Cancer Immunology, Immunotherapy

, Volume 66, Issue 5, pp 551–564 | Cite as

PD-1 and PD-L1 antibodies in cancer: current status and future directions

Review

Abstract

Immunotherapy has moved to the center stage of cancer treatment with the recent success of trials in solid tumors with PD-1/PD-L1 axis blockade. Programmed death-1 or PD-1 is a checkpoint molecule on T cells that plays a vital role in limiting adaptive immune responses and preventing autoimmune and auto-inflammatory reactivity in the normal host. In cancer patients, PD-1 expression is very high on T cells in the tumor microenvironment, and PD-L1, its primary ligand, is variably expressed on tumor cells and antigen-presenting cells within tumors, providing a potent inhibitory influence within the tumor microenvironment. While PD-L1 expression on tumors is often regarded as a negative prognostic factor, it is clearly associated with a positive outcome for treatment with PD-1/PD-L1 blocking antibodies, and has been used to select patients for this therapy. Responses of long duration, a minority of patients with atypical responses in which progression may precede tumor shrinkage, and a pattern of autoimmune side effects often seen with this class of drugs characterize therapy with PD-1/PD-L1 blocking drugs. While excellent efficacy has been seen with a limited number of tumor types, most epithelial cancers do not show responses of long duration with these agents. In the current review, we will briefly summarize the scientific background data supporting the development of PD-1/PD-L1 blockade, and then describe the track record of these antibodies in multiple different histologies ranging from melanoma and lung cancer to less common tumor types as well as discuss biomarkers that may assist in patient selection.

Keywords

PD-1 PD-L1 Immunotherapy Checkpoint inhibitors Biomarkers Microbiome 

Abbreviations

AACR

American Association of Cancer Research

ASCO

American Society of Clinical Oncology

BCG

Bacillus Calmette–Guerin

CI

Confidence interval

CR

Complete response

CTLA-4

Cytotoxic T-lymphocyte associated protein-4

DCR

Disease control rate (ORR and SD)

FKSI-DRS

Functional assessment of cancer therapy–kidney symptom index–disease-related symptoms

GVHD

Graft-versus-host disease

HCT

Hematopoietic stem cell transplant

HL

Hodgkin’s lymphoma

IC

Immune cell

IDO1

Indoleamine 2,3 dioxygenase 1

IHC

Immunohistochemistry

MRD

Mismatch repair deficiency

ORR

Objective response rate

PCR

Polymerase chain reaction

PD-1

Programmed death-1

PD-L1

Programmed death ligand-1

PD-L2

Programmed death ligand-2

PTEN

Phosphatase and tensin homolog

SD

Stable disease

Introduction

PD-1 or programmed death-1 was first identified and cloned in 1992 as a gene transcriptionally induced upon programmed cell death in T cells [1]. It was subsequently found to be an expressed on activated T, B and myeloid cells, and its cytoplasmic region contains an immunoreceptor tyrosine-based inhibitory motif [2, 3]. Mice deficient in PD-1 develop a lupus-like arthritis and glomerulonephritis with predominant IgG3 deposition as they age. In a manner similar to that reported in the lupus-prone MRL mice, introduction of the lpr mutation leads to accelerated onset of disease and severity of symptoms. When 2C-TCR (anti-H-2Ld) transgenic mice are made homozygous for the PD-1 null mutation in the H-2b/d background, the mice develop a chronic graft-versus-host-like disease [4]. Therefore, it appeared that PD-1 was a T cell molecule that limited T cell activation and proliferation and promoted tolerance. PD-1 is expressed at low levels by resting T cells and has been shown to be expressed by what some investigators have referred to as “exhausted” T cells in animal models of chronic infection [5, 6]. In patients with multiple different types of epithelial, hematologic and other malignancies, high levels of PD-1 are detected in circulating and tumor-infiltrating lymphocytes including T cells that are tumor antigen specific, presumably due to chronic antigenic stimulation. These tumor-associated PD-1 expressing effector cells are dysfunctional, and their biological activity can be partially recovered using PD-1 or PD-L1 blocking antibodies [7, 8, 9, 10, 11]. The ligands for the PD-1 receptor are PD-L1 and PD-L2, which are molecules found on antigen-presenting cells, and in the case of PD-L1, it is often expressed on epithelial and other types of tumor cells, resulting in an inhibitory interaction within the tumor microenvironment. The generation of interferon-gamma by infiltrating T cells contributes to high levels of PD-L1 expression in the tumor microenvironment [12]. The induction of PD-L1 expression by tumor cells may be an adaptive resistance mechanism for tumor cells in response to a developing antitumor immune response [12, 13]. In addition, oncogenic PTEN loss is associated with increased PD-L1 expression in glioma [14] and triple-negative breast cancer cells [15]. PD-L1 expression can thus also be up-regulated by intrinsic oncogenic pathways as well as interferon-gamma secreted by infiltrating immune cells. PD-L1 and PD-1 are expressed by different cellular components in the tumor microenvironment, where their interaction can inhibit T cell immunity. The engagement of PD-1 by its principal ligand PD-L1 may result in apoptosis in T cells, anergy, “exhaustion”, and secretion of interleukin-10. PD-L1 expression may protect tumor cells expressing it from CD8+ T cell-mediated lysis [16, 17]. In addition to PD-1, an interaction between PD-L1 and CD80 has been demonstrated in mouse models [18, 19]. Activated T cells and APCs may express CD80, which may function as a receptor and deliver inhibitory signals when engaged by PD-L1. It has been also shown that PD-L1 acts as a receptor to “back” transmit signals into T cells [19] and tumor cells [20] to impact on their survival, whose mechanism is yet to be determined. Finally, PD-1 and PD-L1 can be expressed on T regulatory cells and may control their function [21], and innate immune effectors like NKT cells may also involve the PD-1/PD-L1 circuit [22]. Thus, PD-L1 could act as both ligand and receptor to execute immuno-regulatory functions. Based on those data, the development of antibodies to interrupt and negate the interaction between PD-1 and PD-L1 seemed appropriate (Table 1).

Table 1

FDA-Approved PD-1 and PD-L1 antibodies in cancer

Agent

Indication

Setting

Dose/schedule

Study phase and setting

N=

Key outcomes (by primary end point)

Nivolumab

Classical Hodgkin lymphoma

Relapsed/refractory

3 mg/kg Q2 weeks

Stem cell transplant refractory; phase II [72]

23

ORR 87% (17% CR)

Metastatic melanoma

First line

3 mg/kg Q2 weeks

First line; phase III vs dacarbazine [26]

418

1 year OS 72.9 vs 42.1% for dacarbazine

Relapsed/refractory

Anti-CTLA-4 refractory phase III vs chemotherapy [28]

405

ORR 31.7 vs 10.6% for chemotherapy

Metastatic melanoma

First line

1 mg/kg Q3 weeks in combination with ipilimumab for 4 doses, then 3 mg/kg Q2 weeks

First-line phase III Ipilimumab vs nivolumab vs combination [36]

945

11.5 months median PFS for Ipi/Nivo vs 2.9 months for ipi vs 6.9 months for nivo

Metastatic NSCLC

Relapsed/refractory

3 mg/kg Q2 weeks

Non-squamous NSCLC phase III vs docetaxel [44]

582

12.2 months median OS vs 9.4 months for docetaxel

Squamous NSCLC phase III vs docetaxel [45]

272

9.2 months median OS vs 6.0 months for docetaxel

Clear cell RCC

Relapsed/refractory

3 mg/kg Q2 weeks

Anti-VEGF(R) refractory, phase III vs everolimus [69]

821

25.0 median OS vs 19.6 months for everolimus

Pembrolizumab

Metastatic melanoma

First line

2 mg/kg Q3weeks

Phase III vs ipilimumab [33]

834

PFS HR 0.58 vs Ipi

OS HR 0.69 for Pem Q3w vs Ipi

Relapsed/refractory

Anti-CTLA-4 refractory phase I [31]

173

ORR 26%

Metastatic NSCLC

Relapsed/refractory

2 mg/kg Q3weeks

Previously treated; phase III Pem 2 vs 10 mg/kg vs docetaxel [47]

1034

OS HR 0.71 for Pem 2 mg/kg vs docetaxel and OS HR 0.61 for pem 10 mg/kg vs docetaxel

H&N SCC

Relapsed/refractory

200 mg Q3weeks

Platinum-refractory/relapsed Phase I [73]

174

16% ORR

Atezolizumab

Urothelial cancer

Relapsed/refractory

1200 mg IV Q3 weeks

Platinum-refractory/relapsed Phase II [57]

310

15% ORR

Metastatic NSCLC

Relapsed/refractory

1200 mg IV Q3 weeks

Platinum-refractory/relapsed

Randomized phase III vs docetaxel

144

13.8 months mOS for Atezo (HR 0.73)

H&N head and neck, HR hazard ratio, Ipi ipilimumab, Nivo nivolumab, NSCLC non-small cell lung cancer, OS overall survival, PFS progression-free survival, RCC renal cell carcinoma, SCC squamous cell carcinoma, VEGF (R) vascular endothelial growth factor

Melanoma

The initial clinical trials testing antibodies to block the PD-1/PD-L1 interaction employed an IgG4 human anti PD-1 antibody called BMS-936558, later nivolumab (Opdivo; Bristol Myers Squibb, Princeton, NJ) in melanoma, lung cancers, colon cancers and renal cancer [23]. Nivolumab was evaluated in the Checkmate-003 phase I trial with single doses from 0.1 to 10 mg/kg and then repeated doses were given every 2 weeks for up to 96 weeks [24]. No maximal tolerated dose was reached, and there were antitumor responses over the 100-fold dose range without evidence of a dose response for toxicity or efficacy. A total of 107 ipilimumab-naïve melanoma patients were treated in second- or later-line therapy at all doses, with a 30% response rate and an excellent duration of response seen, and a plateau of survival at 35% at 3–5 years [25]. This was followed by the Checkmate-066 phase III study for front-line ipilimumab-naïve patients in which patients were randomized to receive either nivolumab at 3 mg/kg every 2 weeks until progression or dacarbazine at 1000 mg/m2 every 3 weeks for up to eight cycles [26]. That study was stopped early due to an imbalance in progression-free and overall survival favoring nivolumab with a hazard ratio for survival of 0.40 with p = 0.001. Ninety-two patients that were ipilimumab refractory were treated in a phase I/II study with nivolumab at 1, 3 and 10 mg/kg every 2 weeks for 24 weeks, then every 12 weeks for up to 2.5 years with or without a peptide vaccine. The response rate was also 30% with a median survival of 20 months and a median duration of response of 14 months [27]. These data led to the phase III Checkmate-037 study of nivolumab at 3 mg/kg compared to the investigator’s choice chemotherapy (dacarbazine or carboplatin/paclitaxel) in patients who had progressed after ipilimumab [28]. The response rate favored nivolumab (32 versus 11%) with lower grades 3 and 4 toxicity (8% for nivolumab versus 31% for chemotherapy). Patients with BRAF mutant melanoma did as well as those with wild-type tumors in the phase II and III studies [29]. The results of the two phase III studies led to the approval of nivolumab for first-line or previously treated melanoma.

The toxicity, tolerability and clinical efficacy of MK-3475, now pembrolizumab (Keytruda; Merck Inc, Kenilworth, NJ), an IgG4 fully humanized antibody, was evaluated in the large Keynote-001 phase I/II study that included 611 melanoma patients [30]. The results in 135 first- and second-line patients who received 2 or 10 mg/kg of drug every 2 or 3 weeks showed a response rate of 38%. Within that trial, 173 patients who were ipilimumab refractory were randomly assigned to receive 2 or 10 mg/kg of pembrolizumab every 3 weeks until progression [31]. The response rate was 26% in either group, and treatment was well tolerated, with fewer than 10% drug-related grade 3–4 adverse events. These data supported the randomized KEYNOTE-002 phase II crossover study of pembrolizumab versus chemotherapy in the same ipilimumab-refractory population [32]; 540 patients were randomly assigned to receive pembrolizumab at 2 or 10 mg/kg compared to chemotherapy, every 3 weeks. Progression-free survival was improved in patients assigned to both pembrolizumab 2 mg/kg (HR 0·57; p < 0·0001) and 10 mg/kg (0·50; p < 0·0001) compared with those receiving chemotherapy. The phase III KEYNOTE-006 study included 834 patients with advanced untreated melanoma assigned in a 1:1:1 ratio to receive pembrolizumab at 10 mg/kg every 2 or every 3 weeks or four doses of ipilimumab at 3 mg/kg every 3 weeks [33]. The response rate was superior with pembrolizumab every 2 weeks (33.7%) and every 3 weeks (32.9%) compared with ipilimumab (11.9%) (p < 0.001). Survival was improved for either pembrolizumab regimen compared to ipilimumab; hazard ratio for death for pembrolizumab every 2 weeks, 0.63; p = 0.0005; hazard ratio for pembrolizumab every 3 weeks, 0.69; p = 0.0036. The data from this initial phase I/II trial led to the FDA breakthrough status and subsequent approval of pembrolizumab in October 2014 for patients with advanced melanoma.

Combination studies with the CTLA-4 blocking antibody ipilimumab and nivolumab were pursued in the Checkmate-004 phase I, Checkmate-069 randomized phase II and Checkmate-067 randomized phase III studies [34, 35, 36]. Response rates of 55, 61 and 57% were observed in those studies, respectively, for the combination, although immune-related side effects were correspondingly higher at 50–55% for grade 3–4.

When ipilimumab and nivolumab were given sequentially with a planned switch at week 12 in a randomized phase II trial in metastatic melanoma, response and overall survival for the nivolumab > ipilimumab cohort was superior to that ipilimumab > nivolumab cohort, but with similar toxicities to that of concurrent combination therapy, suggesting that in practice concurrent therapy was at least as good as sequential nivolumab than ipilimumab, but the availability of mature overall survival data from combination trials will be needed to make a rational decision to choose combination versus monotherapy [37, 38]. With longer follow-up, it has become clear that at least a third of patients with an initial partial response to PD-1 blockade will progress [39], whereas in those with a complete response progression is rare [40]. In melanoma patients treated with ipilimumab, most patients in remission at 3 years from starting therapy will remain in remission [41].

Over 100 trials are in progress that are testing combination therapies with checkpoint inhibition for melanoma, and one strategy that is quite well explored is the combination with a directly injected engineered herpesvirus, TVEC, which may function as an in situ vaccine to bring T cells into tumors that lack them and thereby augment the efficacy of PD-1 blockade [42].

Lung cancer

The results of the initial phase I nivolumab trial noted above led to expansion cohorts in which 129 patients with heavily pretreated advanced squamous and non-squamous non-small cell lung cancer (NSCLC) received nivolumab at 1, 3 or 10 mg/kg intravenously every 2 weeks in 8-week cycles for up to 96 weeks [43]. Median OS across doses was 9.9 months; 3-year survival was 27% at the 3 mg/kg dose with 37 patients treated. Among 22 patients (17%) with objective responses, the estimated median response duration was 17.0 months. An additional six patients (5%) had unconventional immune-related responses. These data led to two phase III studies in second-line therapy. Patients with non-squamous non-small cell lung cancer (NSCLC) that progressed after platinum-based doublet chemotherapy received nivolumab at a dose of 3 mg/kg every 2 weeks or docetaxel at a dose of 75 mg/M2 every 3 weeks in the Checkmate-057 study [44]. The median overall survival was 12.2 months among 292 patients in the nivolumab group and 9.4 months among 290 patients in the docetaxel group (HR 0.73; p = 0.002). There was no clear relationship between PD-L1 expression on tumors and survival in that study. Among patients with squamous non-small cell lung cancer that were randomly allocated to receive nivolumab or docetaxel in the Checkmate-017 phase III study, the median overall survival was 9.2 months with nivolumab versus 6.0 months with docetaxel (HR 0.59; p < 0.001) [45]. In that study, there was a clear relationship between PD-L1 tumor expression at the 5% level and outcome. These data led to the approval of nivolumab as second-line therapy for both squamous and non-squamous NSCLC in 2015.

In the lung cancer expansion cohorts totaling 495 patients in the large pembrolizumab phase KEYNOTE-001 I/II trial, an objective response rate of 19.4% was demonstrated, with a median duration of response of 12.5 months and a median overall survival of 12.0 months [46]. These data supported a randomized trial of pembrolizumab at 2 or 10 mg/kg every 3 weeks until progression compared with docetaxel at 75 mg/M2 every 3 weeks in the KEYNOTE-010 study [47]. 1034 patients who were PD-L1 positive, indicated by greater than 1% immunohistochemical tumor staining, were randomized 1:1:1, with median overall survival of 10.4 months with pembrolizumab 2 mg/kg, 12.7 months with pembrolizumab 10 mg/kg, and 8.5 months with docetaxel. Overall survival was significantly longer for pembrolizumab 2 mg/kg versus docetaxel (HR 0.71; p = 0.0008) and for pembrolizumab 10 mg/kg versus docetaxel (0.61; p < 0.0001). These data led to the approval of pembrolizumab as second-line therapy for PD-L1-positive NSCLC in 2016. The absolute PD-L1 expression level in that study was associated with better outcome with higher levels conferring better survival, providing further evidence that PD-L1 expression falls along a continuum and is associated with response and improved outcomes with PD-1 targeted treatment. Further studies in lung cancer have evaluated MPDL3280A (Atezolizumab; Genentech), an IgG1 engineered antibody against PD-L1, and have demonstrated similar activity [48]. An initial randomized phase II study of atezolizumab versus taxane in previously treated patients demonstrated promising outcomes [49]. This led to a phase III study in 1225 patients with previously treated advanced NSCLC which was presented at the 2016 ESMO Congress and demonstrated a median survival of 13.8 months for atezolizumab compared to 9.6 months with chemotherapy (HR 0.73) [50]. The FDA approved atezolizumab in platinum pre-treated metastatic NSCLC on the basis of these two studies in October 2016.

In the first-line setting, Checkmate-012 evaluated nivolumab 3 mg/kg every 2 weeks as monotherapy in 52 patients with advanced NSCLC and demonstrated an ORR of 23% (4 patients achieved CR), median PFS of 3.6 months and median OS of 19.4 months, with a tolerable safety profile [51]. In a separate arm of Checkmate-012, nivolumab 5 or 10 mg/kg combined with platinum-based chemotherapy on a 3-weekly schedule was evaluated in the first-line setting in 56 patients. Forty-five percent of patients developed a grade 3 or 4 treatment-related toxicity, including 7% developing pneumonitis and 21% discontinuing treatment due to toxicity [52]. The observed frequencies of immune-related toxicities in this study were greater than expected with single-agent nivolumab, which may have been influenced by the dose and schedule in this combination study with chemotherapy. These data led to Checkmate-026, a phase III randomized study testing single-agent nivolumab every 2 weeks versus the investigator’s choice chemotherapy as first-line treatment in 541 patients with advanced PD-L1 expressing (defined as ≥5% PD-L1 expression) NSCLC. The study sponsor reported in a press release that the trial did not meet the primary end point of an improvement in progression-free survival for nivolumab, and complete data for the trial is expected to be reported soon [53]. However, an ongoing phase III study of nivolumab plus ipilimumab vs standard chemotherapy (Checkmate-227) may still define a role for first-line immune checkpoint blockade in first-line advanced NSCLC (NCT02477826).

Urothelial cancer

Until recently, there were no FDA-approved therapies in the second-line setting in metastatic urothelial cancer (mUC), and response rates for chemotherapy-refractory patients with single cytotoxic agents were in the range of 10% [54]. Invasive and metastatic urothelial cancer is associated with a high mutational burden, suggesting that immune checkpoint inhibition may have therapeutic efficacy [55].

An initial phase Ia basket study of atezolizumab in advanced solid tumors included a cohort of heavily pre-treated mUC patients [56]. Rapid and durable responses coupled with a highly favorable safety profile in the phase Ia study led to the multinational phase II IMVigor210trial in locally advanced or metastatic urothelial cancer that enrolled two cohorts: 119 cisplatin-ineligible patients treatment naïve in the metastatic setting (Cohort 1), and 310 patients previously treated with platinum-based chemotherapy (Cohort 2). In cohort 2, the centrally confirmed ORR was 15%, with a 26% response rate for patients with the highest level of PD-L1 expression on immune cells (IC 2/3, defined as ≥5% staining by a Ventana SP142 immunohistochemical assay) [57]. The most recent updated analysis presented at the 2016 ASCO Annual Meeting showed that 71% of responses were still ongoing at a median follow-up of 17.5 months, and additional CRs and PRs were observed, with an overall ORR of 16% (7% CR rate) [58]. Patients with IC0 and IC1 levels of PD-L1 expression had a 10% ORR, which is comparable to response rates typically observed with chemotherapy [59]. The FDA approved atezolizumab (Tecentriq) on the basis of these data in May 2016 in patients with locally advanced or metastatic urothelial cancer following progression during or after platinum-based chemotherapy, the first new treatment to be approved for urothelial cancer in over three decades. The Ventana SP142 assay for testing PD-L1 expression on infiltrating immune cells is approved for use as a companion diagnostic; however it is not required for atezolizumab use, since absence of PD-L1 expression does not preclude response to treatment.

Similar studies of PD-1 antibodies in previously treated patients have since been reported. These include the Checkmate-275 phase II study of nivolumab in 270 previously treated patients which demonstrated a 19.6% ORR, with higher response rates observed in PD-L1 overexpressing patients (28% ORR in ≥5% tumor cell PD-L1 expression) [60]. Recently, the KEYNOTE-45 phase III trial of pembrolizumab versus investigator’s choice chemotherapy (taxane or vinflunine) in 542 previously treated patients demonstrated a median OS of 10.3 months for pembrolizumab versus 7.4 months for chemotherapy (HR 0.73; P = 0.0022). The objective response to pembrolizumab was 21.1% ORR in the all-comer population, but was not higher in the PD-L1 overexpressing population (21.6% ORR) [61]. These data collectively establish PD-1/PD-L1 targeted therapy as a new standard of care in the second-line setting for mUC.

In the first-line setting, cohort 1 of IMvigor 210 investigated atezolizumab in 119 cisplatin-ineligible patients. These patients typically have a median survival of 9–10 months with carboplatin-based therapy which has no proven survival benefit [62]. The initial analysis of this cohort was presented at the 2016 ASCO Annual Meeting and demonstrated an ORR of 24% with 7% of patients achieving a CR [63]. At a median follow-up of 14.4 months, 75% (21 of 28) of responses were ongoing and estimated median survival was 14.8 months (47% event rate) with a 57% 1-year OS rate. The grade 3 and 4 treatment-related toxicity rate was 15% with a 6% discontinuation rate, which compares very favorably with the 21% rate of treatment discontinuation with carboplatin-based therapy, a standard treatment for cisplatin-ineligible patients [62]. The promising outcomes observed in this trial support first-line therapy with atezolizumab as a new standard of care, and randomized trials are currently underway to definitively establish the role for first-line immunotherapy in this disease.

Additional PD-1 or PD-L1 agents such as durvalumab and avelumab have demonstrated similar activity and safety in previously treated mUC [64, 65], and multiple additional studies of checkpoint inhibitors in the adjuvant and metastatic settings are currently underway (pembrolizumab: NCT02370498; durvalumab and tremelimumab: NCT02516241; nivolumab: NCT02632409; atezolizumab: NCT02450331).

Renal cell carcinoma

Renal cell carcinoma (RCC) has historically been a tumor responsive to immunotherapy, established with the advent of high-dose IL-2 leading to durable cures in a subset of patients [66]. This therapy, however, was toxic, limiting its use to only selected patients with ideal disease characteristics, excellent performance status and high levels of cardiopulmonary reserve. PD-1 and PD-L1 blocking antibodies are active in advanced RCC and are associated with an excellent safety profile as demonstrated in initial phase I and II studies [67, 68]; however, responses do not appear to be durable. In a randomized phase II study of nivolumab at three dose levels (0.3, 2 and 10 mg/kg) in 168 pre-treated advanced RCC patients, objective responses were observed at all dose levels: 20, 22, and 20%, respectively. Median survivals were 18.2, 25.5, and 24.7 months (80% CI 15.3–26.0 months), respectively. Therapy was well tolerated, with only 19 patients (11%) experiencing grade 3–4 treatment-related toxicity. A dose of 3 mg/kg every 2 weeks was selected for further development. These data led to the pivotal Checkmate 025 phase III trial of nivolumab at 3 mg/kg vs everolimus at 10 mg orally daily in 821 previously treated advanced RCC patients [69]. The ORR and median survival were 25 versus 5% and 25.0 months (95% CI 21.8–NE) versus 19.6 months (95% CI 17.6–23.1) for nivolumab and everolimus, respectively. The hazard ratio for death with nivolumab was 0.73 (98.5% CI 0.57–0.93; p = 0.002) which met the primary end point for superiority. Further, 19% of patients treated with nivolumab experienced grade 3 or 4 treatment-related toxicity compared to 37% of the patients treated with everolimus, with a significantly higher proportion of patients treated with nivolumab reporting an improvement in quality of life scores [70]. These data led the FDA to approve nivolumab 3 mg/kg every 2 weeks in 2015 as second-line therapy in advanced RCC. Multiple additional studies investigating anti PD-1/PD-L1 antibodies added to CTLA-4 and, notably, VEGF-targeted therapies are now currently underway (NCT02231749; NCT02420821; NCT02133742).

Other histologies

In classical Hodgkin’s lymphoma (HL), PD-1 is commonly overexpressed and is a marker of T cell exhaustion. Up to 97% of patients with HL will have alterations in the PD-L1 and PD-L2 gene loci which are associated with increased PD-L1 protein expression [71]. The FDA approved a regimen of nivolumab 3 mg/kg every 2 weeks for the treatment of classical HL after failure of autologous HCT and post-transplantation brentuximab vedotin on the basis of two small prospective studies. The efficacy data for 95 patients in Checkmate-039 and -205 demonstrated a 65% ORR (7% CR) and median response duration of 8.7 months [72]. Toxicities were typical of PD-1 blockade; however, patients treated with nivolumab who subsequently received allogeneic stem cell transplant experienced a high rate of transplant-related complications such as GVHD, fever requiring steroids, hepatic sinusoidal obstruction syndrome, and other immune-related toxicities.

PD-1 antibodies are also active in H&N squamous cell carcinoma. Data from the KEYNOTE-012 phase Ib study of pembrolizumab in 192 previously treated advanced H&N cancer patients demonstrated an ORR of 16% (5% CR rate) with durable responses >6 months in 82% (23/28) of the responding patients at the median follow-up of approximately 12 months [73]. The ORR and duration of response were similar regardless of the human papillomavirus (HPV) status. The data from this study led to the approval by the FDA of pembrolizumab 200 mg IV every 3 weeks for the treatment of previously treated advanced H&N squamous cell carcinoma in August 2016.

Other solid tumors such as ovarian cancer, gastrointestinal cancers (esophagus, gastric, colon), hepatocellular cancer and glioma have limited evidence for responsiveness to PD-1 blockade. A recent update of a phase II study of pembrolizumab in selected tumors with DNA mismatch repair deficiency (MRD, which is a hallmark of genomic instability defined in this trial as somatic or germ-line deficiency in MLH1, MSH2, MSH6 or PMS2 or microsatellite instability) presented at the 2016 ASCO Annual Meeting demonstrated significant clinical activity [74]. In 30 pre-treated patients with advanced non-colorectal MRD cancers (endometrial, N = 9; biliary, N = 7; pancreatic, N = 4; small bowel, N = 4; gastric, N = 3, other, N = 3), pembrolizumab had an ORR of 53% (95% CI 36–70) with 9 patients (30%) achieving a CR. The 1-year OS rate is 81%; however, the median follow-up is 10 months and thus these data are still immature. Previously, data from 35 patients with advanced colon cancer (14 patients with MRD and 21 patients without MRD) treated on this study demonstrated 62% ORR and 92% DCR in the MRD group [75]. In contrast, the ORR and DCR was 0 and 16% in patients without MRD. Taken together, these data suggest that MRD may define a small subset of patients with cancers not commonly regarded as immunotherapeutically sensitive that may respond to treatment with PD-1 blockade.

PD-L1 expression and the tumor microenvironment

Predicting tumor responses to PD-1 blockade remains a major challenge. It is clear that pre-existing antitumor immunity with antigen-specific CD8+ T cells that are negatively regulated by PD-1/PD-L1 is associated with the therapeutic efficacy of PD-1 blockade [76, 77, 78]. Thus, PD-L1 expression assessed by immunohistochemistry is a plausible biomarker to predict response to PD-1 blockade. However, PD-L1 expression, whether assessed on tumor or infiltrating immune cells, is a highly variable, heterogeneous and dynamic marker when measured by immunohistochemistry, thus posing inherent limitations in its potential utility as a predictive marker for the efficacy of PD-1/PD-L1 blockade. Additionally, the location of PD-L1 expressing cells within the tumor microenvironment is also important. In one study involving melanoma patients treated with pembrolizumab, serially obtained tumor samples demonstrated proliferation of intra-tumoral CD8+ T cells in responding patients. Pre-treatment samples analyzed from these patients demonstrated PD-1 and PD-L1 expressing CD8+ T cells at the invasive margin, which were subsequently validated in a predictive model based on CD8 expression in an independent cohort of 15 patients [77]. Nonetheless, three tests of PD-L1 expression by immunohistochemistry are currently approved by the FDA to guide treatment decision making in urothelial cancer, melanoma and non-small cell lung cancer [44, 45, 47, 57], each using a different assay with different screening thresholds for PD-L1 expression. Others are also in development such as the Ventana SP263 assay, which is being developed with durvalumab (Astra Zeneca/Medimmune) (Table 2). Despite the technical challenges and differences in testing for PD-L1 expression, each assay seems to demonstrate some association of expression with response. The proportion of tumor cells that are actually PD-L1 positive may be quite low in many tumors, with the DAKO positivity defined in BMS trials at 5% or greater. The Blueprint PD-L1 IHC Assay Comparison Project is a major collaboration between four pharmaceutical companies (AstraZeneca PLC, Gaithersburg, MD, Bristol-Myers Squibb Company, Genentech, Inc. and Merck & Co. Inc.) and two diagnostic companies (Agilent Technologies Inc./Dako Corp, Carpinteria, CA and Roche/Ventana Medical Systems, Inc, Mountain View, CA) to compare and characterize each of their PD-1/PD-L1 IHC assays in an attempt toward harmonization. Phase I of the project was recently presented at the 2016 AACR Annual Meeting and focused on the feasibility of harmonization of PD-L1 expression assays in a small cohort of non-small cell lung cancer patients and demonstrated clinical validity as well as concordance between assays [79]. Phase II which would need a larger effort to validate the findings is currently underway. Nonetheless, while the presence of PD-L1 expression is associated with a higher probability of response to PD-1/L1-targeted therapy, its absence does not preclude response and thus has limited clinical utility as it cannot currently be used to exclude patients from treatment.

Table 2

PD-L1 Immunohistochemistry Assays

Agent

Nivolumab

Pembrolizumab

Atezolizumab

Durvalumab

Diagnostic company

Dako

Dako

Ventana

Ventana

Antibody

28-8

22C3

SP263

SP142

Cell scored

TC

TC or Tumor Stroma

IC

TC

Diagnostic cut-offs

1, 5 or ≥10%

≥50% for TC

>1% for Stroma

1, 5 or 10%

≥25%

TC tumor cell membrane, IC infiltrating immune cell

Non-T cell inflamed tumors (i.e., “cold” tumors) are far less likely to respond to PD-1/L1 blockade, and thus understanding mechanisms that drive immune exclusion are critical for the development of alternative treatment strategies [80]. An important initial study of human melanoma samples demonstrated a correlation between activation of the WNT/b-catenin signaling pathway and absence of a T cell gene expression signature. WNT/b-catenin signaling appeared to be tumor intrinsic and mediated resistance to anti-PD-L1 and CTLA-4 therapy in autochthonous mouse melanoma models [81]. Alterations of an interferon-gamma gene signature appear to be important in determining resistance to PD-1 blockade [82], and loss of PTEN expression also is associated with resistance to checkpoint inhibition [83]. Similar mechanisms appear to govern resistance in urothelial cancer as well, suggesting common pathways for immune exclusion [84], several of which are targetable in addition to beta-catenin such as FGFR3, justifying further investigation in the clinic.

Mutational load and neoantigens

Somatic alterations in the tumor genome such as mutations, rearrangements, insertions and deletions may have the capacity to encode mutated proteins (neoantigens) that may be subsequently recognized by the host immune system and generate antitumor immunity. Multiple mechanisms for the generation of immunogenic neoantigens are implicated, including de novo affinity for the peptide-binding domain of MHC, generation of a new TCR contact residue, or alterations in proteosomal cleavage sites that enable more efficient processing for MHC presentation or generates a novel peptide that would otherwise not be expressed [85], which can be achieved through essentially any genomic insult, whether a functional or passenger event. Thus, mutational load, which is a global assessment of genomic instability in a tumor, can predict the development of neoantigens, and thus a higher likelihood for the generation of tumor antigen-specific T cells. An association between mutational load and response to immune checkpoint inhibitors was first observed in studies of ipilimumab in advanced melanoma [86, 87]. Subsequent studies demonstrated the highest response rates to PD-1 and PD-L1 blocking antibodies in tumors with the highest mutational burden (melanoma, NSCLC, SCCHN, gastric cancer and most recently urothelial cancer) [55, 57, 88]. In contrast, tumor types with the lowest relative mutational loads have had the lowest response rates to PD-1 blockade, notably pancreatic and prostate cancers, although there is a great variation of mutational density within cancer subtypes (up to 2 log-fold) that may account for outlier responses. The challenge ahead in utilizing mutational load as a clinically useful biomarker for PD-1-directed therapy is the identification of a numerical cutoff that could be used to justify excluding certain patients from therapy that is limited with currently available analyses. Additionally, other host or tumor factors beyond neoantigenicity may be equally important in predicting response. Additional variables to be considered include the role of CD4+ cells in responding to tumor neoantigens and the T cell repertoire of the host. Recent data suggest that the phenotype of the intratumoral T cells that express multiple checkpoints such as PD-1 with CTLA-4 may be associated with the outcome [89]. Epigenetic mechanisms may regulate the expression of mutated antigens versus non-mutated self-antigens, and the heterogeneous tumor microenvironment presents unique challenges to successful immunotherapy. Inhibitory mechanisms within the tumor microenvironment including local concentrations of cytokines (e.g., IL-10, TGF-beta), additional immune checkpoints (e.g., TIM3, LAG3, OX40) and the presence of metabolic enzymes (e.g., IDO1 and arginase) may generate a highly immunosuppressive environment and thus eliminate the function of tumor antigen-specific T cells even in the context of PD-1 blockade.

The gut microbiome and response to immune checkpoint blockade

Another potential biomarker for response to PD-1 blockade currently under investigation is the composition of the gut microbiome. In a melanoma model, mice with microbiomes high in Bifidobacter species were observed to have spontaneous antitumor immunity, which was eliminated upon co-housing or after fecal transfer. Further, oral administration of Bifidobacterium alone improved tumor control similar to PD-1 blockade, which was significantly enhanced with combination treatment and was felt to be mediated by enhanced dendritic cell function leading to improved CD8+ T cell priming and tumor infiltration [90]. In humans with advanced melanoma, a study suggested that Bacteroides species (Bacteroides fragilis and thetaiotaomicron species), might mediate similar effects on antitumor immunity with CTLA-4 blockade [91]. The role for the gut microbiome in shaping antitumor immunity likely occurs through multiple mechanisms, and its interaction with checkpoint blockade is now being further explored prospectively in multiple other studies and may be a useful tool to guide immunotherapy in the future [92].

Combination therapies and future directions

Outcomes observed with antibodies targeting the PD-1/L1 axis have undoubtedly ushered in a dramatic shift in both our understanding of host–tumor biology as well as our overall approach to cancer therapy. T cell inflammation within tumors is a common hallmark of pre-existing antitumor immunity and predicts response to PD-1/PD-L1 blockade. Combination strategies and therapies targeting alternative immune-regulatory pathways are now aimed at addressing tumors that are not responsive to single-agent PD-1/L1 therapies. Antibodies targeting additional checkpoints such as CD137, OX40 and IDO are currently under investigation as single agents and in combination in a variety of solid tumors. Further, mutation-inducing conventional cancer therapies, including radiation and chemotherapy, may also pair successfully with immune checkpoint blockade, and studies addressing this question are also underway. The use of a vaccination approach such as locally injected TVEC [41] and the employment of radiation to induce local immunogenic cell death [93] may augment the utility of checkpoint inhibition. Combination therapy with PD-1 blockade and CTLA-4 blockade has shown promise in melanoma, and recent results with lung and GU cancers suggest that this strategy may be useful in multiple histologies, albeit with a higher rate of grade 3–4 immune-related adverse events, particularly pneumonitis. Altering the doses and scheduling of ipilimumab in those regimens may reduce the toxicities [94], while retaining clinical activity. Ultimately, the advent of modern immunotherapy has required investigators to redefine traditional end points of clinical efficacy of cancer therapy, which currently do not accurately capture the potential benefit of immunotherapy. Responses to immunotherapies can be delayed and exhibit atypical kinetics, but are very often durable (unlike cytotoxic chemotherapy), and thus end points focusing on landmark survival at longer follow-up (i.e., the “tail of the curve”) more accurately assess the clinical benefit [95]. The dynamic and adapting nature of the immune system makes biomarker development challenging, but also lends to its limitless potential to maintain pace with cancer evolution and lead to durable outcomes previously impossible with conventional cancer therapies.

Notes

Acknowledgements

Jeffrey S. Weber has received honoraria from Bristol Myers Squibb, GlaskoSmithKline, Merck, Astra Zeneca, Genentech and EMD Serono, has equity in Celldex, Cytomx and Altor, and has been named on a patent by Moffitt Cancer Center for a biomarker for ipilimumab sensitivity.

Compliance with ethical standards

Conflict of interest

Arjun Vasant Balar has received honoraria from Merck, Genentech and Astra Zeneca, and has received contracted research support from Merck, Genentech and Astra Zeneca.

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© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  1. 1.Laura and Isaac Perlmutter Cancer CenterNYU Langone Medical CenterNew YorkUSA

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