Immunotherapy has represented a breakthrough therapy for many cancer subtypes in the last years. Among genitourinary (GU) neoplasms, the urothelial carcinoma (UC) and the renal cell carcinoma (RCC) have benefitted mainly from immune checkpoint inhibitors (ICIs) both as single agents and in combination with other ICIs or tyrosine kinase inhibitors (TKIs) [1,2,3,4,5,6,7,8,9,10,11,12,13]. However, in prostate cancer (PCa), ICIs have shown limited efficacy primarily due to an immunologically ‘cold’ and immunosuppressive tumor microenvironment (TME) [14,15,16,17,18].

Improving immunotherapy efficacy requires combination therapies or different pharmacological approaches [19]. In fact, the two principal ways to enhance the immune system’s antitumor activity are blocking the immune-suppressive signals responsible for the decreased antitumor response (that is, how ICIs work) or stimulating the immune activation against specific tumor-associated antigens (TAAs). The latter is the mechanism used by anticancer vaccines, capable of triggering the immune response actively by administering antigens conjugated with co-stimulatory molecules or loaded on patients’ immune cells [20,21,22,23]. In this way, antigen-presenting cells (APCs) can recognize, uptake, process, and present TAAs to naïve T-cells. Generally, intracellular antigens are presented with the class I major histocompatibility complex (MHC) molecules to CD8⁺ cells, turning them into effector cytotoxic lymphocytes (CTLs) [24]. It is more difficult to elicit a cytotoxic response in the case of extracellular antigens. The class II MHC molecules usually present them to CD4⁺ cells [24,25]. However, APCs—especially dendritic cells (DCs)—can process and present some extracellular antigens through the class I MHC to CD8⁺ cells, a process known as antigen cross-presentation whose discovery has been of great importance for therapeutic vaccines development [25].

PCa represents the most frequent tumor and the second leading cause of death among the Western male population [28]. PCa is an ideal candidate for vaccine therapies, given its high targetable number of TAAs, prostatic acid phosphatase (PAP), prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) among the most important [29,30]. The majority of studies focused on mCRPC. Only three phase III trials have been conducted. Even if specific immune activation was detectable, vaccines usually did not determine significant survival improvement (Table 1).

3. Vaccine Therapy in Urothelial Cancer (UC)

UC has a long and successful history of vaccines use, starting from the Bacillus Calmette–Guerin (BCG), which represents a cornerstone for the treatment of non-muscle invasive bladder cancer (NMIBC) since the 1990s [27]. However, BCG failure occurs in 20–50% of patients [84]. Intending to potentiate BCG efficacy, in a randomized phase I study (NCT01498172), 24 NMIBC patients received a vaccine containing the recombinant MAGE-A3 protein + the adjuvant AS15 before BCG instillations. In half of the patients, specific T-cells were subsequently detectable in blood. No survival data are available [85].

Some UC TAAs have been tested mainly on DCs or as peptide vaccines, inducing immune responses with controversial survival effects in phase I/II trials (Table 1). Survivin-2B80-88 improved OS in phase I (p = 0.0009) [86]. CDX-1307, targeting the mannose receptor, induced immune responses in bladder cancer (BCa), but it did not get over phase I because the N-ABLE NCT01094496 phase II study was stopped early due to slow enrollment [87]. DCs loaded with Wilms tumor (WT)-1 in seven patients with mUC or mRCC determined specific immune responses and decreased T-regs [88]. S-288310, derived from DEP domain-containing 1 (DEPDC1) and M-phase phosphoprotein 1 (MPHOSPH1), was administered to pretreated mUC patients in a phase I/II trial: 89% of patients developed specific T-cells, reaching mOS of 14.4 mos, with better results if a double induction against both peptides was obtained [89]. NEO-PV-01 peptide derives by the genomic profiling of patients’ BCa: in a phase Ib trial, 10/14 patients achieved PR or stable disease (SD) [90].

The PPV strategy has been evaluated in the platinum-progressing mUC. A phase I trial did not meet its primary endpoint of prolonging PFS among 80 BCa patients; however, a significantly longer OS was reached than best supportive care (7.9 vs. 4.1 mos; p = 0.049) [91]. In a phase II trial enrolling 48 patients with metastatic upper tract urothelial cancer (mUTUC), the development of specific T-cells was associated with longer OS (p = 0019). A median OS of 7.7 mos was achieved, reaching 13.0 mos if salvage chemotherapy was associated [92]. Finally, among 12 mUC patients, a phase I trial reported one complete response (CR), one PR, two SDs, mPFS of 3 mos, and mOS of 8.9 mos [93].

Current trials are ongoing: the peptide vaccine ARG1 (targeting arginase-1) is under evaluation as a single agent in a phase I trial (NCT03689192); the NCT03715985 study is evaluating the multi-peptides neo-antigen vaccine NeoPepVac in combination with anti-PD1/PD-L1 in many solid tumors, including mUC (Table 2).

4. Vaccine Therapy in Renal Cell Cancer (RCC)

In the mRCC, different DCs and peptide vaccines have been tested, mostly in phase I/II trials, with only two published phase III studies (Table 1). With a similar Sipuleucel-T mechanism, Rocapuldencel-T is composed of DCs plus amplified tumor RNA plus CD40L RNA. In the ADAPT phase III trial, 462 patients were randomized 2:1 to receive Rocapuldencel-T plus sunitinib versus standard of care. Even if immune responses were recorded, the trial failed its primary endpoint of improving OS compared to the control group (mOS 27.7 vs. 32.4 mos; HR = 1.10, 95% CI, 0.83–1.40). Still, a trend toward better OS was evidenced in the case of more robust immune responses [94]. In the adjuvant setting, autologous-antigens loaded DCs plus cytokine-induced killer cells (CIK) were compared to α-interferon (IFN) in 410 patients, improving PFS and OS (3-year OS rate 96% vs. 83%; 5-year OS rate 96% vs. 74%; p < 0.01) [95].

Among the peptide vaccines, EC90, a folate-targeted vaccine, plus α-IFN and IL-2, induced seven SDs and one PR in 24 patients in a phase I/II study [96]. Nine patients with progressive mRCC, treated with hypoxia-inducible protein-2 (HIG-2) peptide vaccine obtained a DCR of 77.8% and an mPFS of 10.3 mos [97]. GX301 vaccine is composed by four telomerase peptides plus Imiquimod and Montanide ISA-51 as adjuvant [98]. Telomerase contributes to tumor immortalization, but it is not expressed by somatic cells [99]. GX301 induced specific immunological responses in over 2/3 of vaccinated mRCC or mCRPC patients, with a trend for better OS (around 11 mos) [98].

Among the different subtypes of renal cancer, clear-cell renal cell carcinoma (ccRCC) is exceptionally responsive to immunotherapy and has been historically considered the ideal subtype to treat with vaccines [100]. However, in the IMPRINT phase III trial, IMA901 (composed of 10 tumors-associated peptides) plus GM-CSF, cyclophosphamide and sunitinib did not improve OS for the 339 randomized patients in the first-line setting (mOS 33.2 vs. 33.7 mos; HR = 1.34, 95% CI, 0.96–1.86; p = 0.087), even if immune activation had previously been evidenced in phase II [101,102]. PPV with vascular endothelial growth factor receptor (VEGFR)-1 was administered in 18 ccRCC patients. Among them, two PRs and five SDs with a median duration of response of 16.5 mos were observed [103]. TG-4010 is an MVA vector-based vaccine of IL-2 and MUC-1 that induced an mOS of 19.3 mos among the 27 ccRCC patients in a phase II trial [104].

Aiming to identify predictive biomarkers for therapeutic vaccines, blood parameters at baseline (platelets, neutrophils, monocytes, hemoglobin, and LDH), the presence of bone metastases, the MSKCC score, the Fuhrman grade, and the ECOG-performance status have been investigated in RCC [66,68,95].

Novel vaccine targets have been proposed for future clinical studies: hypoxia-inducible factor (HIF)-1α, being the RCC often associated with the mutation of Von Hippel-Lindau (VHL) gene and dependent on the upregulation of HIF; PD-L1 derived peptides, as RCC is sensitive to immunotherapy control [105,106]. Among the ongoing trials, NCT02950766 evaluates the neo-antigen NeoVax plus Ipilimumab (phase I); the NCT03289962 phase I study is testing the vaccine RO7198457 plus atezolizumab; the NCT03294083 phase Ib trial is assessing the Pexa-Vec vaccine (Thymidine Kinase-Deactivated Vaccinia Virus) plus the anti-PD1 Cemiplimab. Finally, the NCT02643303 phase I/II study evaluates the combination of tremelimumab as in situ vaccination, durvalumab and the TME modulator polyICLC, in subjects with advanced solid tumors, including RCC, UC, PCa and testicular cancer (Table 2).