Combined Treatment of Radiotherapy and Immunotherapy for Urological Malignancies: Current Evidence and Clinical Considerations

Figures & data

Figure 1 (A) Radiation induces changes to the tumor cell phenotype and release of cytokines; (B) HMGB1 activate dendritic cells by binding to Toll-like receptors; (C) The migration of dendritic cells to regional lymph nodes and the subsequent T-cell activation and proliferation. TLR, Toll-like receptors; TCR, T cell receptor.

Table 1 Clinical Trials Combining Immunotherapy with Radiotherapy in Prostate Cancer

Trial	Condition	Aims	Phase	Intervention	Institution/Group
NCT01436968	Intermediate-high risk localized PCa	The purpose of this study is to evaluate the effectiveness of ProstAtak immunotherapy in combination with RT for patients with intermediate-high risk localized PCa	Phase III	RT + valacyclovir ± AdV-tK	Advantagene, Inc. d.b.a. Candel Therapeutics
NCT02107430	High risk localized PCa	To determine whether DCVAC/PCa added after radical primary prostatectomy can improve PSA progression times within 5 years for patients with high risk localized PCa	Phase II	RT ± dendritic cells (DCVAC/PCa)	Sotio a.s. (Czech Republic)
NCT01807065	mCRPC	To study how well giving sipuleucel-T with or without RT works in treating patients with mCRPC	Phase II	RT followed by sipuleucel-T	City of Hope Medical Center
NCT01818986	mCRPC	Sipuleucel-T and SABR for patients with mCRPC	Phase II	SABR + sipuleucel-T	University of Texas Southwestern Medical Center
NCT01303705	Metastatic PCa	To examine a novel combination of anti-OX40 to induce proliferation of memory and effector T-cells in conjunction with cyclophosphamide (CTX) and radiation to induce tumour antigen release with the overall goal of promoting an immune response against prostate cancer	Phase I/II	RT + cyclophosphamide + anti-OX40	Providence Portland Medical Center
NCT02232230	mCRPC	To assess the effect of RT to augment antitumor responses from immune therapy with Provenge	Phase II	RT + sipuleucel-T	21st Century Oncology
NCT03477864	Locally advanced prostate cancer	To study the side effects of anti-PD-1 monoclonal antibody REGN2810 and/or ipilimumab when given together with SBRT before surgery in treating participants with progressive advanced or oligometastatic PCa	Phase I	SBRT + anti-PD-1 ± ipilimumab before radical prostatectomy	Sidney Kimmel Cancer Center at Thomas Jefferson University
NCT03007732	Hormone-naïve oligometastatic PCa	SBRT and pembrolizumab with or without intratumoral SD-101 in patients with newly diagnosed hormone-naïve oligometastatic PCa	Phase II	SBRT + ADT + pembrolizumab ± TLR9 agonist (SD-101)	Lawrence Fong, University of California
NCT01833208	mCRPC	Impact of radiation therapy on the immunogenicity of sipuleucel-T	Pilot study	RT + sipuleucel-T	Roswell Park Cancer Institute
NCT02463799	mCRPC	To study the effect of radium-223 when added to sipuleucel-T for treating castrate-resistant prostate cancer that has spread to the bone	Phase II	Radium-223 + sipuleucel-T	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Abbreviations: PCa, prostate cancer; mCRPC, metastatic castrate-resistant prostate cancer; RT, radiation therapy; PSA, prostate-specific antigen; SABR, stereotactic ablative radiosurgery; SBRT, stereotactic body radiation therapy; Anti-PD-1, antibody against programmed cell death protein 1; ADT, androgen deprivation therapy; AdV-tK, adenoviral vector expressing the herpes thymidine kinase gene; TLR9, toll-like receptor 9.

Table 2 Clinical Trials Combining Immunotherapy with Radiotherapy in Renal Cell Carcinoma

Trial	Condition	Aims	Phase	Intervention	Institution/Group
NCT01896271	Metastatic ccRCC	To evaluate the RR in patients with mRCC after treatment with high-dose IL-2 immediately following SABR to multiple metastatic sites	Phase II	SABR + high-dose IL-2	University of Texas, Southwestern
NCT03065179	Metastatic ccRCC	To determine whether the combination of nivolumab plus ipilimumab and SBRT yields a clinically compelling antitumor activity measured as ORR	Phase II	SBRT + nivolumab + ipilimumab	University of Texas, Southwestern
NCT02306954	ccRCC	To compare the RR among renal cell cancer (RCC) patients of high dose IL-2 to SBRT + IL-2 in patients with metastatic renal cancer	Phase II	SBRT + high-dose IL-2	Providence Health
NCT02781506	Metastatic ccRCC	To increase the RR of treatment with Nivolumab by the concurrent administration of SABR	Phase II	SABR + nivolumab	University of Texas, Southwestern
NCT01884961	Metastatic RCC or melanoma	Radiotherapy as an immunological booster in patients with metastatic melanoma or renal cell carcinoma treated with high-dose IL-2	Phase II	RT boost + high-dose IL-2	Istituto Scientifico Romagnolo (Italy)
NCT02855203	Metastatic ccRCC	To examine the safety, efficacy and biological effects of combining pembrolizumab (MK-3475) an antibody targeted against anti-(PD-1), with SABR for oligometastatic RCC	Phase I/II	SABR + pembrolizumab	Peter MacCallum Cancer Centre (Australia)
NCT03050060	Metastatic RCC, melanoma, or NSCLC	To study how well image guided hypofractionated radiation therapy works with nelfinavir mesylate, pembrolizumab, nivolumab, and atezolizumab in treating patients with metastatic RCC, melanoma, or NSCLC	Phase II	IGRT + nelfinavir + (pembrolizumab or nivolumab or atezolizumab)	University of Washington
NCT02318771	Recurrent/metastatic H&N, RCC, melanoma, or lung cancer	To study RT and pembrolizumab (MK-3475) in treating patients with head and neck cancer, RCC, melanoma, or lung cancer that has returned, has spread to other parts of the body, or cannot be removed by surgery	Phase I	RT + pembrolizumab	Thomas Jefferson University
NCT02599779	Metastatic RCC	To investigate if a treatment strategy where SBRT is given with pembrolizumab is sufficiently active to warrant further investigation in randomized phase II or III studies	Phase II	SBRT + pembrolizumab	Sunnybrook Health Sciences Centre
NCT03149159	Metastatic ccRCC	To see if continued nivolumab with the addition of ipilimumab plus hypo-fractionated SBRT of a single lesion results in partial or complete responses in patients with metastatic ccRCC who fail initial treatment with single agent nivolumab	Phase II	SBRT + nivolumab + ipilimumab	Medical University of South Carolina
NCT03115801	Metastatic RCC or UC	To examine the overall response rates of combining immunotherapy (nivolumab/atezolizumab) with RT for metastatic RCC or UC	Phase II	Nivolumab + atezolizumab ± RT	Weill Medical College of Cornell University
NCT02864615	Metastatic RCC	To evaluate safety and preliminary efficacy of stereotactic body radiation therapy in patients with metastatic renal cell carcinoma treated with VEGFR, mTOR or immune checkpoint inhibitors	Phase 1b	SBRT + (VEGFR inhibitor or mTOR inhibitor or checkpoint inhibitor)	Kidney Cancer Research Bureau
NCT03469713	Metastatic RCC	Combining SBRT with nivolumab in patients with metastatic RCC	Phase II	SBRT + nivolumab	Gruppo Oncologico Italiano di Ricerca Clinica (Italy)
NCT03474497	Metastatic NSCLC, RCC, or HNSCC after failed PD-1/PD-L1 therapy	To evaluate the safety and toxicity of pembrolizumab and intralesional IL-2 in combination with hypofractionated radiotherapy in patients with metastatic NSCLC, RCC, or HNSCC after failed PD-1/PD-L1 therapy	Phase I/II	RT + IL-2 + pembrolizumab	University of California, Davis
NCT03511391	NSCLC, UC, melanoma, RCC, H&N or HNSCC cancer	To investigate whether the addition of SBRT to checkpoint inhibitor treatment in patients with NSCLC, UCC, melanoma, RCC, H&N or HNSCC cancer can improve progression-free survival as compared to checkpoint inhibitor monotherapy.	Phase II	SBRT ± (pembrolizumab or nivolumab)	University Hospital, Ghent (Belgium)
NCT03226236	Metastatic RCC	To evaluate the ORR in patients with mRCC after treatment with IL-2+dendritic cell vaccine following RT	Phase II	RT + IL-2 + dendritic cell vaccine	UO Immunoterapia e Laboratorio TCS, IRCCS IRST (Italy)
NCT03693014	Metastatic cancer, melanoma cancer, lung cancer, bladder cancer, renal cancer, head/neck cancers	Combining SBRT with checkpoint inhibitors in patients with solid tumors	Phase II	SBRT+ (ipilimumab, nivolumab, pembrolizumab or atezolizumab)	Memorial Sloan Kettering Cancer Center

Abbreviations: ccRCC, clear cell renal cell carcinoma; NSCLC, non-small cell lung carcinoma; H&N, head and neck; UC, urothelial carcinoma; HNSCC, head and neck squamous cell carcinoma; SABR, stereotactic ablative radiosurgery; SBRT, stereotactic body radiation therapy; RT, radiation therapy; IL-2, interleukin-2; mTOR, mammalian target of rapamycin; VEGFR, vascular endothelial growth factor receptor; RR, response rate; ORR, objective response rate.

Table 3 Clinical Trials Combining Immunotherapy with Radiotherapy in Urothelial Carcinoma

Trial	Condition	Aims	Phase	Intervention	Institution/Group
NCT02891161	UC of bladder	To evaluate the safety and efficacy of combining durvalumab with RT followed by adjuvant durvalumab for patients with UC of bladder	Phase Ib/II	RT + durvalumab	Big Ten Cancer Research Consortium
NCT03317158	NMIBC	To establish the safety of durvalumab monotherapy and durvalumab in combination with BCG and EBRT in NMIBC patients	Phase I/II	Durvalumab alone, durvalumab + EBRT, or durvalumab + BCG	Hoosier Cancer Research Network
NCT02662062	MIBC	To assess the safety and feasibility of combining pembrolizumab with chemoradiotherapy for patients with MIBC	Phase II	RT + cisplatin + pembrolizumab	Australian and New Zealand Urogenital and Prostate Cancer Trials Group
NCT03171025	MIBC	To evaluate the rate of failure free survival at 2 years after start of chemoradiation with adjuvant nivolumab in adult subjects who undergo chemoradiation for localized bladder cancer	Phase II	Chemoradiation followed by nivolumab	University of Utah
NCT03419130	MIBC	How well radiation therapy and pembrolizumab work in treating patients with urothelial bladder cancer that is restricted to the site of origin, without evidence of spread	Phase II	Pembrolizumab + (conventional RT or hypofractionated RT)	University of California
NCT02621151	MIBC	To assess the efficacy of pembrolizumab (MK3475) added to concurrent radiation and gemcitabine in the management of patients with muscle-invasive urothelial cancer who are not candidates for or decline radical cystectomy	Phase II	RT + gemcitabine + pembrolizumab	NYU Langone Health
NCT02560636	MIBC	To investigate the safety, tolerability and effectiveness of an immunotherapy drug called pembrolizumab used in combination with radiotherapy	Phase I	RT + pembrolizumab	Royal Marsden NHS Foundation Trust
NCT03421652	MIBC ineligible for chemotherapy	How well nivolumab works with radiation therapy in treating patients with urothelial bladder cancer that has spread from its original site of growth to nearby tissues or lymph nodes and are ineligible for chemotherapy	Phase II	RT + nivolumab	Barbara Ann Karmanos Cancer Institute
NCT03287050	Metastatic UC	To investigate the feasibility of anti-PDL1/PD1 (pembrolizumab) and SBRT in patients with advanced, platinum-refractory urothelial carcinoma	Phase I	SBRT + pembrolizumab	University of Michigan Rogel Cancer Center
NCT03529890	Locally advanced UC of bladder	To assess safety and efficacy of preoperative RT before radical cystectomy combined with immunotherapy in locally advanced urothelial carcinoma of the bladder	Phase II	RT + nivolumab followed by radical cystectomy	Technische Universität München (Germany)
NCT03115801	Metastatic UC or RCC	To examine the overall response rates of combining immunotherapy with RT for mUC or RCC	Phase II	Atezolizumab ± RT	Weill Medical College of Cornell University

Abbreviations: UC, urothelial carcinoma; NMIBC, non-muscle-invasive bladder cancer; MIBC, muscle-invasive bladder cancer; RCC, renal cell carcinoma; RT, radiation therapy; BCG, bacillus Calmette-Guérin vaccine; EBRT, external beam radiation therapy; SBRT, stereotactic body radiation therapy.