Nine patients with metastatic RCC who had undergone radical nephrectomy were enrolled in the study. Escalating doses of AdGMCA IX were administered: 5, 15 and 50 x 106 cells/dose. Intradermal injections were given as 3 doses, 2 weeks apart. The primary endpoints were focused on safety and tolerability and found that the vaccine was relatively well tolerated with all toxicities classified as grade 1 or 2, with fatigue and leukopenia being the most common. There were no grade 3, 4, or 5 toxicities, nor any delayed hypersensitivity-type responses at the injection sites. 

Regarding efficacy, there was no reduction in tumor burden using any of the doses. Fifty-six percent (5 of 9) of patients had stable disease (SD) at 3 months and 11% (1 of 9) at 6 months. There was 1 patient who had SD at 27 months, whom received the highest dose. Six patients were alive at the end of the study period and were transitioned to standard-of-care therapies. Although there appeared to be an initial increase in CA IX-specific IFN-gamma producing T-cells, there did appear to be an element of immune tolerance based on decreased response after subsequent cycles. Overall, there were better immune responses in those patients who received higher doses, but immune-tolerance was still observed with these higher doses.

The authors concluded that Ad-GMCA IX is relatively well tolerated without significant safety concerns. Additionally, authors highlighted that this type of vaccine made using autologous immature DCs transduced by the Ad-GMCA IX vector appears to be feasible in patients with mRCC.

Although there were no major concerns regarding the safety profile of this vaccine, the limited efficacy findings were not impressive. Immune tolerance and the limited number of patients potentially contributed to the lack of efficacy. Also from a feasibility standpoint, multiple doses of a vaccine may be challenging to administer to patients in a “real-world” setting. As this phase 1 study was primarily focused on safety outcomes, future studies will have to improve certain clinical outcomes if vaccinations are to become a possible adjunctive therapy in RCC.


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One way to potentially augment the effectiveness of RCC vaccines is by combining them with established treatments, including sunitinib or immune checkpoint inhibitors (ICIs). Combining a vaccine like Ad-GMCA IX with these treatments could work jointly to stimulate an immune response and diminish tumor-driven immune suppression.2

Previous attempts at combining vaccines with mRCC treatments such as sunitinib have not shown a clinically significant impact on outcomes. The IMPRINT trial evaluated IMA901, which was a vaccine composed of 10 tumor-associated peptides that had promising phase 2 data, in conjunction with sunitinib as first-line therapy in patients with mRCC.6  This open-label, phase 3 trial found no statistical significance in median overall survival between IMA901-sunitinib and sunitinib alone (hazard ratio [HR], 1.34 [0.96-1.86]; P =.087). The IMA901 group also had more patients (57%) with grade 3 or worse adverse events compared with sunitinib alone (47%).

Although these data were discouraging, there is a growing focus on combining vaccines with ICIs. Most of the available data are preclinical and outside of RCC, however, the goals are the same: using vaccines to synergistically activate an antitumor immune response with ICIs.7 Preclinical data have been promising in multiple cancer types including pancreatic, breast, and colon cancer.7

Although there isn’t as much research in RCC, there are developing data evaluating dual therapy with vaccines and ICIs in pancreatic ductal adenocarcinoma.8 The vaccine aims to stimulate T cells within the TME that are traditionally suppressed in the setting of cancer. With this stimulation, programmed cell death 1/programmed cell death ligand 1 PD-1/PD-L1 antibodies may prove to be more effective.8 Similar studies will undoubtedly be performed in patients with RCC, with improvements on the type of vaccine used in the Faiena et al study being focused in conjunction with ICIs. More in-depth research evaluating the RCC TME and how vaccinations can better target will also be critical.

References

  1. Choueiri TK, Cheng S, Qu AQ, Pastorek J, Atkins MB, Signoretti S. Carbonic anhydrase IX as a potential biomarker of efficacy in metastatic clear-cell renal cell carcinoma patients receiving sorafenib or placebo: analysis from the treatment approaches in renal cancer global evaluation trial (TARGET). Urol Oncol. 2013;31(8):1788-1793. doi:10.1016/j.urolonc.2012.07.004
  2. Faiena I, Comin-Anduix B, Berent-Maoz B, Bot A, Zomorodian N, Sachdeva A, et al. A phase 1, open-label, dose-escalation, and cohort expansion study to evaluate the safety and immune response to autologous dendritic cells transduced with AdGMCA9 (DC-AdGMCA IX) in patients with metastatic renal cell carcinoma. J Immunother. 2020;43(9):273-282. doi:10.1097/CJI.0000000000000336
  3. Sonmez MG, Sonmez LO. New treatment modalities with vaccine therapy in renal cell carcinoma. Urol Ann. 2019;11(2):119-125. doi:10.4103/UA.UA_166_17
  4. Dorai T, Sawczuk IS, Pastorek J, Wiernik PH, Dutcher JP. The role of carbonic anhydrase IX overexpression in kidney cancer. Eur J Cancer. 2005;41(18):2935–47. doi:10.1016/j.ejca.2005.09.011
  5. Ivanov S, Liao SY, Ivanova A, Danilkovitch-Miagkova A, Tarasova N, Weirich G, et al. Expression of hypoxia-inducible cell-surface transmembrane carbonic anhydrases in human cancer. Am J Pathol. 2001;158(3):905–919. doi:10.1016/S0002-9440(10)64038-2
  6. Rini BI, Stenzl A, Zdrojowy R, Kogan M, Shkolnik M, Oudard S, et al. IMA901, a multipeptide cancer vaccine, plus sunitinib versus sunitinib alone, as first-line therapy for advanced or metastatic renal cell carcinoma (IMPRINT): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2016;17(11):1599-1611. doi:10.1016/S1470-2045(16)30408-9
  7. Kleponis J, Skelton R, Zheng L. Fueling the engine and releasing the break: combinational therapy of cancer vaccines and immune checkpoint inhibitors. Cancer Biol Med. 2015;12(3):201-208. doi:10.7497/j.issn.2095-3941.2015.0046
  8. Soares KC, Rucki AA, Wu AA, Olino K, Xiao Q, Chai Y, et al. PD-1/PDL-1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors. J Immunother. 2015;38(1):1-11. doi:10.1097/CJI.0000000000000062