Novel Therapeutic Approaches and Targets Currently Under Evaluation for Renal Cell Carcinoma: Waiting for the Revolution
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Management of metastatic renal cell carcinoma has drastically changed in the last few years, witnessing the advent of more and more target therapies and, recently, of immune-checkpoint inhibitors. On the other hand, the adjuvant setting still lacks a clear beneficial treatment. Medical treatment still remains a compelling challenge. A large number of clinical trials is ongoing with the aim to identify new therapeutic approaches to expand the options in our repertoire. Several strategies are under investigation in renal cell carcinoma (RCC). These include new targeted agents and combinations of target therapy and immunotherapy. Programmed death receptor-1 (PD-1), programmed death receptor ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA4) are just part of the intricate network that regulates our immune response to cancer cells. Co-stimulators, such as glucocorticoid-induced TNFR-related protein (GITR) and tumor necrosis factor receptor superfamily, member 4 (OX40), and co-repressors, example.g. T cell immunoglobulin and mucin domain 3 (TIM-3) and lymphocyte-activation gene 3 (LAG-3), also take part. As knowledge of the functioning of the immune system grows, so do these pathways to target with new drugs. This review is an overview of the current state of the clinical research, providing a report of ongoing Phase I, II and III clinical trials for localized and metastatic RCC, including novel target therapies, novel immunotherapy agents and new combinations strategies.
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The authors declare that no source of funding was obtained for this research.
Conflict of interest
Mollica V, Di Nunno V, Gatto L, Santoni M, Cimadamore A, Cheng L, Lopez- Beltran A, Montironi R, Pisconti S, Battelli N and Massari F declare no potential conflicts of interest with respect to the research, authorship, and/or publication of the article.
- 6.Bhindi B, Abel EJ, Albiges L, Bensalah K, Boorjian SA, Daneshmand S, et al. Systematic review of the role of cytoreductive nephrectomy in the targeted therapy era and beyond: an individualized approach to metastatic renal cell carcinoma. Eur Urol. 2019;75(1):111–28. https://doi.org/10.1016/j.eururo.2018.09.016.Google Scholar
- 7.Massari F, Di Nunno V, Gatto L, Santoni M, Schiavina R, Cosmai L, et al. Should carmena really change our attitude towards cytoreductive nephrectomy in metastatic renal cell carcinoma? A systematic review and meta-analysis evaluating cytoreductive nephrectomy in the era of targeted therapy. Target Oncol. 2018;13(6):705–14. https://doi.org/10.1007/s11523-018-0601-2.Google Scholar
- 12.Tartour E, Pere H, Maillere B, Terme M, Merillon N, Taieb J, et al. Angiogenesis and immunity: a bidirectional link potentially relevant for the monitoring of antiangiogenic therapy and the development of novel therapeutic combination with immunotherapy. Cancer Metastasis Rev. 2011;30(1):83–95. https://doi.org/10.1007/s10555-011-9281-4.Google Scholar
- 14.Guislain A, Gadiot J, Kaiser A, Jordanova ES, Broeks A, Sanders J, et al. Sunitinib pretreatment improves tumor-infiltrating lymphocyte expansion by reduction in intratumoral content of myeloid-derived suppressor cells in human renal cell carcinoma. Cancer Immunol Immunother. 2015;64(10):1241–50. https://doi.org/10.1007/s00262-015-1735-z (Epub 2015 Jun 24).Google Scholar
- 15.Liu XD, Hoang A, Zhou L, Kalra S, Yetil A, Sun M, et al. Resistance to antiangiogenic therapy is associated with an immunosuppressive tumor microenvironment in metastatic renal cell carcinoma. Cancer Immunol Res. 2015;3(9):1017–29. https://doi.org/10.1158/2326-6066.CIR-14-0244 (Epub 2015 May 26).Google Scholar
- 17.Atkins MB, Plimack ER, Puzanov I, Fishman MN, McDermott DF, Cho DC, et al. Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion Phase 1b trial. Lancet Oncol. 2018;19:405–15. https://doi.org/10.1016/S1470-2045(18)30081-0 (Epub 2018 Feb 10).Google Scholar
- 20.Nadal RM, Mortazavi A, Stein M, Pal SK, Davarpanah NN, Parnes HL, et al. Results of Phase I plus expansion cohorts of cabozantinib (Cabo) plus nivolumab (Nivo) and CaboNivo plus ipilimumab (Ipi) in patients (pts) with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignancies. J Clin Oncol. 2018;36:515. https://doi.org/10.1200/JCO.2018.36.6_suppl.515.Google Scholar
- 21.Choueiri TK, Larkin J, Oya M, Thistlethwaite F, Martignoni M, Nathan P, et al. Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear- cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose- finding and dose-expansion, Phase 1b trial. Lancet Oncol. 2018;19:451–60. https://doi.org/10.1016/S1470-2045(18)30107-4 (Epub 2018 Mar 9).Google Scholar
- 24.Motzer R, Thomas Powles, Michael B. Atkins, Bernard Escudier, David F. McDermott, Cristina Suarez et al. IMmotion 151: randomized Phase III study of atezolizumab plus bevacizumab versus sunitinib in untreated metastatic renal cell carcinoma. J Clin Oncol. 2018. https://doi.org/10.1200/jco.2018.36.6_suppl.578.
- 25.Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019. https://doi.org/10.1056/nejmoa1816047.
- 26.Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019. https://doi.org/10.1056/nejmoa1816714.
- 29.Du W, Huang H, Sorrelle N, Brekken RA. Sitravatinib potentiates immune checkpoint blockade in refractory cancer models. JCI Insight. 2018. https://doi.org/10.1172/jci.insight.124184. (Epub ahead of print).
- 34.Ramapriyan R, Caetano MS, Barsoumian HB, Mafra ACP, Zambalde EP, Menon H et al. Altered cancer metabolism in mechanisms of immunotherapy resistance. Pharmacol Ther. 2018. https://doi.org/10.1016/j.pharmthera.2018.11.004. (Epub ahead of print).
- 35.Lunt SY, Vander Heiden MG. Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol. 2011;27:441–64. https://doi.org/10.1146/annurev-cellbio-092910-154237.Google Scholar
- 37.Wang Q, Feng F, Wang J, Ren M, Shi Z, Mao X et al. Liver X receptor activation reduces gastric cancer cell proliferation by suppressing Wnt signalling via LXRβ relocalization. J Cell Mol Med. 2018. https://doi.org/10.1111/jcmm.13974. (Epub ahead of print).
- 48.Bendell JC, Patel MR, Moore KN, Chua CC, Arkenau HT, Dukart G et al. Phase I, First-in-human, dose-escalation study to evaluate the safety, tolerability, and pharmacokinetics of vorolanib in patients with advanced solid tumors. Oncologist. 2018. https://doi.org/10.1634/theoncologist.2018-0740. (Epub ahead of print).
- 51.Choueiri TK, Halabi S, Sanford BL, Hahn O, Michaelson MD, Walsh MK, et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the alliance A031203 CABOSUN trial. J Clin Oncol. 2017;35(6):591–7. https://doi.org/10.1200/JCO.2016.70.7398.Google Scholar
- 54.Baybutt TR, Flickinger JC Jr, Caparosa EM, Snook AE. Advances in chimeric antigen receptor (CAR)-T cell therapies for solid tumors. Clin Pharmacol Ther. 2018. https://doi.org/10.1002/cpt.1280. (Epub ahead of print).
- 63.Zhou E, Huang Q, Wang J, Fang C, Yang L, Zhu M, et al. Up-regulation of Tim-3 is associated with poor prognosis of patients with colon cancer. Int J Clin Exp Pathol. 2015;8:8018–27.Google Scholar