The diverse landscape of genitourinary cancer immunotherapy



  1. Australia and New Zealand Urogential and Prostate (ANZUP) Cancer Trials Group Australia
  2. Department of Medical Oncology, Calvary Mater Newcastle, NSW, Australia
  3. School of Biomedical Sciences and Pharmacy, University of Newcastle, Hunter Medical Research Institute, New Lambton Heights NSW Australia


Prostate, bladder, kidney, testis and penile cancers cause over 10% of all cancer deaths, and standard treatments are largely palliative in advanced or metastatic disease. Cancer immunotherapy has an established and rapidly expanding role in the management of genitourinary cancers, but the different cancers also give insights across the landscape of immunotherapy.

Renal cancers can often have a well-established immune response, and can be poised for impressive responses to checkpoint immunotherapy. Combination immunotherapy will likely improve these ‘fertile plains’ further. The ‘desert’ of prostate cancer immunotherapy is currently hostile and unappealing, but vaccine strategies to increase immune recognition and novel checkpoint inhibitors are being explored to enrich this territory. Urothelial carcinoma is a veritable ‘jungle’ of therapeutic choices, where treatment individualisation and identification of new pathways to circumvent current pitfalls and improve outcomes. The largely unexplored zones of testicular germ cell and penile cancers suggest novel targets and complementary strategies to improve treatment.

With several immunotherapies in routine clinical use for genitourinary cancer patients, immunotherapy has a solid footing, and many opportunities to explore new ideas and combinations to change the landscape of cancer immunotherapy and open new frontiers.

Genitourinary (GU) cancers such as prostate, bladder, kidney, testis and penile cancers represent over 20% of all cancers and 10% of all cancer deaths. Many of these deaths occur in patients that present with advanced or metastatic disease. Screening programs are ineffective or unavailable for many of these cancers. There is an urgent and unmet need for improved systemic therapies in GU cancers.

While hormonal, cytotoxic and targeted therapies are increasingly useful, cancer immunotherapy has an established and rapidly evolving place in the management of GU malignancies, at all stages of disease and in a range of combinations and strategies. This review will explore the refinements being tested using existing therapies and then review how immunotherapy is currently in use, in clinical trials, and then imagine how GU cancer immunotherapy might evolve in coming years.

Renal cell carcinoma: sowing an early harvest

Renal cell carcinoma (RCC) is well known as an immunologically active cancer. Spontaneous regressions have been reported from biopsy proven tumours, but occur rarely (<1%).1 Tumour infiltrating lymphocytes (TILs) are apparent in many primary and metastatic RCC, and the complexity of these infiltrates is now becoming better understood. T cells are more frequent in renal cancers than normal tissues, and macrophages increase with worsening tumour grade.2 Using state-of-the-art mass cytometry, dozens of distinct CD4, CD8 and macrophage populations can be detected in RCC, where patient survival is associated with different phenotypes of infiltrating immune cells.3 Immune cells in the peripheral circulation may also be predictive of early relapse in patients undergoing curative attempt resection.4

Immune cytokines like interleukin-2 (IL2) and interferon-alpha (IFN) were first used as active immunotherapy in RCC and melanoma. IL2 was offered in a variety of doses, schedules and combinations to extremely fit patients. Despite toxicity, including up to 4% treatment-related deaths, response rates of 15% (~5% complete response) were observed.5 Long-term follow-up of complete responders showed most were durable over decades,6 leading to speculation that IL2 was curative in 5-10% of patients.7 IFN, in various schedules, in very well patients, was associated with a small improvement in overall survival (~4 months).8 Bevacizumab plus IFN was shown to be superior to IFN alone, but was costly, toxic and supplanted by vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI). VEGFR TKI may themselves modulate the tumour immune microenvironment,9 but can be immunosuppressive causing neutropenia and lymphopaenia.

Checkpoint immunotherapy has been extensively examined in ccRCC, and is now standard-of-care in some settings. Single agent anti-CTLA4-antibody ipilimumab demonstrated infrequent responses, with responses more likely in patients experiencing immune related toxicity.10 The anti-PD1-antibody nivolumab elicited radiological responses (27%) and produced stable disease (another 27% of patients) in heavily pre-treated (2-5 therapies) patients with ccRCC,11 many of whom experienced longer than expected survival; 1, 2, and 3-year survival were 71%, 48%, and 44%, respectively.12 Nivolumab is superior to everolimus in patients with ccRCC previously treated with a VEGFR TKI,13 with median survival 25 vs. 19.6 months (HR for death 0.73). The objective response rate was 25% and while severe toxicity occurred in 19% of patients, this was half the incidence of patients taking everolimus. Nivolumab (Opdivo®) is now PBS-reimbursed in Australia for patients with VEGFR TKI refractory ccRCC.

Combinations of checkpoint antibodies and other agents are being tested in RCC. The anti-PDL1-antibody atezolizumab has shown single agent activity in a variety of cancers, and showed a response rate of 15% in patients with heavily pre-treated ccRCC, with an association of response and PDL1 expression.14 32% of treatment-naïve patients responded to combination atezolizumab plus anti-VEGF-antibody bevacizumab.15 A phase 3 trial of this combination is fully accrued.

VEGFR TKIs have been combined with checkpoint immunotherapy, but severe hepatotoxicity occurred when the anti-PD1-antibody pembrolizumab was combined with pazopanib.16 In a phase 1b study the anti-PDL1-antibody avelumab plus axitinib caused severe toxicity in ~60% of patients including one death due to myocarditis.17 Hypertension, palmar planter erythrodysesthesia, abnormal liver and pancreas blood tests were most common serious adverse events. Activity seemed high however; radiological responses were experienced by 58% of patients, and disease control (response plus stable disease) in 78%.

Checkpoint co-inhibition may soon be a standard of care in ccRCC. Nivolumab and ipilimumab were tested in different dosing schedules; a lower dose of ipilimumab showed decreased toxicity but promising efficacy.18 A recent conference presentation reported the first results of a phase 3 trial of first-line ipilimumab/nivolumab vs. sunitinib in metastatic ccRCC, with complex findings. In the entire patient cohort, overall survival was greater with combination immunotherapy (HR for death 0.68, CI 0.49-0.95, P<0.0003). Quality of life was generally better on immunotherapy.19 However, PD-L1 expression and IMDC risk group (favourable vs. intermediate/poor) were contra-associated with response rate and progression free survival; favouring sunitinib in well patients, and immunotherapy in high PDL1/poor risk patients. This is further data that progression free survival is an unhelpful measure of the benefit of immunotherapy,20 but we await longer-term follow-up and analysis of predictive biomarkers to drive the optimal sequencing and personalisation of immunotherapy and angiogenesis inhibitors.

Urothelial carcinoma: it’s a jungle out there

Urothelial carcinoma (UC) of the bladder, ureter, renal pelvis and urethra, is falling in incidence due to declining smoking rates, but remains a morbid, costly and difficult cancer to manage. The therapeutic importance of immunotherapy is readily apparent in non-muscle invasive bladder cancer where intravescial use of Bacille-Calmette Guerin (BCG) is used as a live attenuated vaccine in first-line adjuvant therapy.21 BCG causes cytokine release recruiting an immune cell infiltrate, generating response rates from 60-90%. Intravesical BCG is the standard of care for non-muscle-invasive bladder cancer after transurethral resection, generating immunological memory to protect from recurrences. Unfortunately 40% patients recur and many may develop muscle-invasive or metastatic disease.

The relationship of the immune system and UC is complex, with inflammatory conditions like recurrent urinary tract infection associated with an increased risk of UC,22 while the presence of TILs is predictive of prognosis and response to neoadjuvant chemotherapy.23,24 As in other cancers PDL1 expression, immune infiltration and survival are interrelated, but the relationship with response to checkpoint immunotherapy unclear.25 UC has seen intensive clinical activity in checkpoint immunotherapy,26 with many recent reports in platinum-refractory metastatic disease, and numerous ongoing studies in combinations and first line therapy.

The PDL1 antibody atezolizumab was approved for treatment of platinum-resistant metastatic UC after a phase 2 trial (IMvigor210, n=310). Tumour responses were seen in 23%, with complete responses in 9% of patients (only 19 of 27 complete responses were durable). Benefit was not related to mutational burden, but higher response rates were seen in patients with the luminal II genotype (associated with activated TILs).27 The phase 3 randomised trial of atezolizumab vs. secondline chemotherapy (IMvigor211) is reported to have failed to achieve the primary efficacy endpoint.

Avelumab is the second anti-PDL1-antibody FDA-approved in UC, based on analysis of cohorts of the phase 1b JAVELIN study.28 Tumour responses were seen in 18% of patients (5% complete responses) most of whom (88.9%) were ongoing at six months of follow-up. Durvalumab is the third registered anti-PD-L1 antibody in metastatic UC. Responses were seen in 18% of 191 evaluable patients, with 4% complete responses. Median duration of response was not yet reached. Response were more frequent in patients with PDL1+ tumours (28% vs. 5%).29

PD1 antibodies are also active in metastatic UC. Nivolumab was studied in small cohorts of patients with metastatic UC and in a larger phase 2 trial (Checkmate-275), delivering responses in 19.6% of patients, again higher in patients with PD-L1+ tumours.30 Pembrolizumab has been examined in patients with PD-L1+ metastatic UC, with 25% of patients responding, including 11% complete responses.31 In the phase 3 trial of pembrolizumab was associated with a higher response rate (21% vs. 11%), longer median overall survival (10.3 vs. 7.4 months) and lower toxicity (G3-5 15% vs. 50%) than investigator’s choice of chemotherapy in patients with advanced UC.32 Firstline pembrolizumab monotherapy has also been studied in patients deemed unable to tolerate platinum chemotherapy, whether for poor performance status (ECOG2) or renal dysfunction. Responses were seen in 27% of patients, with 6% experiencing a complete response.33

Surveying this jungle of agents and trials, only ~1/5 of patients seem to benefit from single agent PD1 or PDL1 antibodies, perhaps unsurprisingly as less than half of patients’ tumours show evidence of immune activity (TILs or PDL1 expression). Combination therapy is being tested with more interesting results. Durvalumab was combined with the anti-CTLA-4 antibody tremelimumab in firstline treatment of metastatic UC, with results of a phase 3 DANUBE trial keenly awaited. A dosing pilot of nivolumab and ipilimumab in metastatic UC has been reported.34 Nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg led to a higher rate of response (38%) than other combinations or monotherapy. Median overall survival was 10.2 months and disease control was experienced in ~60% of patients. A phase 3 trial is in progress.

Prostate carcinoma: walking into the desert

Prostate cancer is the most common invasive cancer in men, and will cause 3500 deaths in Australia this year, second only to lung cancer in male cancer mortality.35 Effective prostate cancer immunotherapy faces many challenges, including a largely immunosuppressive immune infiltrate (e.g. macrophages, T-regulatory and TH-17 cells which may aid in prostate cancer progression36), a relative paucity of tractable antigenic targets, and generally impaired immune function in the typical host for advanced prostate cancer, elderly men. This immunosenescence or “senescent immune remodeling” may be due to the chronic low-level inflammation associated with general aging, permitting tumour cell invasion and exhausting the pool of naïve T-cells, thus reducing responses to neoantigens.37

Androgen deprivation by GnRH antagonists is the mainstay of advanced prostate cancer treatment, and may in fact have local and systemic immunotherapeutic actions. Androgen withdrawal in patients with prostate cancer triggers T cell infiltration, within weeks of therapy and is predominantly a CD4+ T cells infiltrate with fewer CD8+ T cells.38 Androgen deprivation may expand the naïve T cell compartment, with an increase in effector cell response to stimulation, and the generation of prostate tissue-associated IgG antibody responses.39 Conversely pre-clinical data shows intraprostatic expansion of T-regulatory cells upon castration of cancer-bearing Pten −/− mice, suggesting compensatory immunosuppressive mechanisms can be triggered.40

Antigenic targets are sparse for prostate cancer immunotherapy. Patient-specific mutation-derived neoantigens,41 and in particular clonal neoantigens,42 are proposed to be optimal targets for checkpoint immunotherapy, though tumour associated antigens (TAA) can also act as immunological targets for adaptive immunity. Prostate cancer has one of lowest burdens of non-synonymous exome mutational frequencies of epithelial cancers,43 and very low numbers of indel events, and in particular infrequent immunogenic frameshift indel events.44 This mutational quietness is one factor contributing to the low activity of PD1/PDL1 antibodies in prostate cancer.

Men who might experience robust responses to checkpoint immunotherapy are those whose tumours display DNA mismatch repair (MMR). Families with Lynch syndrome have shown a 2-5x increase in prostate cancer risk,45 and conversely microsatellite instability and/or somatic MMR mutations are reported to occur in 1-12% (primary vs. metastatic) prostate cancers.46 MMR cancers across all histotypes have been shown to be potentially responsive to PD1 immunotherapy.47

Prostate-lineage TAA have been actively pursued as one pool of potential immune targets, and form the basis for several prostate cancer vaccines, including GVAX, Prostvac and Sipuleucel -T. GVAX used allogenic prostate cancer cell lines genetically modified to bear GM-CSF to act as a whole cell vaccine to generate both humoral and cellular immune responses. While initial studies were encouraging, phase 3 trials failed to show any efficacy.48 Prostvac-VF was a recombinant vaccinia viral vector vaccine encoded for PSA and three immune costimulatory molecules (B7-1, ICAM1 and LFA3) coadministered with GM-CSF. Again, although early studies showed immunogenicity, the phase 3 study was halted for futility.

Sipuleucel-T (Provenge®) has modest efficacy in castrate-resistant prostate cancer, but is logistically complex, extremely expensive and unavailable outside North America. Patients undergo leukapheresis, peripheral blood mononuclear cells are shipped to a central laboratory, cultured ex vivo with a chimeric protein containing the tumour-associated antigen prostatic acid phosphatase together with GM-CSF, primed cells are re-infused, and the process is repeated fortnightly for a total of three treatments. Side-effects (chills, pyrexia, headache, and myalgia) are mild and short-lived.

An initial randomised trial versus placebo failed to extend progression free survival improvement,49 but overall survival was later noted to be improved. Only comparatively well men were treated; ECOG 0/1, asymptomatic or minimally symptomatic, absence of visceral metastases or pathologic long-bone fractures, 0-1 prior chemotherapy regimens. Sipuleucel-T was associated with a reduced risk of death (HR 0.78, 95% CI 0.61–0.98; P = 0.032), a 4.1-month improvement in median survival (25.8 vs. 21.7 months), and 32.1% of men survived three years versus 23% for placebo.50 Cost and development of androgen-receptor antagonists have limited development of sipuleucel-T, but trials in combination with checkpoint immunotherapy are maturing.

As in every other cancer, checkpoint antibodies have been studied in prostate cancer, with initially very modest outcomes. Single agent anti-CTLA4 antibody ipilimumab in castrate-resistant prostate cancer intriguingly showed progression free survival and PSA-response benefits in a first trial, but no overall survival advantage in later studies.48 A tiny fraction (2-4%) of prostate cancers are MMR/MSI-high and in small series, the majority of MMR positive metastatic prostate cancer patients (5/6) taking a PD1 antibody appeared to benefit.47 Trials of combinations of checkpoint inhibitors, and in combination with other therapies such as androgen receptor antagonists are underway, and research activity is increasing rapidly.

Germ cell tumours

Testicular germ cell tumours (GCT) have high cure rates exceeding 95%. Unfortunately a handful of men develop treatment-refractory disease that can be palliated with further chemotherapy but not cured. Checkpoint immunotherapy has been reported to be effective in case reports, for example with a durable response in one of four patients treated with pembrolizumab,51 and in a case report of radiological and biochemical response to a single dose of nivolumab.52 47% of testicular GCTs show a T-cell inflammation gene signature associated with benefit from immunotherapy, which is inversely associated AFP RNA levels suggesting that more advanced tumours may be less immune infiltrated. PD-L1 expression is found in 73% of seminomas and in 64% of non-seminomas.53 Formal clinical trials of checkpoint inhibitors are in progress (NCT02499952).

The typical targets for checkpoint immunotherapy, neoantigens, are very sparse in GCT, which are genomically quiet cancers arising from germ cells. GCT may however express novel targets for the immune system, cancer-testis antigens, proteins only expressed in the immunologically privileged germ cell compartment, but re-expressed in cancers. Spontaneous CD4+ and CD8+ T-cell responses against cancer-testis antigens have been found in the peripheral blood of approximately half of primary testicular cancer patients, suggesting spontaneous endogenous immune responses in many patients.54

Penile carcinoma

Penile cancer is rare, most are squamous in histology, and many are related to human papillomavirus (HPV) infection. HPV causes a number of human cancers, and arguably the most important form of cancer immunotherapy is preventative vaccination against the oncogenic strains of HPV, first in females to protect against cervical cancer, but increasingly also in males to protect whole populations from these genital cancers, as well as head and neck and anal cancers.

Squamous carcinomas in other organs have shown responses to anti-PD1-checkpoint immunotherapy (e.g. squamous lung carcinoma, squamous oesophageal carcinoma and head and neck carcinoma) so it is reasonable to imagine that some patients with squamous penile carcinoma may also experience responses to PD1 therapy. 62.2% of penile tumours are positive for PD-L1 expression.55 Formal clinical trials of PD1-inhibitors are underway (NCT02837042, NCT02426892).

An alternative immune therapy may be aimed directly at the causative viral oncogenes in HPV positive carcinomas. VGX-3100 is a combination of DNA synthetic plasmids that encode the E6 and E7 genes of HPV-16 and HPV-18, and are administered by electroporation to evoke an immune response against transformed cancer cells.56 VGX-3100 is undergoing trials in HPV-related cancers.

Looking to the horizon

GU cancer immunotherapy is well established and rapidly innovating. Some now dare to dream of cure by immunotherapy for cancers like metastatic prostate cancer.57 How will we realise these aspirations for GU cancers?

Improved personalisation of immunotherapy will be one frontier. For example, given the high prevalence of prostate cancer (and for example breast and colorectal cancers, which also tend to be PD1-unresponsive), biomarker screening (via whole genome sequencing and standard IHC) to identify patients that are MSI-high/MMR+, with a high chance of benefit from PD1 antibodies.

Detailed genomic analysis of metastatic lesions may reveal treatments for some patients as the genetics of advanced disease are often markedly different to primary cancers.58 Some genetic variants such as frameshift indels are strongly predictive of response to immunotherapy.59 These are very common in ccRCC and non-clear cell RCC; a trial of sequential nivolumab followed by ipilimumab + nivolumab recently opened to enrolment for Australian patients with non-clear cell RCC. Whole genome sequencing may even become a necessary precursor to checkpoint immunotherapy, if early reports of ‘hyperprogression’ due to checkpoint immunotherapy60,61 hold true, and the association with specific genotypes is confirmed.62

We know the abbreviations PD1, PDL1 and CTLA4 well, but more than 50 other immune checkpoints have been identified to date. Preclinical and early clinical trial development probing these immune checkpoints are in early phase trials, with checkpoints such as LAG3, TIM3, VISTA, OX40, CD40L, CD137 and GITR all being examined.

Of special note is CD276/B7-H3/PD-L3. Previously thought to be a ‘dummy’ receptor, B7-H3 expression correlates with androgen signalling, immune infiltration, Gleason grade, tumour stage and poor survival in prostatectomy cohorts.63 Enoblituzumab (MGA271) is a humanised antibody targeting B7-H3, and has shown single agent activity in patients with heavily pre-treated prostate, bladder, kidney and other cancers.64 Combination studies are underway.

Finally, combinations of checkpoint antibodies with other immunotherapeutics and other therapies are revealing new opportunities for patients with GU cancers. Denosumab is an osteoclast-inhibiting anti-RANKL-antibody, which may have immune modulatory effects in the tumour microenvironment by blocking immunosuppressive macrophages. The KeyPAD trial will test denosumab in combination with pembrolizumab in TKI-refractory ccRCC in Australia. Another potent pathway of immunosuppression in tumours occurs via enzymatic action of indoleamine 2,3-dioxygenase (IDO). IDO inhibitors such as epacadostat are being combined with checkpoint inhibitors, delivering intriguing responses with minimal toxicity in early phase trials in various cancers, including UC.65

GU cancers illustrate the landscape of approaches to cancer immunotherapy; immune stimulants like IL2 and BCG; vaccination strategies like sipeleucel-T and HPV vaccines; antigenic paucity in prostate cancer, the antigenic richness of GCT and non-clear cell RCC; and rapidly evolving and improving checkpoint immunotherapy combinations in ccRCC and UC. Early successes have given us direction, and ongoing failures spur us to explore new vistas.

Figure 1: The landscape of GU cancer immunotherapy; the relatively fertile plains of renal cell carcinoma contrast with the desert of prostate carcinoma, and the tropical jungle of urothelial carcinoma.






Figure 2: Response rates of checkpoint immunotherapy antibodies as monotherapy or selected combinations in GU cancers.

  1. Checkpoint antibody monotherapy delivers responses in a minority of patients across GU cancers.
  2. Response rates for different agents are higher in ccRCC and urothelial cancers, but some activity is seen in prostate carcinoma.
  3. Selected combinations of immunotherapy agents are improving response rates in ccRCC and urothelial carcinoma.






Table 1: Response rates of checkpoint immunotherapy antibodies as monotherapy or selected combinations in GU cancers.

































Nivolumab + Ipilimumab

Pembrolizumab + epacadostat

Atezolizumab + bevacizumab

Avelumab + axitinib


















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