Combining Radiotherapy with Immunocheckpoint Inhibitors or CAR-T in Renal Cell Carcinoma

Author(s): Matteo Santoni, Daniel Y.C. Heng, Gaetano Aurilio, Andrea Iozzelli, Lucilla Servi, Andrea Fabiani, Massimo Giannini, Roberta Mazzucchelli, Alessia Cimadamore, Marina Scarpelli, Mohamed S. Zaghloul, Nicola Battelli, Rodolfo Montironi*

Journal Name: Current Drug Targets

Volume 21 , Issue 4 , 2020

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Radiotherapy is considered a second life in Renal Cell Carcinoma (RCC) patients, mainly due to the introduction of immune checkpoint inhibitors, such as anti-Programmed-death (PD)-1, alone or in combination with anti-Cytotoxic T-Lymphocyte Antigen (CTLA)-4. Several trials are investigating the efficacy/safety of immune checkpoint inhibitors in sequential or combined strategies with radiotherapy. Chimeric Antigen Receptor (CAR)-T cells therapy as a promising approach in cancer patients has opened the way to novel possibilities of integrating therapies. The identification of biomarkers of tumor response to these combinations represents a challenge in RCC, together with the research for the best partner for immunotherapy in metastatic patients. In this review we illustrated preclinical/clinical data on the integration of radiotherapy with immunocheckpoint inhibitors or CART cells in RCC.

Keywords: CAR-T cells, immunocheckpoint inhibitors, immunotherapy, programmed-death-1, radiation therapy, renal cell carcinoma.

Massari F, Santoni M, Ciccarese C, et al. PD-1/PD-L1 blockade alone or in combination in renal cell carcinoma: current studies and future promises. Cancer Treat Rev 2015; 41: 114-23.
[] [PMID: 25586601]
Massari F, Santoni M, Ciccarese C, Santini D. The immunocheckpoints in modern oncology: the next 15 years. Expert Opin Biol Ther 2015; 15(7): 917-21.
[] [PMID: 26063384]
Kucharczyk J, Matrana MR, Santoni M, et al. Emerging Immunotargets in Metastatic Renal Cell Carcinoma. Curr Drug Targets 2016; 17(7): 771-6.
[] [PMID: 26648075]
Ciccarese C, Alfieri S, Santoni M, et al. New toxicity profile for novel immunotherapy agents: focus on immune-checkpoint inhibitors. Expert Opin Drug Metab Toxicol 2016; 12(1): 57-75.
[] [PMID: 26565919]
Santoni M, Massari F, Di Nunno V, et al. Immunotherapy in renal cell carcinoma: latest evidence and clinical implications. Drugs Context 2018; 7(7)212528
[] [PMID: 29899754]
Fisher RI, Rosenberg SA, Fyfe G. Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am 2000; 6(Suppl. 1): S55-7.
[PMID: 10685660]
Kuusk T, Albiges L, Escudier B, et al. Antiangiogenic therapy combined with immune checkpoint blockade in renal cancer. Angiogenesis 2017; 20(2): 205-15.
[] [PMID: 28401381]
Motzer RJ, Escudier B, McDermott DF, et al. checkmate 025 investigators. nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015; 373(19): 1803-13.
[] [PMID: 26406148]
Motzer RJ, Tannir NM, McDermott DF, et al. CheckMate 214 Investigators. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med 2018; 378(14): 1277-90.
[] [PMID: 29562145]
Escudier B, Barthelemy P, Ravaud A, Negrier S, Needle MN, Albiges L. ivozanib combined with nivolumab: Phase Ib/II study in metastatic renal cell carcinoma (mRCC). J Clin Oncol 2018; (6_suppl): 618-8.
Motzer RJ, Powles T, Atkins MB, et al. IMmotion151: A Randomized Phase III Study of Atezolizumab Plus Bevacizumab vs Sunitinib in Untreated Metastatic Renal Cell Carcinoma (mRCC). J Clin Oncol 2018; (6_suppl): 578-8.
Atkins MB, Plimack ER, Puzanov I, 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(3): 405-15.
[] [PMID: 29439857]
Rini BI, Plimack ER, Stus V, et al. KEYNOTE-426 Investigators. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2019; 380(12): 1116-27.
[] [PMID: 30779529]
Choueiri TK, Larkin J, Oya M, 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(4): 451-60.
[] [PMID: 29530667]
Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2019; 380(12): 1103-15.
[] [PMID: 30779531]
Onufrey V, Mohiuddin M. Radiation therapy in the treatment of metastatic renal cell carcinoma. Int J Radiat Oncol Biol Phys 1985; 11(11): 2007-9.
[] [PMID: 2414257]
Hoerner-Rieber J, Duma M, Blanck O, et al. Stereotactic body radiotherapy (SBRT) for pulmonary metastases from renal cell carcinoma-a multicenter analysis of the German working group “Stereotactic Radiotherapy”. J Thorac Dis 2017; 9(11): 4512-22.
[] [PMID: 29268521]
Ippen FM, Mahadevan A, Wong ET, Uhlmann EJ, Sengupta S, Kasper EM. Stereotactic Radiosurgery for Renal Cancer Brain Metastasis: Prognostic Factors and the Role of Whole-Brain Radiation and Surgical Resection. J Oncol 2015; 2015 636918
[] [PMID: 26681942]
Siva S, Kothari G, Muacevic A, et al. Radiotherapy for renal cell carcinoma: renaissance of an overlooked approach. Nat Rev Urol 2017; 14(9): 549-63.
[] [PMID: 28631740]
Walle T, Martinez Monge R, Cerwenka A, Ajona D, Melero I, Lecanda F. Radiation effects on antitumor immune responses: current perspectives and challenges. Ther Adv Med Oncol 2018; 10 1758834017742575
[] [PMID: 29383033]
Durante M, Reppingen N, Held KD. Immunologically augmented cancer treatment using modern radiotherapy. Trends Mol Med 2013; 19(9): 565-82.
[] [PMID: 23831337]
Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996; 271(5256): 1734-6.
[] [PMID: 8596936]
Simpson TR, Li F, Montalvo-Ortiz W, et al. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J Exp Med 2013; 210(9): 1695-710.
[] [PMID: 23897981]
Pentcheva-Hoang T, Simpson TR, Montalvo-Ortiz W, Allison JP, Cytotoxic T. Cytotoxic T lymphocyte antigen-4 blockade enhances antitumor immunity by stimulating melanoma-specific T-cell motility. Cancer Immunol Res 2014; 2(10): 970-80.
[] [PMID: 25038199]
Sharabi AB, Lim M, DeWeese TL, Drake CG. Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncol 2015; 16(13): e498-509.
[] [PMID: 26433823]
Twyman-Saint Victor C, Rech AJ, Maity A, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 2015; 520(7547): 373-7.
[] [PMID: 25754329]
Rudqvist NP, Pilones KA, Lhuillier C, et al. Radiotherapy and CTLA-4 Blockade Shape the TCR Repertoire of Tumor-Infiltrating T Cells. Cancer Immunol Res 2018; 6(2): 139-50.
[] [PMID: 29180535]
Demaria S, Kawashima N, Yang AM, et al. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res 2005; 11(2 Pt 1): 728-34.
[PMID: 15701862]
Ngiow SF, McArthur GA, Smyth MJ. Radiotherapy complements immune checkpoint blockade. Cancer Cell 2015; 27(4): 437-8.
[] [PMID: 25873170]
Formenti SC, Rudqvist NP, Golden E, et al. Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nat Med 2018; 24(12): 1845-51.
[] [PMID: 30397353]
Atkins MB, Hodi FS, Thompson JA, et al. Pembrolizumab Plus Pegylated Interferon alfa-2b or Ipilimumab for Advanced Melanoma or Renal Cell Carcinoma: Dose-Finding Results from the Phase Ib KEYNOTE-029 Study. Clin Cancer Res 2018; 24(8): 1805-15.
[] [PMID: 29358500]
Tang C, Welsh JW, de Groot P, et al. Ipilimumab with stereotactic ablative radiation therapy: phase I results and immunologic correlates from peripheral T cells. Clin Cancer Res 2017; 23(6): 1388-96.
[] [PMID: 27649551]
Vatner RE, Cooper BT, Vanpouille-Box C, Demaria S, Formenti SC. Combinations of immunotherapy and radiation in cancer therapy. Front Oncol 2014; 4: 325.
[] [PMID: 25506582]
Rini BI, Stein M, Shannon P, et al. Phase 1 dose-escalation trial of tremelimumab plus sunitinib in patients with metastatic renal cell carcinoma. Cancer 2011; 117(4): 758-67.
[] [PMID: 20922784]
Seyedin SN, Schoenhals JE, Lee DA, et al. Strategies for combining immunotherapy with radiation for anticancer therapy. Immunotherapy 2015; 7(9): 967-80.
[] [PMID: 26310908]
Deng L, Liang H, Burnette B, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest 2014; 124(2): 687-95.
[] [PMID: 24382348]
Santoni M, Berardi R, Amantini C, et al. Role of natural and adaptive immunity in renal cell carcinoma response to VEGFR-TKIs and mTOR inhibitor. Int J Cancer 2014; 134(12): 2772-7.
[] [PMID: 24114790]
Sakaguchi S, Sakaguchi N, Shimizu J, et al. Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev 2001; 182: 18-32.
[] [PMID: 11722621]
Finke J, Ko J, Rini B, Rayman P, Ireland J, Cohen P. MDSC as a mechanism of tumor escape from sunitinib mediated anti-angiogenic therapy. Int Immunopharmacol 2011; 11(7): 856-61.
[] [PMID: 21315783]
Adams DL, Adams DK, He J, et al. Sequential Tracking of PD-L1 Expression and RAD50 Induction in Circulating Tumor and Stromal Cells of Lung Cancer Patients Undergoing Radiotherapy. Clin Cancer Res 2017; 23(19): 5948-58.
[] [PMID: 28679765]
Pike LRG, Bang A, Ott P, et al. Radiation and PD-1 inhibition: Favorable outcomes after brain-directed radiation. Radiother Oncol 2017; 124(1): 98-103.
[] [PMID: 28662869]
Park SS, Dong H, Liu X, et al. PD-1 restrains radiotherapy-induced abscopal effect. Cancer Immunol Res 2015; 3(6): 610-9.
[] [PMID: 25701325]
Joseph RW, Millis SZ, Carballido EM, et al. PD-1 and PD-L1 Expression in Renal Cell Carcinoma with Sarcomatoid Differentiation. Cancer Immunol Res 2015; 3(12): 1303-7.
[] [PMID: 26307625]
Geynisman DM. Anti-programmed Cell Death Protein 1 (PD-1) Antibody Nivolumab Leads to a Dramatic and Rapid Response in Papillary Renal Cell Carcinoma with Sarcomatoid and Rhabdoid Features. Eur Urol 2015; 68(5): 912-4.
[] [PMID: 26194044]
Piva F, Santoni M, Scarpelli M, et al. Re: Daniel M. Geynisman. anti-programmed cell death protein 1 (pd-1) antibody nivolumab leads to a dramatic and rapid response in papillary renal cell carcinoma with sarcomatoid and rhabdoid features. Eur Urol 2015; 68: 912-4.
[] [PMID: 26947604]
Tolay S, Nair R, McIntosh AF, Sopka DM, Nair SG. Dramatic response to concurrent anti-pd-1 therapy and radiation in resistant tumors with sarcomatoid differentiation. Oncologist 2019; 24(1): e49-52.
[] [PMID: 30104290]
Gross G, Waks T, Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci USA 1989; 86(24): 10024-8.
[] [PMID: 2513569]
Kalos M, Levine BL, Porter DL, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 2011; 3(95)95ra73
[] [PMID: 21832238]
Reits EA, Hodge JW, Herberts CA, et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med 2006; 203(5): 1259-71.
[] [PMID: 16636135]
Sharma A, Bode B, Wenger RH, et al. γ-Radiation promotes immunological recognition of cancer cells through increased expression of cancer-testis antigens in vitro and in vivo. PLoS One 2011; 6(11)e28217
[] [PMID: 22140550]
Dobrzanski MJ, Reome JB, Dutton RW. Immunopotentiating role of IFN-gamma in early and late stages of type 1 CD8 effector cell-mediated tumor rejection. Clin Immunol 2001; 98(1): 70-84.
[] [PMID: 11141329]
Lugade AA, Sorensen EW, Gerber SA, Moran JP, Frelinger JG, Lord EM. Radiation-induced IFN-gamma production within the tumor microenvironment influences antitumor immunity. J Immunol 2008; 180(5): 3132-9.
[] [PMID: 18292536]
Ganss R, Ryschich E, Klar E, Arnold B, Hämmerling GJ. Combination of T-cell therapy and trigger of inflammation induces remodeling of the vasculature and tumor eradication. Cancer Res 2002; 62(5): 1462-70.
[PMID: 11888921]
Diamond MS, Kinder M, Matsushita H, et al. Type I interferon is selectively required by dendritic cells for immune rejection of tumors. J Exp Med 2011; 208(10): 1989-2003.
[] [PMID: 21930769]
Demaria S, Ng B, Devitt ML, et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys 2004; 58(3): 862-70.
[] [PMID: 14967443]
Lamers CH, Sleijfer S, Vulto AG, et al. Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience. J Clin Oncol 2006; 24(13): e20-2.
[] [PMID: 16648493]
Lhuillier C, Vanpouille-Box C, Galluzzi L, Formenti SC, Demaria S. Emerging biomarkers for the combination of radiotherapy and immune checkpoint blockers. Semin Cancer Biol 2018; 52(Pt 2): 125-34.
[] [PMID: 29258856]
Houchins JP, Yabe T, McSherry C, Bach FH. DNA sequence analysis of NKG2, a family of related cDNA clones encoding type II integral membrane proteins on human natural killer cells. J Exp Med 1991; 173(4): 1017-20.
[] [PMID: 2007850]
López-Soto A, Gonzalez S, Smyth MJ, Galluzzi L. Control of metastasis by NK cells. Cancer Cell 2017; 32(2): 135-54.
[] [PMID: 28810142]
López-Soto A, Gonzalez S, Galluzzi L. Soluble NKG2D ligands limit the efficacy of immune checkpoint blockade. OncoImmunology 2017; 6(10) e1346766
[] [PMID: 29123961]
Lim JY, Gerber SA, Murphy SP, Lord EM. Type I interferons induced by radiation therapy mediate recruitment and effector function of CD8(+) T cells. Cancer Immunol Immunother 2014; 63(3): 259-71.
[] [PMID: 24357146]
Burnette BC, Liang H, Lee Y, et al. The efficacy of radiotherapy relies upon induction of type i interferon-dependent innate and adaptive immunity. Cancer Res 2011; 71(7): 2488-96.
[] [PMID: 21300764]
McDermott DF, Huseni MA, Atkins MB, et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med 2018; 24(6): 749-57.
[] [PMID: 29867230]
Chen Q, Chen J, Yang Z, et al. Nanoparticle-Enhanced Radiotherapy to Trigger Robust Cancer Immunotherapy. Adv Mater 2019; 31(10) e1802228
[] [PMID: 30663118]
Fuks Z, Kolesnick R. Engaging the vascular component of the tumor response. Cancer Cell 2005; 8(2): 89-91.
[] [PMID: 16098459]
Kothari G, Foroudi F, Gill S, Corcoran NM, Siva S. Outcomes of stereotactic radiotherapy for cranial and extracranial metastatic renal cell carcinoma: a systematic review. Acta Oncol 2015; 54(2): 148-57.
[] [PMID: 25140860]
Svedman C, Sandström P, Pisa P, et al. A prospective Phase II trial of using extracranial stereotactic radiotherapy in primary and metastatic renal cell carcinoma. Acta Oncol 2006; 45(7): 870-5.
[] [PMID: 16982552]
Young K, Cottam B, Baird JR, Gough MJ, Crittenden M. Ideal timing of immunotherapy with radiation in murine tumor models. Int J Radiat Oncol 2014; 90: S58.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Published on: 16 October, 2019
Page: [416 - 423]
Pages: 8
DOI: 10.2174/1389450120666191017113051
Price: $65

Article Metrics

PDF: 42