Clinical potential of PD-1/PD-L1 blockade therapy for renal cell carcinoma (RCC): a rapidly evolving strategy

Abstract

Programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade therapy has become a game-changing therapeutic approach revolutionizing the treatment setting of human malignancies, such as renal cell carcinoma (RCC). Despite the remarkable clinical activity of anti-PD-1 or anti-PD-L1 monoclonal antibodies, only a small portion of patients exhibit a positive response to PD-1/PD-L1 blockade therapy, and the primary or acquired resistance might ultimately favor cancer development in patients with clinical responses. In light of this, recent reports have signified that the addition of other therapeutic modalities to PD-1/PD-L1 blockade therapy might improve clinical responses in advanced RCC patients. Until, combination therapy with PD-1/PD-L1 blockade therapy plus cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitor (ipilimumab) or various vascular endothelial growth factor receptors (VEGFRs) inhibitors axitinib, such as axitinib and cabozantinib, has been approved by the United States Food and Drug Administration (FDA) as first-line treatment for metastatic RCC. In the present review, we have focused on the therapeutic benefits of the PD-1/PD-L1 blockade therapy as a single agent or in combination with other conventional or innovative targeted therapies in RCC patients. We also offer a glimpse into the well-determined prognostic factor associated with the clinical response of RCC patients to PD-1/PD-L1 blockade therapy.

Introduction

Renal cell carcinoma (RCC) denotes cancer resulting from the renal epithelium and includes about 90% of kidney cancers [1]. It includes > 10 histological and molecular subtypes, of which clear cell RCC (ccRCC) is the most common, yielding the most tumor-related deaths [2]. Localized RCC could be efficiently managed with surgery, while showing robust resistance to conventional chemotherapy by metastatic RCC [3, 4]. Nevertheless, groundbreaking advances in the treatment of metastatic RCC have been enabled with targeted compounds including axitinib, sunitinib, sorafenib, bevacizumab, everolimus, temsirolimus, cabozantinib, and pazopanib. They inhibit vascular endothelial growth factor (VEGF) and its receptor (VEGFR) or mechanistic target of rapamycin (mTOR) complex, eliciting an inhibitory effect on angiogenesis [5,6,7].

Currently, immunological analyses of RCC have caused important mechanistic and clinical perceptions. Indeed, immune infiltration properties of RCC are of growing interest by the increase of immune checkpoint inhibitor (ICI) therapy in this condition [8]. Notably, among 19 tumor types evaluated by The Cancer Genome Atlas (TCGA), a landmark cancer genomics program, RCC has the uppermost T cell infiltration score [9]. As well, advanced RCC has association with a rise in T helper 2 (Th2) and T regulatory cell (Tregs) infiltration [10]. These findings confer the importance of immunotherapy-based approaches to moderate RCC progress.

Immune checkpoints (ICs) denote specific membrane molecules situated mainly, but not exclusively, on T lymphocytes [11]. They bind responding ligands on antigen-presenting cells (APCs) like dendritic cells (DCs) or tumor cells [12]. Main cell surface inhibitory ICs encompass programmed cell death receptor-1 (PD-1 or CD279), cytotoxic T lymphocyte antigen-4 (CTLA-4), B and T lymphocyte attenuator (BTLA), lymphocyte activation-gene-3 (LAG-3) and T cell membrane protein-3 (TIM-3) [13, 14]. Apart from anti-angiogenic agents, more attention has been paid to immune checkpoint inhibitors (ICIs) such as nivolumab to manage metastatic RCC [15, 16]. Although conventional therapies such as chemotherapy and radiotherapy directly influence the tumor [17, 18], novel treatments such as the diversity of immunotherapies usually affect the microenvironment and the immune system. In fact, immunotherapeutics, such as ICIs, indirectly eliminate tumor cells through modifying the tumor microenvironment (TME) and/or effector immune cells [15, 19]. During the last decade, the ICIs targeting PD-1/PDL-1 interaction have shown promising results for the second-line treatment of metastatic RCC [20]. They establish apparent advantages such as broad applicability across cancer types and durable clinical response. Nonetheless, anti- PD-1/PDL-1 antibodies as a single agent remain ineffective in about 70–75% of RCC patients, especially in cancers with a low mutational burden [21, 22]. Hence, administration of dual ICI treatments or combining the PD1/PD-L1 blockade therapy with angiogenesis inhibitors and chemo-radiotherapy or other therapeutics might bypass RCC resistance to ICI therapy and also modify treatment-related adverse events (TRAEs) [23, 24].

Herein, we deliver an outline respecting the therapeutic capability of PD-1/PDL-L1 blockade therapy as a single agent or with other modalities for advanced RCC patients. Besides, a glimpse of the most applicable predictive biomarkers affecting a patient’s response to PD-1/PDL-L1 blockade therapy will be delivered.

Immunotherapy for RCC

In principle, tumor progression can be regulated by cytotoxic innate and adaptive immune cells; however, as the tumor develops from neoplastic tissue to clinically detectable tumors, cancer cells evolve various mechanisms that mimic peripheral immune tolerance for deterring tumoricidal attack. Intrinsic mechanisms in cancer cells, including negative regulation of the major histocompatibility complex (MHC) class I and II molecules and/or tumor-associated antigens (TAAs) reduces presentation and resultant targeting by immune effector mechanisms [25, 26]. In addition to the secretion of immunosuppressive biomolecules like interleukin-10 (IL-10) and transforming growth factor-β (TGFβ), cancer cells also release immunosuppressive extracellular vesicles (EVs), in particular, exosomes [27,28,29]. Moreover, overexpressing PD-L1 and Fas ligand and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) are other mechanisms by which tumor cells evade immune attack [

The rationality of targeting the PD-1/PD-L1 axis

Firstly, Ishida et al. discovered the PD-1 inhibitory receptor (CD279) in 1992 [101]. They suggested that PD-1 gene activation contributes to the classical type of programmed cell death [101]. In 1999, Nishimura et al. evinced its role in sustaining the peripheral immune tolerance by researching PD-1-deficient mice models [102]. Based on the literature, activated T cells, NK cells, B cells, macrophages, and DCs express the PD-1 on their surface [103,104,105,106]. The PD-1 expression on naïve T cells is prompted when TCR is activated [107]. This short-term expression is diminished in the absence of TCR signaling while increasing upon chronic activation, such as in chronic viral infections as well as tumors. The connection between PD-1 and its ligand, PD-L1, expressed on the cancer cell surface, barriers TCR signaling and CD28 co-stimulation and ultimately causes down-regulated T cell activity and ensuing tumor evasion [108].

The PD-1/PD-L1 interaction triggers signaling via the cytoplasmic tail of PD-1, resulting in T cell depletion. The PD-1 cytoplasmic tail consists of two tyrosine-based structural motifs, an immunoreceptor tyrosine-based inhibitory motif (ITIM) (V/L/I/XpYXX/L/V) and an immunoreceptor tyrosine-based switch motif (ITSM) (TXpYXXV/I) [109]. As a result of activation by PD-L1, the PD-1 phosphorylation occurs by Src kinases at ITIM and ITSM motifs. ITSM phosphotyrosine underlies the PD-1-mediated suppressive activities by recruiting Src homology region 2 domain-containing phosphatase-2 (SHP-2) [109, 110]. SHP-2 eliminates phosphate groups from neighboring effector proteins, in particular, PI3K and AKT, finally decreasing both cytokine manufacture and T cell growth [109]. Further, the nuclear factor kappa B (NF-κB) and mammalian target of rapamycin (mTOR) activation accompanied with the IL-2 and B-cell lymphoma-extra large (Bcl-xL) expression are decreased in activated T cells following PD-1/PD-L1 interaction. These events, in turn, inhibit T cells proliferation, cytotoxicity, and cytokine release, promote the apoptosis of tumor-specific T cells, up-regulate the differentiation of CD4+ T cells into foxp3+ Tregs, and finally potentiates tumor cell's resistance to CTL attack [111, 112]. In the lack of PD-1 signaling, number of long-lived plasma cells was evidently decreased [113]. Improved expression of PD-L1 is usually found in cancers and correlates with metastatic disease stage and undesired prognosis in RCC, gastric cancer, melanoma, breast cancer and etc. [114,115,116]. Iacovelli et al. (2016) demonstrated that PD-L1 was expressed in 24.2% of RCC tumors, and a higher level of PD-L1 expression augmented the risk of death by 81% [117]. Another study on 1,644 patients also signified the association between PD-L1 expression and OS in RCC patients [178, 179].

Combination therapy

In the last years, researchers have sought various approaches to potentiate the efficacy and ameliorate the safety profile of atezolizumab in RCC patients. In this regard, anti-angiogenic drugs, in particular bevacizumab and cabozantinib, have attracted growing attention [6, 180]. A randomized phase 2 IMmotion150 study provides clear evidence that combination therapy with atezolizumab and bevacizumab has superiority over sunitinib in terms of the PFS [181]. Interestingly, biomarker analyses showed that tumor mutation burden (TMB) and neoantigen burden has no association with PFS. It was thus suggested that blocking VEGF by bevacizumab may defeat resistance to atezolizumab [179, 181]. After that, a phase 3 trial IMmotion151 study indicated that atezolizumab 1200 mg plus bevacizumab 15 mg/kg intravenously once every 3 weeks improved PFS more evidently than sunitinib (11.2 months versus 7.7 months) in RCC patients with better safety profile [175]. These results authenticated the clinical activity of atezolizumab plus bevacizumab as a first-line treatment for RCC. Notwithstanding, the final analysis of phase 3 IMmotion151 trial displayed no significant enhancement in OS with atezolizumab plus bevacizumab over sunitinib for previously untreated RCC patients [182, 183]. As a result, FDA has not yet approved this treatment regimen for RCC, while atezolizumab plus bevacizumab has previously been approved for other tumors, such as HCC [174]. Besides, another trial showed that the addition of the PEG-IFNα-2a to atezolizumab might have preliminary clinical activity and acceptable tolerability in advanced RCC patients [184]. As described, IFN-α improves tumor immunogenicity and DC response to the tumor, augments Th1/Th2 ratio, and thus potentiates T cell-mediated cytotoxicity [185, 186]. Although IFN-α plus bevacizumab has been approved for RCC [187, 188], its clinical activity when used plus atezolizumab is being investigated and has not yet strongly been documented. Further, Jung et al. reports (2019) for the first time signified that the addition of indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, navoximod, to atezolizumab might improve its efficacy in advanced tumors like RCC [189]. IDO1 triggers immune suppression in T cells by l-tryptophan depletion and kynurenine collections in the TME, suppressing CTL and Th1 cells and promoting Tregs activity [190, 191]. Thus, targeting its activity may be a rational strategy to alleviate tumor progress [192, 193]. Achieved results implied that a combination of navoximod and atezolizumab had acceptable safety, tolerability, and pharmacokinetics for patients with advanced tumors such as RCC [189]. Nonetheless, further information is required to corroborate the benefit of adding navoximod to atezolizumab.

Avelumab

Avelumab (Bavencio®) is an IgG1 mAb directed to PD-L1 that was discovered by Merck KGaA and Pfizer [194]. As a single agent, it has been approved for the metastatic Merkel cell carcinoma (MCC) [195] and also UC [196]. FDA also approved avelumab in combination with axitinib for the first-line treatment of advanced RCC patients [197].

Monotherapy

Study of the safety and efficacy and avelumab monotherapy in patients with advanced RCC verified its clinical activity in a phase 1 trial [198]. Meanwhile, avelumab 10 mg/kg intravenously every 2 weeks led to an ORR of about 16.1%, with median DOR and PFS about 9.9 and months 8.3, respectively [198]. Also, the intervention showed a manageable safety profile [198]. Nonetheless, there was no further proof showing the clinical activity of avelumab as a single agent in phase 2/3 trials. As described, avelumab monotherapy is indicated for UC and MCC based on results from phase 3 JAVELIN Bladder 100 and JAVELIN Merkel 200 study, respectively. It’s acceptable safety profile and capability to stimulate durable responses in otherwise deadly tumors offer the justification for its application in other tumor types and in combination with other therapeutic approaches.

Combination therapy

Recently, a phase 3 JAVELIN Renal 101 study on 886 RCC patients exhibited that the addition of the axitinib to avelumab caused objective responses in patients with advanced RCC [199, 200]. Motzer et al. showed that avelumab 10 mg/kg intravenously every 2 weeks plus axitinib 5 mg orally twice daily had superiority over sunitinib 50 mg orally once daily for 4 weeks in terms of ORR and PFS [199]. The median PFS in PD-L1-positive tumors was 13.8 months in the combination therapy arm compared with 7.2 months in the sunitinib arm [199, 201]. In the same population, ORR was 55.2% versus 25.5% in the combination therapy arm compared with the sunitinib arm. These results suggested this regimen as a first-line treatment for advanced RCC [199, 201]. In May 2019, based on the JAVELIN Renal 101 study results, the FDA approved avelumab in combination with axitinib for the first-line treatment of people with advanced RCC. Study of the possible prognostic factor presented NLR as a prognostic biomarker in advanced RCC patients who underwent avelumab plus axitinib or sunitinib administration [202]. There was an association with baseline NLR and OS, and PFS in advanced RCC patients who received avelumab plus axitinib [202]. Accordingly, patients with below-median NLR experienced extended PFS and OS. Interestingly, median PFS was 13.8 and 11.2 months in RCC patients with below-median NLR and 13.3 and 5.6 months in patients with median-or-higher NLR [202]. These analyses confer the role of NLR in underlying mechanisms affecting clinical outcomes.

A brief overview of clinical trials targeting PD-L1 alone or in combination with other treatments in RCC patients has been delivered in Table 2.

Table 2 Anti-PD-L1 antibody alone or in combination with other treatments in RCC patients

Small molecule compounds inhibiting PD-1/PD-L1 interactions

The restricted success and shortcoming of antibodies have persuaded investigators to examine more efficient approaches for the negative regulation of the PD-1/PD-L1 axis and expand the capacity of cancer immunotherapy. In light of this, substantial efforts are being made to develop low-molecular-weight agents targeting PD-1/PD-L1 interaction [203]. Currently, several companies, including Bristol Myers Squibb (BMS), Arising International Inc, Guangzhou Maxinovel Pharmaceuticals Co, Chemocentryx Inc, Institute of Materia Medica, Incyte Corporation, and Aurigene, have industrialized a variety of small-molecule chemical compounds as well as peptides [204]. Such companies have applied for a series of patents related to inhibitors. These patents offered the structure of PD-1/PD-L1 inhibitors, compound synthesis strategies, and their application as immunomodulators [205]. Further, the patents demonstrate the approved inhibitory impacts of these inhibitors. While some of the evolved small molecule compounds might only deter PD-L1/PD-1 interactions, other inhibitors (e.g., peptides invented by BMS Company) suppress PD-L1 interactions with PD-1 or B7-1 [206]. All inhibitors advanced by Aurigene, such as small molecule chemical compounds and peptides, demonstrated significant inhibitory impact on the PD-1 signaling axis [207]. Notably, most of them demonstrated IC50 values of 1 μM or even 0.018 μM as determined by the PD-1/PD-L1 homogenous time-resolved fluorescence (HTRF) binding assay [204]. Of course, the progress of small molecule compounds inhibiting PD-1/PD-L1 interactions has only just been ongoing. Most of these inhibitors are studied in preclinical studies and are associated with stimulating outcomes [208]. Meanwhile, CA-170, a PD-L1 inhibitor developed by Aurigene and Curis, has arrived phase I clinical trial [209]. Further focus on these novel types of PD-/PD-L1 inhibitors may result in groundbreaking progress in the next future.

Conclusion and future direction

The treatment setting of advanced RCC has progressed in the last years with emerging ICIs accompanied by the advancement development of novel anti-angiogenic drugs and other therapeutics (Tables 3 and 4). This progress brought about the amelioration of prognosis and improvement of OS and PFS in advanced RCC patients. Nevertheless, there is no head-to-head trial proof to compare the efficacy of the several therapeutic modalities available comprising ICIs, TKIs, or a combination of both. Facts from the further prospective investigation are requisite to directly compare the clinical advantage of ICI in the treatment of clear cell RCC and various subtypes of non-clear cell RCC.

Table 3 Completed clinical trials based on monotherapy with anti-PD-1/PD-L1 therapy for renal cell carcinoma (RCC) registered in ClinicalTrials.gov (June 2022)

Table 4 Completed clinical trials based on combination therapy with anti-PD-1/PD-L1 therapy for renal cell carcinoma (RCC) registered in ClinicalTrials.gov (June 2022)

Several reports have tried to predict ICIs’ response exploiting several parameters, including the clinical features, laboratory parameters (e.g., NLR), lactate dehydrogenase (LDH), tumor markers, and genetic landscape [210]. Most of them have caused a poor performance because of the absence of comprehensive evaluation in risk stratification. Recent investigations have exhibited that the anti-tumor response to ICIs is a multifaceted process complicating several factors. Previous reports have evolved various prognostic models for prognostic evaluation in ICIs therapy. For instance, a risk scoring criteria comprising monocyte-to-lymphocyte ratio (MLR), sites of metastasis, and nutritional index–body mass index (BMI) were progressed for various for human tumors, in particular RCC patients, who received ICIs [

Availability of data and materials

Not applicable.