**5. Immune checkpoint inhibitors**

Peptides derived from tumor-associated antigens are presented via MHC I and II epitopes to stimulate CD8<sup>+</sup> and CD4+ T cells, respectively [30]. The binding of the T-cell receptor (TCR) to the peptide presented by MHC requires further co-stimulatory signals, resulting in the activation of downstream pathways and secretion of cytotoxic molecules, such as granzyme and perforin [31]. Regulatory mechanisms exist to weaken or inhibit immune response, avoiding excessive autoimmune response. These breaks in the immune system are often referred to as "immune checkpoints," including PD-1/PD-L1, CTLA4/CD80, and so on. Immune checkpoint proteins on CTLs cut off co-stimulatory signals after ligand binding and give rise to T-cell anergy and immune suppression. However, immune checkpoint proteins may become dysregulated under tumor settings, typically via an overexpression of inhibitory ligands and receptors [32]. Blocking these immune checkpoint proteins could improve the capability of CTL to mount and maintain an effective T-cell response [32–34].

Over the past decade, immune checkpoint inhibition (ICI) has become a major focus of research given its durable response rates and promising survival benefits in various malignancies. Current ICIs include the cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) antibodies (ipilimumab and tremelimumab), the programmed cell death protein 1 (PD-1) antibodies (nivolumab, pembrolizumab, and pidilizumab), and the programmed cell death protein ligand 1 (PD-L1) antibodies (atezolizumab, BMS-936559, durvalumab, and avelumab) [35] (**Figure 2**). Multiple clinical trials studying the efficacy of these agents on mRCC are being conducted (**Table 1**), among which nivolumab is the only agent approved for the treatment of mRCC by USFDA in 2015 [36].

**Figure 2.** Immune checkpoint inhibitors and agonists being tested in renal cell carcinoma.

Checkpoint inhibitors cause immune-associated adverse events due to hyper-activated T-cell response in healthy tissues. The most common adverse reactions include skin rash, fatigue, and colitis. The incidence and grade of toxicities caused by CTLA-4 antibodies are greater than PD-1/PD-L1-directed monotherapy. Asymptomatic hepatitis and endocrinopathies are also occasionally encountered. Other rare, affected organs include eyes, lungs, kidneys, pancreas, and the hematologic system [37].

T-cell activation is regulated by various co-stimulatory and inhibitory checkpoints. Both agonistic antibodies to activating receptors and blocking antibodies to inhibitory receptors can stimulate T-cell activity and are being tested in advanced renal cell carcinoma and other solid tumors. Activation of T-cells first requires an antigen-presenting cell (APC), such as a dendritic cell, to present an antigen. Here, an APC presents a tumor antigen complexed to major histocompatibility complex (MHC) class I to the T-cell via the T-cell receptor (TCR). Co-stimulatory signals are also needed at this time. At this point, B7 on an APC can bind to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) creating an inhibitory signal, but ipilimumab or tremelimumab—CTLA-4 antibodies—can inhibit the inhibitory signal by binding to CTLA-4 and promote T-cell activation. Once the activated T-cell is in the tumor environment it can recognize the antigen presented by an APC cell in the tumor. At this time, the programmed cell death protein 1 (PD-1) receptor can also send an inhibitory signal to the T-cell when the receptor binds to programmed cell death 1 ligand 1 (PD-L1), which is often expressed on tumor cells. Inhibition of PD-L1 or PD-1 could block that signal. Several PD-1 inhibitors are under investigation for RCC, including pembrolizumab and pidilizumab, and

**Agent and trial**

Nivolumab

III

Advanced and

Second trial

Arm A: nivolumab 3

every 2 weeks

Arm B: everolimus 10

every 2 weeks

 mg

 mg/kg

Open-label, 1:1 randomized

821 • 25

• 19

•

everolimus:

37%

ORR

•

nivolumab:

25%

• 5%

PFS (months)

• 4.6

• 4.4

everolimus:

nivolumab:

everolimus:

everolimus:

•

nivolumab: 19%

(*<sup>P</sup>* = 0.002)

nivolumab:

AEs:

OS (months)

Grade 3–4

treatment-related

metastatic RCC

Prior systemic

therapies:

antiangiogenic

therapy

MSKCC risk

group:

•

favorable:

36%

• •

> NCT01354431

II

Metastatic RCC

Second

Blinded, 1:1 randomized trial

168

OS (months)

Grade 3–4

No doseresponse

[46]

treatment-related

Arm A: nivolumab 0.3

every 3 weeks

Arm B: nivolumab 2

every 3 weeks

Arm C: nivolumab 10

every 3 weeks

 mg/kg

 mg/kg

• ORR

• • •

Arm C: 20%

PFS (months)

Immunotherapy for Renal Cell Carcinoma http://dx.doi.org/10.5772/intechopen.77377 49

• • •

Arm C: 4.2

Arm B: 4.0

Arm A: 2.7

Arm B: 22%

Arm A: 20%

Arm C: 24.7

• •

Arm C: 13%

Arm B: 17%

 mg/kg

• •

Arm B: 25.5

•

Arm A: 5%

Arm A: 18.2

AEs:

relationship

was detected as

measured by PFS

Prior systemic

therapies:

Antiangiogenic

therapy

poor: 15%

intermediate: 49%

(CheckMate

025/

NCT01668784)

**Phase**

**Population**

**Line**

**Design**

*n*

**Response**

**Toxicities**

**Comments** Hazard ratio

[36]

for death with

nivolumab = 0.73

**Refs**


Checkpoint inhibitors cause immune-associated adverse events due to hyper-activated T-cell response in healthy tissues. The most common adverse reactions include skin rash, fatigue, and colitis. The incidence and grade of toxicities caused by CTLA-4 antibodies are greater than PD-1/PD-L1-directed monotherapy. Asymptomatic hepatitis and endocrinopathies are also occasionally encountered. Other rare, affected organs include eyes, lungs, kidneys, pan-

**Figure 2.** Immune checkpoint inhibitors and agonists being tested in renal cell carcinoma.

T-cell activation is regulated by various co-stimulatory and inhibitory checkpoints. Both agonistic antibodies to activating receptors and blocking antibodies to inhibitory receptors can stimulate T-cell activity and are being tested in advanced renal cell carcinoma and other solid tumors. Activation of T-cells first requires an antigen-presenting cell (APC), such as a dendritic cell, to present an antigen. Here, an APC presents a tumor antigen complexed to major histocompatibility complex (MHC) class I to the T-cell via the T-cell receptor (TCR). Co-stimulatory signals are also needed at this time. At this point, B7 on an APC can bind to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) creating an inhibitory signal, but ipilimumab or tremelimumab—CTLA-4 antibodies—can inhibit the inhibitory signal by binding to CTLA-4 and promote T-cell activation. Once the activated T-cell is in the tumor environment it can recognize the antigen presented by an APC cell in the tumor. At this time, the programmed cell death protein 1 (PD-1) receptor can also send an inhibitory signal to the T-cell when the receptor binds to programmed cell death 1 ligand 1 (PD-L1), which is often expressed on tumor cells. Inhibition of PD-L1 or PD-1 could block that signal. Several PD-1 inhibitors are under investigation for RCC, including pembrolizumab and pidilizumab, and

creas, and the hematologic system [37].

48 Evolving Trends in Kidney Cancer


nivolumab was recently FDA approved for patients with RCC who have failed prior antiangiogenic therapy. PD-L1 inhibitors under investigation include atezolizumab, BMS-936559, durvalumab, and avelumab. In addition to inhibitory receptors, several activating receptors exist that stimulate T-cell activity, including CD137, CD27, OX40, and GITR. Similarly, several agonist antibodies target these receptors which are under investigation for RCC. These include urelumab targeting CD137, varlilumab targeting CD27, MEDI10562 targeting OX40,

NK cells and B cells. The expression of PD-1 is increased by several cytokines, such as IL-2, IL-7, IL-15, and IL-21. PD-1 belongs to the CD28/CTLA-4 superfamily and has an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM) which is able to recruit tyrosine phosphatases, anti-SRC homology phosphatase (SHP)-1 and SHP-2, to modulate inhibitory signaling [38, 39]. When interacting with its ligands, PD-1 suppresses signaling pathways that are involved in T-cell activity [32, 40]. Blockade of PD-1 was evaluated and the initial clinical trial demonstrated impressive antitumor response in several refractory cancer types, including RCC [41]. Thompson and his colleagues examined the expression of PD-1 and PD-L1 in a large number of renal tumors and found PD-1 being expressed in 56% of patient tumors with mononuclear cell infiltration. In addition, PD-1 expression was correlated with advanced tumor stage and worse survival in RCC patients [42–44].

Nivolumab is a fully human immunoglobulin (Ig) G4 anti-PD-1 monoclonal antibody that selectively inhibits the interaction between PD-1 and its ligands PD-L1 and PD-L2. Several clinical trials of nivolumab have been performed for RCC (**Table 1**). In a phase I study that enrolled 33 patients with mRCC, nivolumab demonstrated an objective response rate of 27% and a manageable safety profile; responses were durable [45]. A phase II study enrolled 168 patients with mRCC who had received previous treatment targeting the vascular endothelial growth factor (VEGF) pathway. Nivolumab was dosed at 0.3, 2, or 10 mg/kg every 3 weeks and showed antitumor activity with no dose-response relationship observed. There was no association between nivolumab dosage and the number of adverse events (AEs), which suggested that the incidence of immune-related AEs was limited [46]. Moreover, a randomized phase III study (Check Mate 025) evaluating nivolumab (3 mg/kg every 2 weeks) versus second-line everolimus (10 mg orally every day, pretreated with antiangiogenic therapy) represented a 5.4-month improvement in median OS (25 months and 19.6 months, respectively). Although the ORR was significantly higher in the nivolumab group than in the everolimus group (25% versus 5%, odds ratio: 5.98 [95% CI, 3.68–9.72], p < 0.001), PFS was similar (4.6 versus 4.4 months, HR 0.88 [95% CI, 0.75–1.03], p = 0.11). This is the first time that an immune checkpoint inhibitor has demonstrated an OS benefit when compared with patients treated with TKIs for mRCC. The exact mechanism behind the discrepancy between PFS and OS is still unknown, and the authors hypothesized that there might be a potential delayed

and CD8<sup>+</sup>

Immunotherapy for Renal Cell Carcinoma http://dx.doi.org/10.5772/intechopen.77377 51

T cells as well as

and MK-4166 and TRX518 targeting GITR.

PD-1 (CD279) is a cell surface receptor that is expressed on CD4<sup>+</sup>

**5.1. Anti-PD-1 antibodies**

*5.1.1. Nivolumab*

nivolumab was recently FDA approved for patients with RCC who have failed prior antiangiogenic therapy. PD-L1 inhibitors under investigation include atezolizumab, BMS-936559, durvalumab, and avelumab. In addition to inhibitory receptors, several activating receptors exist that stimulate T-cell activity, including CD137, CD27, OX40, and GITR. Similarly, several agonist antibodies target these receptors which are under investigation for RCC. These include urelumab targeting CD137, varlilumab targeting CD27, MEDI10562 targeting OX40, and MK-4166 and TRX518 targeting GITR.

#### **5.1. Anti-PD-1 antibodies**

PD-1 (CD279) is a cell surface receptor that is expressed on CD4<sup>+</sup> and CD8<sup>+</sup> T cells as well as NK cells and B cells. The expression of PD-1 is increased by several cytokines, such as IL-2, IL-7, IL-15, and IL-21. PD-1 belongs to the CD28/CTLA-4 superfamily and has an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM) which is able to recruit tyrosine phosphatases, anti-SRC homology phosphatase (SHP)-1 and SHP-2, to modulate inhibitory signaling [38, 39]. When interacting with its ligands, PD-1 suppresses signaling pathways that are involved in T-cell activity [32, 40]. Blockade of PD-1 was evaluated and the initial clinical trial demonstrated impressive antitumor response in several refractory cancer types, including RCC [41]. Thompson and his colleagues examined the expression of PD-1 and PD-L1 in a large number of renal tumors and found PD-1 being expressed in 56% of patient tumors with mononuclear cell infiltration. In addition, PD-1 expression was correlated with advanced tumor stage and worse survival in RCC patients [42–44].

#### *5.1.1. Nivolumab*

**Agent and trial**

NCT01358721

Ib

Metastatic RCC

First,

Arm A: previously treated

91

OS (months)

Grade 3–4

treatment-related

•

Arm A: 16.4

AEs:

second

group

Nivolumab 0.3

3 weeks

Arm B: previously treated

group

Nivolumab 2

3 weeks Arm C: previously treated

group

Nivolumab 10

3 weeks

Arm D: treatment-naive

group

Nivolumab 10

3 weeks

Nivolumab and

I

•

Previously

First,

Randomized trial of three

100 ORR:

Treatment in Arm

Median OS

J.

Clin. Oncol.

32:5s (Suppl.),

4504 (2014).

not reached

with median

follow-up

duration ranging

from 46 to

90 weeks

C stopped owing to

toxicity

Grade 3–4

treatment related

•

ArmA:38%

treated or

second

dosing cohorts:

•

Arm A: nivolumab 3

kg plus ipilimumab 1

kg every 3

weeks × 4

PFS at 24 weeks:

 mg/

 mg/

•

ArmB:40%

treatmentnaive

> •

All MSKCC

risk groups

•

Arm B: nivolumab 1

kg plus ipilimumab 3

kg every 3

> •

Arm C: nivolumab 3

kg ipilimumab 3

kg every 3 weeks × 4 All

followed by nivolumab

3

mg/kg every 2 weeks

until substantial disease

•

ArmB:

81 weeks

progression or toxicity

**Table 1.**

Results of immune checkpoint inhibitors in patients with renal cell carcinoma.

 mg/

 mg/

weeks × 4

 mg/

•

ArmB:68%

•

ArmA:34%

Median duration

• •

ArmC:83%

ArmB:64%

of response:

•

ArmA:

67 weeks

 mg/

•

ArmA:54%

AEs:

permitted

ipilimumab

mg/kg every

mg/kg every

mg/kg every

ORR

• • • •

Arm D: 13%

Arm C: 22%

Arm B: 18%

Arm A: 9%

mg/kg every

• • •

Arm D: NR

• •

Arm D: 50%

Arm C: 57%

Arm C: 25.2

•

Arm B: 36%

Arm B: NR

•

Arm A: 68%

Prior systemic

therapies: not

specified

**Phase**

**Population**

**Line**

**Design**

*n*

**Response**

**Toxicities**

**Comments** This is the first

Clin

Cancer Res

2016;22:5461–71.

50 Evolving Trends in Kidney Cancer

prospective

translational

study involving

analysis of both

baseline and

on-treatment

biopsies in RCC

**Refs**

Nivolumab is a fully human immunoglobulin (Ig) G4 anti-PD-1 monoclonal antibody that selectively inhibits the interaction between PD-1 and its ligands PD-L1 and PD-L2. Several clinical trials of nivolumab have been performed for RCC (**Table 1**). In a phase I study that enrolled 33 patients with mRCC, nivolumab demonstrated an objective response rate of 27% and a manageable safety profile; responses were durable [45]. A phase II study enrolled 168 patients with mRCC who had received previous treatment targeting the vascular endothelial growth factor (VEGF) pathway. Nivolumab was dosed at 0.3, 2, or 10 mg/kg every 3 weeks and showed antitumor activity with no dose-response relationship observed. There was no association between nivolumab dosage and the number of adverse events (AEs), which suggested that the incidence of immune-related AEs was limited [46]. Moreover, a randomized phase III study (Check Mate 025) evaluating nivolumab (3 mg/kg every 2 weeks) versus second-line everolimus (10 mg orally every day, pretreated with antiangiogenic therapy) represented a 5.4-month improvement in median OS (25 months and 19.6 months, respectively). Although the ORR was significantly higher in the nivolumab group than in the everolimus group (25% versus 5%, odds ratio: 5.98 [95% CI, 3.68–9.72], p < 0.001), PFS was similar (4.6 versus 4.4 months, HR 0.88 [95% CI, 0.75–1.03], p = 0.11). This is the first time that an immune checkpoint inhibitor has demonstrated an OS benefit when compared with patients treated with TKIs for mRCC. The exact mechanism behind the discrepancy between PFS and OS is still unknown, and the authors hypothesized that there might be a potential delayed benefit in PFS with nivolumab. Nivolumab was very well tolerated, and a lower proportion of patients developed grade 3 or 4 treatment-related AEs (19 and 37%, respectively), including fatigue, nausea, and diarrhea, which suggested that the safety profile of nivolumab was favorable [36]. Nivolumab was approved by the FDA for pretreated advanced clear-cell RCC in November 2015 [36, 41, 46, 47] and is still under investigation as pre- and postoperative therapy in mRCC (ADAPTeR) (NCT02446860) and is also being studied in combination with other drugs (NCT01472081, NCT02231749, NCT02210117, NCT02335918, and NCT02614456).

*5.2.1. Atezolizumab*

*5.2.2. BMS-936559*

*5.2.3. Avelumab*

*5.2.4. Durvalumab*

advanced malignancies including RCC.

**5.3. Anti-CTLA-4 antibodies**

17 months, respectively [59].

>1 and 9% in those with <1% PD-L1 expression) [58].

Atezolizumab (MPDL3280A), a fully humanized monoclonal IgG1 antibody against PD-L1, is being evaluated in different cancers, including RCC. It has showed promising results in a multicenter phase I trial involving 17 mRCC patients. The ORR was 12% with responses that lasted for 4–17 months. Seven patients (41%) had stable disease for more than 24 weeks [55]. In another phase Ia study, of the 63 patients with clear-cell RCC that were evaluable, median PFS was 5.6 months and median OS was 28.9 months. The ORR was 15% (18% in patients with

Immunotherapy for Renal Cell Carcinoma http://dx.doi.org/10.5772/intechopen.77377 53

BMS-936559 (MDX-1105) is a fully human monoclonal antibody with high affinity to PD-L1 and blocks the binding of PD-L1 to both PD-1 and B7.1. In a phase I trial of evaluating BMS-936559 in 207 patients with different advanced cancer types, 17 patients had mRCC. The study showed that 2 of 17 RCC patients had an objective response with response durations for 4 and

Avelumab (MSB0010718C) is a fully human IgG1 monoclonal antibody against PD-L1 and inhibits PD-1-PD-L1 interactions. It also has a native Fc region that could induce antibody-dependent cell-mediated cytotoxicity (ADCC). In a phase Ib, open-label expansion study, avelumab was used in patients with advanced solid tumors and showed an acceptable safety profile [60]. Two ongoing trials evaluate avelumab in combination with axitinib (NCT02493751, NCT02684006).

Durvalumab (MEDI4736) is another human anti-PD-L1 IgG1 monoclonal antibody. It blocks PD-L1 binding to PD-1 and CD80, with no binding to PD-L2. ADCC and complement-dependent cytotoxicities are removed by an engineered triple mutation in the Fc domain. A Phase 1/2, multicenter, open-label study which evaluated the safety and clinical activity of the drug in patients with multiple solid tumor types such as non-small cell lung cancer noted a very manageable safety profile [61]. There are ongoing trials evaluating durvalumab in combination with other drugs, including tremelimumab (NCT01975831) and MEDI0680 (AMP-514) (a humanized IgG4 monoclonal antibody against PD-1) (NCT02118337) for patients with

In addition to the PD-1/PD-L1 checkpoint, CTLA-4, an immune checkpoint on the surface of cytotoxic T-cells, counteracts the action of the co-stimulatory receptor CD28 and plays a key role in the immune response. Both CTLA-4 and CD28 bind identical ligands CD80 and CD86 (called B7-1 and B7-2), but CTLA4 has a higher affinity for both ligands than CD28. Therefore, CTLA4 can antagonize CD28-ligand interactions by competing for ligand binding. In addition,

#### *5.1.2. Pembrolizumab*

Pembrolizumab (formerly known as MK3475 or lambrolizumab), a highly selective humanized IgG4 monoclonal antibody against PD-1, has been approved for metastatic melanoma, head and neck cancer, and non-small cell lung cancer (NSCLC) mainly as combinational therapy. Pembrolizumab is currently being investigated in two randomized phase II trials of mRCC patients [48]. A phase I/II study (KEYNOTE-029) involving pembrolizumab plus ipilimumab or pegylated interferon alfa-2b (PEGIFN) in patients with advanced melanoma and RCC reported an acceptable safety profile [49]. Nowadays, several trials evaluating pembrolizumab in combination with various agents with different mechanisms are ongoing (NCT02014636, NCT02133742, NCT02348008, NCT02089685, NCT02501096, NCT02619253, NCT02298959, NCT02646748, NCT02178722, and NCT02475213). The most common adverse events were fatigue, pruritus, and dyspnea. Antitumor activity was observed [50].

#### *5.1.3. Pidilizumab*

Pidilizumab (CT-011), another humanized IgG1 kappa monoclonal antibody targeting PD-1, is already under evaluation in several hematologic malignancies, including acute myeloid leukemia (AML), multiple myeloma, Hodgkin lymphoma, non-Hodgkin lymphoma, and chronic lymphocytic leukemia [51]. There are several efforts under way to assess the agent in several solid tumors. As for mRCC, a study is currently under way to assess the combination of pidilizumab with a novel dendritic cell (DC) fusion cell vaccine (NCT01441765). The first group will receive pidilizumab at a dose of 3 mg/kg every 2 weeks intravenously, for a total of 4 cycles. The second group will receive infusions of an autologous DC vaccine during 2–4 cycles of pidilizumab therapy. The noted trial of pidilizumab with an autologous DC vaccine is of substantial interest, especially with emerging vaccine-based therapies, such as AGS-003 and IMA901 [52–54].

#### **5.2. Anti-PD-L1 antibodies**

The encouraging results of PD-1 antibodies in cancer management inspired interest in the inhibition of the PD-1 ligands, namely PD-L1. PD-L1 is expressed on a variety of cells, including cancer cells, APCs, T-cells, B cells, and myeloid cells. PD-L1 inhibits T-cell proliferation and adhesion, as well as cytokine production [17, 55, 56]. PD-L1 expression was detected by immune staining in the RCC tissue, and PD-L1 expression by tumor cells (>10%), on infiltrating lymphocytes (>50%), or the composite of both makers was strongly associated with poor prognosis [42, 57].

#### *5.2.1. Atezolizumab*

benefit in PFS with nivolumab. Nivolumab was very well tolerated, and a lower proportion of patients developed grade 3 or 4 treatment-related AEs (19 and 37%, respectively), including fatigue, nausea, and diarrhea, which suggested that the safety profile of nivolumab was favorable [36]. Nivolumab was approved by the FDA for pretreated advanced clear-cell RCC in November 2015 [36, 41, 46, 47] and is still under investigation as pre- and postoperative therapy in mRCC (ADAPTeR) (NCT02446860) and is also being studied in combination with other drugs (NCT01472081, NCT02231749, NCT02210117, NCT02335918, and NCT02614456).

Pembrolizumab (formerly known as MK3475 or lambrolizumab), a highly selective humanized IgG4 monoclonal antibody against PD-1, has been approved for metastatic melanoma, head and neck cancer, and non-small cell lung cancer (NSCLC) mainly as combinational therapy. Pembrolizumab is currently being investigated in two randomized phase II trials of mRCC patients [48]. A phase I/II study (KEYNOTE-029) involving pembrolizumab plus ipilimumab or pegylated interferon alfa-2b (PEGIFN) in patients with advanced melanoma and RCC reported an acceptable safety profile [49]. Nowadays, several trials evaluating pembrolizumab in combination with various agents with different mechanisms are ongoing (NCT02014636, NCT02133742, NCT02348008, NCT02089685, NCT02501096, NCT02619253, NCT02298959, NCT02646748, NCT02178722, and NCT02475213). The most common adverse

events were fatigue, pruritus, and dyspnea. Antitumor activity was observed [50].

Pidilizumab (CT-011), another humanized IgG1 kappa monoclonal antibody targeting PD-1, is already under evaluation in several hematologic malignancies, including acute myeloid leukemia (AML), multiple myeloma, Hodgkin lymphoma, non-Hodgkin lymphoma, and chronic lymphocytic leukemia [51]. There are several efforts under way to assess the agent in several solid tumors. As for mRCC, a study is currently under way to assess the combination of pidilizumab with a novel dendritic cell (DC) fusion cell vaccine (NCT01441765). The first group will receive pidilizumab at a dose of 3 mg/kg every 2 weeks intravenously, for a total of 4 cycles. The second group will receive infusions of an autologous DC vaccine during 2–4 cycles of pidilizumab therapy. The noted trial of pidilizumab with an autologous DC vaccine is of substantial interest, especially with emerging vaccine-based therapies, such as

The encouraging results of PD-1 antibodies in cancer management inspired interest in the inhibition of the PD-1 ligands, namely PD-L1. PD-L1 is expressed on a variety of cells, including cancer cells, APCs, T-cells, B cells, and myeloid cells. PD-L1 inhibits T-cell proliferation and adhesion, as well as cytokine production [17, 55, 56]. PD-L1 expression was detected by immune staining in the RCC tissue, and PD-L1 expression by tumor cells (>10%), on infiltrating lymphocytes (>50%), or the composite of both makers was strongly associated with poor

*5.1.2. Pembrolizumab*

52 Evolving Trends in Kidney Cancer

*5.1.3. Pidilizumab*

AGS-003 and IMA901 [52–54].

**5.2. Anti-PD-L1 antibodies**

prognosis [42, 57].

Atezolizumab (MPDL3280A), a fully humanized monoclonal IgG1 antibody against PD-L1, is being evaluated in different cancers, including RCC. It has showed promising results in a multicenter phase I trial involving 17 mRCC patients. The ORR was 12% with responses that lasted for 4–17 months. Seven patients (41%) had stable disease for more than 24 weeks [55]. In another phase Ia study, of the 63 patients with clear-cell RCC that were evaluable, median PFS was 5.6 months and median OS was 28.9 months. The ORR was 15% (18% in patients with >1 and 9% in those with <1% PD-L1 expression) [58].
