ad-GMCAIX against renal cell carcinoma (RCC) in a unique immunocompetent mouse tumor model. Methods: Tumor growth inhibition and specificity were studied in BALB/c mice s.c. transplanted with either syngeneic RENCA cells transduced with hCAIX (URCAIX) or with non-hCAIX-expressing RENCA cells (RENCA). In a tumor prevention model, cohorts of mice were first immunized s.c. twice with DC-Ad-GMCAIX, DC-Ad-null, or no DCs, followed by tumor challenge with s.c. transplantation of URCAIX or RENCA cells. In an intervention model, tumors were first established and then immunotherapy was employed. Tumor volume and body weight were regularly assessed. Partial necropsy, immunohistochemistry of harvested tumors, and complete blood count were performed at termination of each study. Results: In the prevention model, URCAIX tumor growth was specifically and significantly inhibited for 15 days (p<0.0001). At termination, median growth inhibition reached 79% (113 vs. 531 mm
3
) and half of the mice remained tumor-free. In the intervention model, DC-Ad-GMCAIX-treated mice showed specific and significant growth inhibition of URCAIX tumors for 8 days (p<0.0018) with a median growth inhibition reaching 60% (487 vs. 1,205 mm
3
). The threshold of 15% weight loss was delayed in the therapeutic groups of both models (p<0.0167). No treatment-related weight loss or organ toxicity was observed. hCAIX staining was absent or minimally present in URCAIX-tumors that evaded DC-Ad-GMCAIX therapy. Conclusions: DC-Ad-GMCAIX therapy in a novel immunocompetent mouse model demonstrated, for the first time, both tumor prevention and growth inhibition of established RCC tumors without evidence of systemic toxicity. These studies form the basis for first-in-human clinical trial in patients with advanced RCC.
Abstract
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
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