IMA901 для mRCC

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IMA901 for metastatic renal cell carcinoma in the context of new approaches to immunotherapy

Steffen Rausch et al. Future Oncol. (2014) 10(6), 937–948


Renal cell carcinoma (RCC) represents 2–3% of all cancers. In general, during the last two decades, there has been an annual increase of approximately 2% in the incidence both worldwide and in Europe. In 2008, it was estimated that there were 88,400 new cases of RCC and 39,300 kidney cancer-related deaths in the EU [1]. A third of newly diagnosed patients with RCC will progress to metastatic renal cell carcinoma (mRCC), whereas another third of patients will present with metastatic disease at time of diagnosis [2].

The ability of renal tumors to evoke an immune response, and the possibility that this may lead to spontaneous regression of mRCC in some patients spurred the idea of developing immunotherapy as an effective treatment for patients with RCC [3,4]. In the history of systemic treatment of mRCC, immunotherapy has played a significant role, based on the observation of spontaneous tumor regression after cytoreductive nephrectomy. In addition, ‘classical’ chemotherapy was ineffective for the treatment of mRCC. RCC is characterized by the expression of different MDR1, such as P-glycoprotein, among others [1,5]. At the level of the luminal membrane of renal proximal tubules, MDR-1 is thought to accelerate drug secretion into the urine. As clear cell RCC is derived from cells of the luminal surface of the proximal tubule, which show a high intrinsic level of MDR-1 expression, this drug resistance may be explained [6]. Although the role of MDR-1 in the pathogenesis of drug resistance has been elucidated, its role to serve as a prognostic factor in RCC is still doubtful and under discussion [7].

With the discovery of novel targeted drugs, and their introduction into the clinical routine within the last decade, the management of mRCC has been revolutionized. It is now based on various agents with specific targets within the signaling cascades of the mTOR and the VEGF receptor pathway. Despite of the magnitude of well-established substances and these new small molecule inhibitors the optimal timing of the sequence is still a matter of debate, which is currently investigated in various clinical trials [8]. Despite the high success rate of a prolonged progression and overall survival (OS) due to the new mTORand VEGF-directed agents, mRCC still remains an incurable condition.

Former approaches to immunotherapy in mRCC

For years, patients with a mRCC have been restricted to the treatment of immunotherapy with the activation of a nonspecific immune response by the application of cytokines, namely IL-2 and IFN-a. In randomized studies, IFN-a showed a superiority of survival in relation to hormonal treatment or placebo in the therapy of mRCC [9]. IFN-a provided a modest response rate of 6 –15% , together with a 25% decrease in the risk for tumor progression and a survival benefit of 3–5 months in comparison to placebo [10]. The positive effect of IFN-a was particularly apparent in mRCC patients with clear cell histology, good-risk Motzer criteria and lung metastases only.

The second clinically established cytokine for mRCC treatment is IL-2. IL-2 is characterized by a substantially higher toxicity compared with IFN-a. Response rates to systemic treatment are low and treatment associated morbidity and mortality is high. Fyfe et al. reported a response rate of 14% with administration of high-dose IL-2 and a notable treatment associated mortality rate of 4% [11]. In a randomized Phase III study, Yang et al. underlined the effectivity of treatment with a high-dose bolus of IL-2 compared with lower dosage [12]. However, a small proportion of patients will develop complete responses and a durable survival from IL-2 treatment. Although histological biomarkers for the prognosis of IL-2 therapy response, such as carbonic anhydrase IX, have been proposed, their clinical utility could not be confirmed [13,14].

The moderate efficacy of immunotherapy was also documented in a Cochrane meta-analysis including 42 eligible studies in 2005 [10]. Here, the rate of complete or partial remissions was 12.9% in 99 analyzed study arms in the combined data analysis compared with 2.5% in ten nonimmunotherapy control arms and 4.3% in two placebo arms. Out of these reported of complete or parital resmissions 28% were complete responders. The median survival rate was 13.3 months [10].

Possible explanations for the limited effectiveness of unspecific cytokine treatment are their potential coexisting immunosuppressive effects. For example, the frequency of CD4+ CD25+ T cells was significantly increased after IL-2 treatment, and these cells expressed phenotypic markers associated with Tregs [15]. Van der Vliet et al. described a decreased frequency of both circulating myeloid dendritic cells (DC)-1 and plasmacytoid DC during high-dose IL-2 treatment. In addition, high-dose IL-2 further decreased the CD1d-restricted invariant natural killer T (iNKT) cells, although the number of CD4-CD8doublenegative iNKT cells increased. For this subset, a preference to produce Th1-tye cytokines has been shown, but in the presence of CD1d-transfected HeLa cells, IFN-? production was surprisingly not increased in this double-negative iNKT cells after high-dose IL-2 treatment [16]. By contrast, the frequency of CD4+CD25+ T cells, including CD4+Foxp3+ T cells, which have been reported to suppress anti-tumor immune responses, increased during high-dose IL-2 therapy [16]

As mentioned above, in the presence of the excellent results of tyrosine kinase inhibitors (TKIs) and mTOR inhibitors in clinical trials, first-line unspecific immunotherapy is rarely administered nowadays [5]. Nevertheless, the routine application of an interferon as an adjunctive is still of relevance. The AVOREN trial of bevacizumab in combination with IFN-a compared with IFN-a monotherapy in mRCC patients demonstrated an increased response rate and prolonged progression-free survival (PFS), leading to a first-line treatment recommendation for this regimen in current clinical guidelines [5,17]. Apa rt from t he obvious drawback s of cytokine-based cancer immunotherapy, recently novel and more specific approaches of immunotherapy for RCC have been developed and investigated in clinical trials. With the success of randomized immunotherapy trials in other tumor entities involving patients with metastatic prostate cancer, malignant melanoma and follicular lymphoma, anticancer vaccines have, once again, come into focus [18–20]. Simultaneously, the deepening in the understanding of the immune system in terms of antigen processing and presentation, T-cell activation and costimulation has led to more specific approaches of immunopharmacologic intervention.

The idea of specific immunotherapy consists in the activation of the body’s physiological defence mechanisms against tumor cells.

Therefore, T-lymphocytes need to be specifically activated to recognize and eliminate cancerous cells. To discriminate between ‘own’ and ‘foreign’, proteins are processed intracellular and the resulting short peptide sequences of eight to ten amino acids are presented on the cell surface by HLA molecules [21,22]. The socalled tumor-associated antigens (TA As) play a key role in specific immunotherapy. If the antigen is recognized as not own, the immune system can start its defense mechanisms. Various approaches of tumor immunotherapy have been under investigation. By the administration of antigen-presenting cells – that is, dendritic cells loaded with tumor-derived lysates or RNA, an activation of the immune system against cancer cells was proposed [23,24].

Multipeptide vaccine IMA901

Multipeptide-based vaccination is characterized by fully defined TA A-derived T-cell epitopes, the so-called tumor-associated peptides (TUMAPs). The combination of multiple, well-def ined TUM APs, is able to induce a broad T-cell response [25]. The application of the peptide vaccine is performed by intradermal or subcutaneous injection. Subsequently, local dendritic cells process the peptides and migrate to regional lymph nodes for T-cell activation. IMA901 is the pioneer drug in the field of multiantigen-based vaccination [26].

The compound IMA901 is a RCC-specific, multiantigen-specif ic synthetic peptide vaccine that consists of nine HLA-A*02 and one HLA-DR restricted TUMAPs derived from antigens overexpressed in RCC (Table 1). IMA901 has been tested in two multicenter trials. Walter et al. report from the treatment of a total of 96 HLAA*02-positive mRCC patients with progressive disease after at least one first-line treatment [26]. IMA901 was administered alongside with granulocyte–macrophage colony-stimulating factor (GM-CSF) ± cyclophosphamide (Cy).

IMA901

Phase I study

In the first Phase I study, T-cell responses of the patients to multiple TUMAPs were associated with a better disease control and lower numbers of prevaccine FOXP3-positive Tregs. In the study design, the vaccination was accompanied by an immunomonitoring program carried out by HLA multimer analysis and IFN-? enzymelinked immunospot assays from peripheral blood mononuclear cells collected at different time points preand post-vaccination. Within the collective of 28 patients, 27 subjects were evaluable for immunomonitoring, 20 showed a vaccine-induced T-cell response to at least one of the TUMAPs, while eight responded to multiple TUMAPs. Furthermore, the study revealed a significant association between disease stabilization and T-cell responses to multiple TUMAPs (p = 0.019) on the one hand, and between the lower prevaccination levels of FOXP3+ Tregs (p = 0.016) on the other hand [26].

Phase II study

The following randomized Phase II trial showed that a single dose of Cy reduced the number of Tregs and confirmed the result that immune responses to multiple TUMAPs were associated with longer OS. In the protocol, 68 HLA-A*02+ patients were randomized to receive single-dose Cy (300 mg/m2) versus no pretreatment, 3 days prior to the start of IMA901 + GM-CSF (75 µg) [26]. PFS was similar in both study groups (with Cy vs without Cy), but for median OS, there was a trend for a prolonged survival in the with Cy arm versus the without Cy arm (23.5 vs 14.8 months; hazard ratio [HR]: 0.57; p = 0.090). Disease control defined as complete or partial response rate or stable disease at 6 months was 31% in patients with previous cytokine treatment and 14% in patients after TKI pretreatment. One complete and two partial response were reported by the investigators with one confirmed partial response by centralized review, which mirrors the practical experience gained form other vaccination trials. As a significant association between clinical benefit, T-cell responses and prevaccination levels of Tregs (defined as FOXP3+ regulatory cells) and multiple immune responses were reported, the positive effect of additional immunomodulation by Cy is proposed.

In addition, based on the available clinical data, the authors analyzed probable biomarkers to predict treatment response for the application of IMA901. Among 300 studied analytes of patient serum samples prior to IMA901 exposure, high concentrations of APOA1 and CCL17 were predictors of a survival advantage (HR: 0.41; p = 0.007 and HR: 0.41; p = 0.011, respectively). This effect was only observed in patients receiving Cy. In addition, APOA1 and CCL17 were positively associated with multipeptide responses (p < 0.0001 and p = 0.0028, respectively). On the other hand, six phenotypes of myeloid-derived suppressor cells (MDSCs) were characterized and the CD14+HLA-DR-/lo and CD11b+CD14CD15+ MDSC phenotype were negatively associated with OS.

In both studies of multipeptide vaccination, clinical safety and tolerability were reported, the only severe adverse events grade 3 were a systemic allergic reaction, which was caused by GM-CSF, and a localized allergic reaction at the side of injection, but with no intolerances after further vaccinations [26].

Table 1. Composition of the vaccine cocktail IMA901.

Peptide Amino acid composition of TUMAP Antigen HLA
ADF-001 SVASTITGV PLIN2 A*02
ADF-002 VMAGDIYSV APOL1 A*02
APO-001 ALADGVQKV APOL1 A*02
CCN-001 LLGATCMFV CCND1 A*02
GUC-001 SVFAGVVGV GUCY1A3 A*02
K67-001 ALFDGDPHL PRUNE2 A*02
MET-001 YVDPVITSI MET A*02
MUC-001 STAPPVHNV MUC1 A*02
RGS-001 LAALPHSCL RGS5 A*02
MMP-001 SQDDIKGIQKLYGKRS MMP7 DR

IMA901 consists of ten TUMAP; the respective amino acid composition, the targeted antigens and the target protein are shown. TUMAP: Tumor-associated peptide.

Data taken from [26].

Phase III study

Currently, IMA901 is investigated in the IMPRINT trial, a large Phase III trial, in which 340 HLA-A*02+ patients have been randomized in a 3:2 fashion to receive IMA901 plus sunitinib versus sunitinib alone as a first-line treatment for metastatic clear cell RCC. Cy and GM-CSF are applied as systemic and local immune modulators at the dose levels used in the Phase II study.

According to the results of the Phase I/II studies in which PFS was not different between the groups, OS was chosen as the primary end point for the IMPRINT trial. The IMPRINT trial has finished recruitment and final results are pending [27]. If the results will turn out to be positive they will only be applicable to patients with the HLA-A*02 allele,which is present in approximately 50% of the population in Europe and Northern America [28].

IMA901 in the context of other specific immunotherapy approaches

Other immune-related treatment regimens have been used or are used to treat high-risk or mRCC patients in the adjuvant or palliative setting. Here, single antigen-based vaccination, application of autologous tumor cell lysates or the utilization of adoptive T-cell transfer have been applied, but failed to demonstrate a clear positive influence on patient outcome in large Phase III trials and have not been approved by regulatory authorities (Figure 1).

Reniale® (Liponova, Hanover, Germany) is an autologous RCC tumor cell lysate, which was administered as an adjuvant treatment in high-risk RCC patients (pT2–T3b, pN0–3 and cM0) after nephrectomy. In this Phase III study, the vaccine improved the 5-year PFS significantly if compared with observation (77.4 vs 67.8%) [29]. However, the vaccine was not approved by the EMA owing to serious issues in the trial methodology with formal weaknesses. The primary end point was “to reduce the risk of tumor progression,” which was defined as progression or death and the study groups were imbalanced as 174 out of 553 patients of the trial did not receive any treatment [29,30]. In addition, it has to be noted that tumor specimens were staged by the old tumor, node, metastasis classification, which stages tumors larger than 2.5 cm to the pT2 stage. Today, this tumor size would be staged as a pT1a tumor.

Vitespen (Oncophage®; Antigenics Inc., MA, USA) is an autologous tumor-derived heat shock protein (HSP) Gp96 preparation tested in an adjuvant Phase III trial [31]. The rationale for vitespen is that HSP are able to create a molecular peptide fingerprint of the cellular protein array of the cell – for example, the RCC cell. Vitespen is the purified Gp96 HSP preparation of the respective cancer cell type, in the above discussed adjuvant Phase III trial of the autologous RCC tissue [31,32]. Gp96 interacts with the antigen-presenting cell through its receptor CD91 and the peptides are then cross-presented on MHC-I and MHC-II molecules [32,33]. The primary end point of PFS prolongation in the vitespen RCC trial was not reached. After 1.9 years of median follow-up recurrence in the intention-to-treat population was 37.7% (136 out of 361 patients) for vitespen and 39.8% (146 out of 367 patients) with a HR of 0.923 (p = 0.506). For the full-analysis set, which excluded patients with metastatic disease or residual disease at baseline, recurrence rate was 25% (75 out of 300) for the vitespen group and 27.3% (83 out of 304) for the observation group (p = 0.390) [31]. In the retrospectively defined subgroups of American Joint Committee on Cancer stage I/II tumors (full-analysis set) this autologous vaccine tended to a prolonged PFS (HR: 0.576; 95% CI: 0.324–1.023; p = 0.056) [31]. Therefore, vitespen did not gain regulatory approval except for intermediate-risk patients in Russia [34].

Trovax (M VA-5T4 ; TroVax™, Oxford BioMedica, Oxford, UK) is a single-tumor antigen vaccine of 5T4, which was used in combination with first-line standard of care (either sunitinib, IL-2 or IFN-a; TRIST trial) [35]. MVA-5T4 is a nonmutated self-antigen expressed in the placenta, but also overexpressed in a variety of tumors including RCC, prostate and colorectal carcinoma, which is located in the microvillus of the plasma membrane. Its overexpression alters cell adhesion, motility and morphology [36,37]. The modified vaccina Ankara virus, derived from the smallpox virus is used as a vector to deliver the 5T4 antigen. The TRIST trial failed to demonstrate any benefit in median OS in comparison to placebo as a firstline treatment (20.1 vs 19.2 months; TROVA X vs control) [35].

IMA901 for metastatic renal cell carcinoma in the context of new approaches to immunotherapy 2014 1

Figure 1. Composition of the different cancer vaccines used in renal cell carcinoma.

†Via CD40, Vitespen leads to independent production of cytokines by the APC.

APC: Antigen-presenting cell; Cy: Cyclophosphamide; GM-CSF: Granulocyte–macrophage colony-stimulating factor; NO: Nitric oxide; TUMAP: Tumor-associated peptide.

AGS-003 (Argos Therapeutic, NC, USA) is a dendritic cell-based vaccine. Matured monocyte-derived dendritic cells are coelectroporated with the patient’s own antigen coding amplified tumor RNA and synthetic CD40L RNA [38]. In a Phase II trial, 21 first-line mRCC patients (poor and intermediate risk) with newly diagnosed advanced-stage and synchronous metastatic disease eligible for unilateral nephrectomy or partial nephrectomy were treated with AGS-003 and sunitinib. In this cohort, the median PFS was 11.2 months and the OS was 30.2 months [39]. In the intermediate subgroup of 11 patients, according to the Heng criteria, OS was 39.5+ months. Mild side effects of grade 1 at the injection side were reported in the majority of patients, but no additive toxicity was observed [39]. In the Phase III trial (ADAPT) of 450 patients are randomized to AGS-003 with sunitinib verusu sunitinib alone as a first-line treatment. The ADAPT study is still recruiting patients [40].

One principle in specific immunotherapy is the selective activation of the immune system with the induction of a T-cell response against TA As present on the RCC cells. In single antigen-based vaccination, the effect of immune evasion by target downmodulation is a potential negative factor [41]. The TA A multicity of autologous tumor cell vaccines may help to overcome this hurdle, but the selection of the displayed TA A selected from the peptidome of the tumor cell is by chance and, therefore, not predictable. Therefore, without the knowledge that TA As are displayed, nothing is known about their antigenicity and immune monitoring to measure the strength of an induced immune response is hardly possible. By contrast, the synthetic multipeptide vaccine IMA901 uses well-defined TUMAPs for the tumor vaccination. In addition, the treatment in the IMA901 trials did not only consist of the peptide vaccine itself, but also of a local (GM-CSF) and a systemic (Cy) immunomodulator, which was combined with the peptide vaccine to booster an effective T-cell activation and response. Furthermore, in the IMPRINT trial IMA901 is combined with sunitinib, which is not only an established first-line treatment in mRCC, but which also has beneficial immunomodulatory capabilities [42–44].

IMA901 in the context of new approaches to immunotherapy

Tumor cells and the local tumor microenvironment release a variety of substances to alter T-cell activation and to prevent the priming of naïve T cells, to silence activated T cells or to influence the composition of the T-cell subgroups – for example, with an increased number of Tregs. This results in an ineffective immune response towards the cancer cells with a diminished elimination of tumor cells [45,46]. Currently, various substances, which are called immunomodulators or immune checkpoint inhibitors are used to overcome this hurdle of immune silencing. These substances can act as a single agent or in combination with specific immunotherapy. They are potential candidates for a combination with specific immunotherapy – for example, with peptide vaccine to booster the immune response.

Adjuvants as local immunomodulators

After the injection of the TA A, the antigen needs to be bound to HLA molecules of DCs and other professional antigen-presenting cells. In order to prime – that means to activate the naive T cells – DCs must present the TA A in the context of a costimulus such as the expression of CD80 and CD86. A high expression of such costimulatory molecules is achieved by activation of APCs. If the costimulatory signal is not present, the DC cells may present the antigen on to the CD8+ T cell as a tolerogenic signal, which is also mediated through PD-1 and CTLA-4 [47,48]. This phenomenon of peripheral tolerance is influenced by the antigen-specific tolerogenic role of DCs, and it is suggested that distinct developmental stages and subsets of DCs and T cells account for the different pathways to this peripheral tolerance [49]. Pattern recognition receptors, among Tolllike receptors, scavenger receptors and C-type lectin receptors can activate DC cells and are used in specific immunotherapy for activation [50]. One of the early treatments that proved the stimulation of the innate immune system to lead to tumor regression is Coley’s toxin. Coley treated cancer patients with a mixture of heat-killed Streptococcus pyogenes and Serratia marcescens, which functions as an adjuvant, facilitating the maturation of DC via Toll-like receptor-transduced signals [48,51,52].

In the IMA901 trials, GM-CSF (75 µg) was used for this reason [26]. GM-CSF, a heterogeneously glycosylated 14–35 kDa polypeptide, was initially identified as a mediator of hematopoiesis and monocyte–macrophage differentiation [53]. The receptor for GM-CSF is expressed by CD34+ progenitor cell of the myeloid lineage including dendritic cells where it promotes myeloid differentiation [54]. In animal models GM-CSF transduced tumor cells increased the immunogenicity by local recruitment and maturation of DC cells [55,56]. This probably results in improved TUMAP presentation to T lymphocytes in lymph nodes [56,57]. On the other hand, high doses of GM-CSF can result in a systemic mobilisation of bone marrow-derived immature myeloid cells, which develop an immunosuppressive phenotype [58] and may not act as effective adjuvants in peptide vaccination as observed in a peptide vaccination trial in prostate cancer patients, where GM-CSF was used at a dose of 225 µg at the time of vaccination [50].

Systemic immunomodulation

Cy was used in the IMA901 trials due to its positive effects to lower the number of pretreatment FoxP3+ Tregs, but Cy did not influence the number of immune responders that were comparable between the Phase I and II trials [26]. In the IMA901 Phase II trial, Cy-treated patients had a trend for a prolonged OS (HR: 0.57; p = 0.090) and among immune responders Cy pretreated patients had a significantly longer survival that those without Cy (HR: 0.38; p = 0.040) [26,59]. Therefore, it seems that an immune response and the immunomodulatory mechanism of Cy are required to improve survival of mRCC patients treated with IMA901. The authors conclude that single-dose Cy may be a beneficial immunomodulator for anticancer vaccines in general and strongly argue against any clinical singleagent activity of Cy [59]. On the other hand, the effects of Cy maybe two-sided, and the complete mechanism of the anti-tumor T-cell immunity modulated by Cy is not unsealed. In patients with hematologic malignancies single-dose Cy simulated T-cell activation by interferon-related mechanisms [60]. The anti-tumor effects of Cy alone or in combination with vaccine restores natural killer and T-cell receptor-driven effector functions in cancer patients, augments the delayed type hypersensitivity response and as also shown by others decreases the amount of Tregs [61–63]. Interestingly, the decreased amount of Tregs does not directly convert into an increased amount of Th17 T cells as it was shown that low-dose Cy promotes a differentiation of Th17 cells, which were detected in the blood and tumor ascites of cancer patients [63]. A very recent report describes that the intestinal microbiota modulates the anticancer effects of Cy [64]. Here, in a tumor bearing animal model Cy altered the composition of the intestinal microbiota in the small intestine and induced a translocation of Gram-positive bacteria into secondary lymphoid organs where the pathogens stimulated the generation of a specific subset of ‘pathogenic’ Th17 cell and memory Th1 immune responses. This may help to push the immune system towards an anticancer immune response [64]. On the other hand, in a mouse study, low-dose Cy increased the accumulation Gr1+CD11b+ MDSCs with an elevated suppressive activity and nitric oxide production, but also the amount of Tregs was decreased in this model [65].

TKIs have replaced unspecific immunotherapy for the treatment of mRCC [5]. Despite their potent antiangiogenetic and antiproliferative capacities TKIs can modulate the immune system [43,66,67]. Suntinib (Su) significantly increases the percentage of IFN-?-producing T cells after 28 days of treatment if compared with baseline and there is an inverse correlation between the increase in type 1 immune response and the decrease in the percentage of Tregs after two cycles of Su treatment [43]. In addition, Su decreases the numbers of MDSC, which were measured in that study as two populations of CD14-CD15+ MDSC and CD33+HLA-DR MDSC. This MDSC decline also correlated with an improvement in T-cell IFN-? production and a decline in Treg numbers [68]. On the other hand, sorafenib inhibits the activation of immature to mature dendritic cells and induces apoptosis in DC cells in vitro [66]. In an ovalbumin mouse vaccination model, sorafenib did not influence the percentage of Tregs in the blood CD4+ T cells and the number of induced peptide-specific CD8+ T cells was significantly lower for sorafenib-treated mice [66]. Axitinib, another TKI used in the second-line treatment of mRCC, yielded positive immune modulatory effects [69,70]. In a melanoma mouse model, combined treatment with axitinib and vaccination resulted in a slower tumor growth rate and an extended OS. This was associated wit a reduced MDSC and Treg population in the tumor [69]. In the peripheral blood mononuclear cells of healthy volunteers, axitinib did not increase the amount of Tregs, but also did not affect the upregulation of the T-cell activation markers CD25 and CD69 [67]. Despite the different immunomodulatory capacities of the different TKIs, timing of the concomitant applied vaccine seems to be important. The simultaneous immunization with a recombinant a-lactalbumin, expressed on breast cancers, and sunitinib treatment inhibited the priming of DC cells to a-lactalbumin due to a decrease in CD11b+CD11c+ antigen-presenting cells. If the priming phase of the vaccination was avoided by the sunitinib treatment a synergistic immune response was observed [71]. In this context of TKI combinations, the results of the IMA901 IMPRINT trial will be interesting as this trial combines sunitinib and vaccination at different time points and as Su decreases the number of CD14CD15+ MDSC and CD33+HL A-DRMDSC, for which OS was negatively associated with this MDSC subtypes in the IMA901 Phase II trial [26,42].

Checkpoint modulation

Immune checkpoints refer multiple inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the extent of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. Cancers utilize certain immune checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumor antigens. As many of these immune checkpoints are initiated by ligand-receptor interactions, blockage by antibodies or modulation by recombinant forms of ligands or receptors are possible options of interaction [72].

CTLA-4 (CD152), is an inhibitory receptor that downmodulates the initial stages of T-cell coactivation. Anti-CTLA-4 monoclonal antibodies mediate tumor regression, although frequently accompanied by immune-related adverse events. The anti-CTLA-4 antibody, ipilimumab, is an approved drug for the treatment of patients with stage IV melanoma on the basis of a randomized Phase III trial that showed an improved OS [73]. Based on the success in melanoma patients ipilimumab was also administered in patients with uro-oncological malignancies. In a Phase II trial, mRCC patients were treated with ipilimumab at a loading dose of 3 mg/kg and then with 1 mg/kg every 2 weeks (n = 21), and in a second cohort all patients received 3 mg/kg of ipilimumab every 2 weeks (n = 40). Prior therapy included in nearly all patients IL-2 [74]. One out of 21 patients in the first cohort and five out of 40 in the second cohort had a partial response. In total, 33% of patients experienced a grade III or IV, immune-mediated adverse events included enteritis and hypothysitis [74]. In a recent Phase III trial of postdocetaxel castration-resistant prostate carcinoma, ipilimumab was given at a dose of 10 mg/kg after a bone-directed 8 Gy radiotherapy in a 1:1 randomization. OS numerically favored ipilimumab (HR: 0.85; 95% CI:  0.72–1.00; p = 0.053), but OS was not different between the treatment arms (ipilimumab vs placebo: 11.2 vs 10.0 months) [75].

Another target of modulating the interaction of tumor cells with the immune system is the PD-1, which plays a pivotal role in the ability of tumor cells to evade the host’s immune system. PD-L1 is the primary PD-1 ligand that is upregulated in solid tumors, where it can inhibit T-cell DC contacts and alters T-cell mobility [76,77]. These properties make the PD-1/PD-L1 axis to a potentially promising target for cancer immunotherapy. A targeted immunotherapy trial with the fully humanized anti-PD1-antibody BMS-936558 (nivolumab, Bristol-Myers Squibb, NY, USA) has shown efficacy and acceptable toxicity after intravenous infusion in patients with mRCC [78]. Among all patients treated 33 had mRCC. The starting dose of Nivolumab was 1 mg/kg and then expanded to 10 mg/kg. Nine (27%) of the 33 patients had an objective response with nine patients stable at the 24-week follow-up and five of the responding patients with a duration of longer than 1 year. Drug-related adverse events of grade 3 or 4 were observed in 14% of all patients with hypophysitis and pneumonitis as immune mediated adverse events [78]. Currently, nivolumab is under investigation in a Phase III trial in comparison to everolimus in patients with failure after previous TKI treatment [79].

Conclusion

In conclusion, unspecific immunotherapy in the treatment of mRCC has been redeemed by targeted therapies with antiangiogenetic and antiproliferative TKIs. Nevertheless immunotherapy seems to evolve from these unspecific roots towards a well-defined anti-tumor T-cell activation against defined TA As. The IMA901 trial has demonstrated that an induced immune response after immunization with TUMAPs can be associated with a prolonged OS. Currently, other trials evaluate specific antibody blockade for an inhibition of immune checkpoints. The results of these trials will prove whether the respective checkpoint is of relevance for future combinations of immune-guided therapy approaches. Well-established therapie, such as Cy or TKI, have additional immune modulatory capacities whose underlying mechanisms are not fully explored.

The activation of the bodies own defence mechanism to fight cancer – for example, mRCC is a challenging anti-tumor strategy. Currently, the specific induction of a T-cell response against the cancer cell is a major focus in specific immunotherapy. For the future, the distinct mechanism to effectively prime naive T cells and to activate DC cells will be explored. This will require a deeper understanding of the crosstalk between the T-cell subsets, DC, macrophages and MDSC not only in the tumor microenvironment, but also in the systemic circulation.

In the next years, we will obtain results from specific immunotherapy trial, which combine vaccination with additional compounds of T-cell activation. These additional compounds, currently investigated, are sunitinib, butalso involve “classical” immune adjuvants like GM-CSF and systemic modulators like cyclophosphamide. Future trials will be required to evaluate the combinations of specific checkpoint inhibitors with vaccination, for example, peptide vaccination and to evaluate which adjuvants in terms of dosage and timing will be most effective. In addition it should not be neglected that specific immunotherapy does not only consists of vaccination strategies. Another emerging immunotherapy for example is the linkage of two antigens by bispecific antibodies, which can bind to the TA A on the tumour cell and to an effector T cell. The further development of this technique is the recombinant generation of bispecific antibodies with no Fc domains such as the bispecific T-cell engager (BiTE) [80].

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