Current Perspectives on Immunotherapy Jeffrey S. Weber After many years of disappointments, the successful development and commercialization of the first immune checkpoint inhibitor, and regulatory approval of a dendritic cell (DC)-based cancer vaccine has led to renewed interest and enthusiasm for cancer immunotherapy. Approval of ipilimumab, an antibody targeting cytotoxic T-lymphocyte–associated antigen 4 for advanced melanoma, and sipuleucel-T, an autologous DC-based vaccine for advanced prostate cancer have brought immunotherapy to the forefront of cancer therapeutics and made the goal of long-term tumor control for patients with advanced metastatic disease seem achievable. Additionally, encouraging data from early clinical trials of other immune checkpoint inhibitors targeting programmed cell death 1 and programmed cell death ligand 1 and numerous therapeutic vaccines in development have further expanded interest in the potential of cancer immunotherapy. These recent developments represent the fruits of years of preclinical and clinical research to better understand the complex mechanisms of immune regulation and the ways in which tumors exploit those mechanisms to evade and avoid the antitumor immune response. Semin Oncol 41:S14-S29 & 2014 Elsevier Inc. All rights reserved.

A

s our knowledge and understanding of immune regulatory mechanisms, such as immune checkpoints and co-stimulatory signals, has improved, it has become clear that earlier approaches to immunotherapy for advanced cancer, which sought primarily to enhance activation of tumor-specific T cells and other immune effector cells, were often inadequate to maintain an effective anti-tumor immune response. The primary reason for the disappointing results for immunotherapy trials in the past is that tumors evolve the ability to exploit regulatory mechanisms that suppress the anti-tumor immune response, mechanisms that function to keep the immune response in check. The recent renewed interest in cancer immunotherapy has primarily been driven by the development and successful commercialization of the first immune checkpoint inhibitor and the first dendritic cell (DC)-based vaccine for the treatment of advanced

H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL. Financial support for this supplement was provided by an unrestricted educational grant from Merck & Co., Inc. Conflict of interest statement: Dr Weber has received honoraria or consulting fees from Bristol-Myers Squibb, Genentech, and Merck. Address correspondence to Jeffrey S. Weber, MD, PhD, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr, SRB-2, Tampa, FL 33612. E-mail: jeffrey.weber@moffitt.org 0093-7754/ - see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.seminoncol.2014.09.003

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cancer. For the first time, immunotherapy has been shown to improve overall survival (OS) in randomized phase III trials in patients with advanced malignancies, as opposed to just a few patients who achieve a durable response. A review of the mechanism of action of these and other approaches to cancer immunotherapy is provided in the article by Mary L. Disis within this supplement. The current article reviews available data on immune checkpoint inhibitors and therapeutic vaccines, with a focus on approved agents as well as those in clinical development.

DEVELOPMENT OF IPILIMUMAB FOR MELANOMA Ipilimumab is a monoclonal antibody (mAb) targeting cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), the prototypical immune checkpoint first described by Allison and colleagues in the mid1990s.1,2 Briefly, CTLA-4 is expressed on activated T cells and counters the co-stimulatory signal provided by CD28, thereby downregulating T-cell activation. Thus, CTLA-4 blockade enhances T-cell activation and proliferation. To date, the development of ipilimumab has spanned nearly two decades (Figure 1).3 Ipilimumab was approved in 2011 by the US Food and Drug Administration (FDA) for the treatment of advanced melanoma.4 This was considered a milestone event because ipilimumab is the

Seminars in Oncology, Vol 41, No 5, Suppl 5, October 2014, pp S14-S29

Current perspectives on immunotherapy

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Figure 1. Key development milestones of ipilimumab. Preclinical studies of CTLA-4 inhibition in murine tumor models began in the mid-1990s in the academic laboratory of Dr James Allison. Ipilimumab was developed as a fully human monoclonal antibody in 1999 and progressed through clinical development over the next decade. In 2011, ipilimumab received regulatory approval in both the United States and the European Union for the treatment of patients with unresectable or metastatic melanoma. Ongoing trials of ipilimumab are evaluating combination therapies, use in the adjuvant setting, and efficacy and safety in tumor types other than melanoma.3 Abbreviations: ASCO, American Society of Clinical Oncology; CTLA-4, cytotoxic T-lymphocyte-associated antigen-4.

first therapy shown to improve OS in a randomized trial of patients with metastatic melanoma.5

Success of Ipilimumab as Both First-Line and Second-Line Therapy for Metastatic Melanoma Results from study MDX010-20, a multinational, randomized, double-blind, phase III trial, supported regulatory approval of ipilimumab for previously treated patients with metastatic melanoma (Table 1).6–19 In this study, patients were randomized (3:1:1) to ipilimumab plus a glycoprotein 100 (gp100) peptide vaccine (n ¼ 403), ipilimumab alone (n ¼ 137), or gp100 alone (n ¼ 136). Ipilimumab (3 mg/kg) with or without gp100 was administered once every 3 weeks for up to four treatments. Treatment with ipilimumab plus gp100 vaccine demonstrated a statistically significant OS benefit compared to that of the OS benefit of gp100 alone (median 10.0 months v 6.4 months; hazard ratio [HR] ¼ 0.68; P o.001). Additionally, 1-year and 2year survival rates were nearly double for patients treated with ipilimumab plus gp100 (43.6% and 21.6%, respectively) compared with 1-year and 2-year survival rates for those treated with gp100 alone (25.3% and 13.7%, respectively). Results also were consistently in favor of ipilimumab plus gp100, regardless of disease state at presentation, baseline serum lactate dehydrogenase levels, or age. Subsequently, study CA184-024, another multinational, randomized, double-blind, phase III trial, compared ipilimumab (10 mg/kg) plus dacarbazine (850 mg/m2; n ¼ 250) with placebo plus dacarbazine

(850 mg/m2; n ¼ 252), given at weeks 1, 4, 7, and 10 followed by dacarbazine alone every 3 weeks through week 22, in treatment-naı¨ve patients with advanced melanoma12 (Table 1). Median OS was significantly longer for patients treated with ipilimumab plus dacarbazine compared to the median OS of dacarbazine plus placebo (11.2 months v 9.1 months), and survival rates were higher with ipilimumab plus dacarbazine compared with those of dacarbazine plus placebo at 1 year (47.3% v 36.3%), 2 years (28.5% v 17.9%), and 3 years (20.8% v 12.2%; HR ¼ 0.72; P o.001). The addition of ipilimumab to dacarbazine also resulted in a 24% reduction in the risk of progression (HR ¼ 0.76; P ¼ .006). In these trials, approximately 10% of patients experienced prolonged tumor regression. In fact, some patients from the initial phase II trials of ipilimumab have remained free of progression for more than 5 years.3,20 Recently, initial results of the randomized, doubleblind, placebo-controlled European Organization for Research and Treatment of Cancer (EORTC) 18071 phase III trial of ipilimumab (10 mg/kg) as adjuvant therapy for patients with resected melanoma were reported13 (Table 1). Compared with placebo (n ¼ 476), ipilimumab (n ¼ 475) significantly improved recurrence-free survival (RFS) at 3 years (46.5% v 34.8%; HR ¼ 0.75; P ¼ .0013), and this benefit was consistent across subgroups.

Lessons Learned From Development of Ipilimumab The unprecedented activity of ipilimumab in patients with metastatic melanoma is exciting but

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Table 1. Key Published Monotherapy Clinical Trials of CTLA-4 Checkpoint Inhibitors in Solid Tumors6–19 Agent Ipilimumab

Phase I

I/II

Tumor Type

Treatment Arms

N

Prostate Ipi (hormonerefractory) CRPC Ipi þ radiotherapy (metastatic)

14

33

II

ED-SCLC (untreated)

Ipi þ pac/carb v pbo (ctrl) þ pac/carb

130

II

NSCLC (untreated)

Ipi þ pac/carb v pbo (ctrl) þ pac/carb

204

II

Renal cell carcinoma

Ipi (21 at lower dose; 40 at higher dose)

61

III

Melanoma

Ipi v ipi þ gp100 v gp100

676

Primary Endpoint

Efficacy Results

Grade 3/4 AEs

Completed6 Completed7 Completed8

Completed9

Completed10

Completed11 J.S. Weber

Z50% 14% 1 asthenia, 1 limb pain, PSA 1 dizziness (7.1%) decline Response 1 CR (11.3þ months), Colitis (16%), 6 SD hepatitis (10%) (2.8-6.1 months) irPFS Phased ipi v ctrl: Rates of 17% and 21% for HR 0.64; P ¼ .03 phased and concurrent Concurrent ipi v ctrl: (phased v concurrent: HR 0.75; P ¼ .11 12/7 fatigue, 0/5 rash, 2/0 pruritus, 10/0 arthralgia, 0/2 decreased appetite, 10/4 diarrhea) irPFS Phased ipi v ctrl: Rates of 15% and 20% for HR 0.72; P ¼ .05 phased and concurrent Concurrent ipi v ctrl: (phased v concurrent: HR 0.81; P ¼ .13 5/8 fatigue, 3/3 rash, 2/0 arthralgia, 2/0 asthenia, 5/7 diarrhea, 2/1 nausea, 2/1 vomiting, 0/1 neuropathy, 3/0 sensory neuropathy) Response Low dose: 1 PR Low dose: 3 enteritis (14%) High dose: 5 PR High dose: 13 enteritis, (ORR ¼ 12.5%) 1 hypophysitis, 1 adrenal insufficiency, 1 aseptic meningitis, 1 with both enteritis and hypophysitis OS 10.0 months Ipi þ gp100: derm (40%), (ipi þ gp100) v GI (32.1%), endo 10.1 (ipi alone) v (3.9%), other (3.2%), 6.4 months hepatic (2.1%) Ipi alone: derm (43.5%), (gp100 only) GI (29%), endo (7.6%),

Status

III

Tremelimumab

I

I/II

II

II II

Completed12

Ongoing13

Completed14

Current perspectives on immunotherapy

III

Completed15 Completed16

Completed17 Completed18

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other (4.6%), hepatic (3.8%) Melanoma Ipi þ dacarbazine 502 OS 47.3% v 36.2% at Diarrhea (32.8%); increase v dacarbazine 1 year; 28.5% v in ALT (29.1%); pruritus (26.7%); increase in AST þ pbo 17.9% at 2 years; 20.8% v 12.2% at (26.7%); rash (22.3%); 3 years colitis (4.5%); hepatitis (1.6%) Melanoma Ipi v pbo 951 RFS 46.5% v 34.8% at Ipi v pbo: GI (15.9% v 3 years 0.8%), hepatic (10.6% v ipi v pbo: HR 0.75; 0.2%), endocrine P ¼ .0013 (8.5% v 0) Hepatocellular Tremelimumab 37 Response PR 17.6% AST (45%); hyponatremia carcinoma (30%); ALT (25%); encephalopathy (15%); acute renal failure, syncope, total bilirubin (10% each); skin rash, diarrhea, diverticulitis, depression, GI hemorrhage, cholangitis, pneumonia, hypoalbuminemia, thrombocytopenia, neutropenia (5% each) Melanoma Tremelimumab 28 þ 89 ORR 1 CR, 3 PR (phase II) 12 (27%) at 15 mg/kg 6 (13%) at 10 mg/kg (phase II) Colorectal Tremelimumab 47 Response ORR 2.2% (1 PR) 5 diarrhea (11%), 1 ulcerative colitis, 1 fatigue, 1 autoimmune thrombocytopenia, and 1 hypokalemia (2% each) Melanoma Tremelimumab 246 ORR 6.6% ORR (16 PR) Diarrhea (11%), colitis (4%), fatigue (2%) Mesothelioma Tremelimumab 29 ORR 2 durable PR (7%); GI (14%); hepatic (7%); neurologic, pancreatic median PFS of (3% each) 6.2 months; median OS of 10.7 months

J.S. Weber Abbreviations: AEs, adverse events; ALT, alanine aminotransferase; AST, aspartate aminotransferase; carb, carboplatin; CR, complete response; CRPC, castration-resistant prostate cancer; ctrl, control; derm, dermatologic; ED-SCLC, extensive-stage disease small cell lung cancer; endo, endocrine; gp100, glycoprotein 100; GI, gastrointestinal; HR, hazard ratio; ipi, ipilimumab; irPFS, immune-related progression-free survival; ns, not significant; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; pac, paclitaxel; pbo, placebo; PFS, progression-free survival; PR, partial response; PSA, prostate-specific antigen; RFS, recurrence-free survival; SD, stable disease.

Diarrhea (18%); fatigue Completed19 (6%); nausea, vomiting, decreased appetite, abdominal pain, (4% each); dyspnea (3%); rash, peripheral edema (2% each); pruritus, thrombocytopenia, pyrexia, neutropenia, constipation, cough, headache, weight decrease (r1% each) Response 10.7% ORR v 9.8% (ns); OS 12.6 months v 10.7 months (ns) 655 Tremelimumab v standard of care chemotherapy Melanoma III

Treatment Arms Tumor Type Phase Agent

Table 1 (continued )

N

Primary Endpoint

Efficacy Results

Grade 3/4 AEs

Status

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not without side effects. Because it “loosens the reins” on T-cell activation and proliferation, ipilimumab can potentially allow self-reactive T cells to proliferate, and this has been associated with characteristic side effects collectively referred to as immune-related adverse events (irAEs). The most common irAEs are associated with symptoms of diarrhea, nausea, constipation, abdominal pain, vomiting, vitiligo, and rash.4,11,12 Approximately 60% of ipilimumab-treated patients in study MDX010-20 experienced irAEs.11 In a small proportion of patients, irAEs can be serious and may include severe hepatitis, enterocolitis, hypophysitis, pancreatitis, nephritis, and neuropathy.4 Due to the risk of developing irAEs, close monitoring is essential during anti-CTLA-4 therapy, and management guidelines recommend symptomatic treatment for mild irAEs and dose delay/omission and intense monitoring for moderate or persistent mild irAEs.4,21,22 In patients with persistent or high-grade irAEs, ipilimumab should be permanently discontinued and high-dose systemic corticosteroid therapy should be initiated. The most common irAEs typically resolve within 4–9 weeks of onset, depending on the organ system involved.3 Ipilimumab also has unique patterns of clinical response compared to that of chemotherapy, which is generally associated with rapid but transient responses in melanoma. The Response Evaluation Criteria in Solid Tumors (RECIST), which defines disease progression as the presence of new or progressing lesions, was developed to provide uniform assessment of responses to chemotherapy.23 Ipilimumab therapy, on the other hand, may result in unusual response patterns and kinetics, such as early apparent disease progression followed by profound and durable tumor regression, or initial regression of established lesions despite development of new, smaller lesions.24 Consequently, immune-related response criteria and immune-related RECIST were established to evaluate tumor response to ipilimumab and other immunotherapies.25,26 These criteria accommodate the presence of new lesions and do not automatically assume progression when new disease arises.

Overview of Other Tumor Types Where Ipilimumab Is Currently Being Investigated Ipilimumab also has demonstrated activity in other advanced cancers (Table 1), most notably small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), and prostate cancer. Ipilimumab was evaluated in combination with standard carboplatin-based doublet chemotherapy in two phase II studies in treatment-naı¨ve patients with SCLC or NSCLC.8,9 In both studies, a phased, but not concurrent, schedule of ipilimumab (10 mg/kg) plus paclitaxel (175 mg/m2) and carboplatin (area

Current perspectives on immunotherapy

under the curve 6) significantly improved progression-free survival (PFS) compared to that of paclitaxel and carboplatin alone. In patients with SCLC, median PFS was 6.4 months for patients treated with ipilimumab plus paclitaxel and carboplatin versus 5.3 months for those treated with paclitaxel and carboplatin alone (HR ¼ 0.64; P ¼ .03), in patients with NSCLC, median PFS was 5.7 months versus 4.6 months, respectively (HR ¼ 0.72; P ¼ .05). Phase III studies of ipilimumab are currently ongoing in patients with newly diagnosed SCLC (NCT01450761) and NSCLC (NCT01285609). Ipilimumab (3, 5, or 10 mg/kg) with or without a single dose of focal radiotherapy was evaluated in a phase I/II study in patients with metastatic castration-resistant prostate cancer (mCRPC).7 Declines in prostate-specific antigen (PSA) Z50% were observed in 22% of patients. Ipilimumab is currently being evaluated in phase III studies of patients with advanced prostate cancer (NCT01057810 and NCT00861614). In addition, numerous trials of ipilimumab are currently ongoing in other solid tumors, including platinum-sensitive ovarian cancer (NCT01611558), unresectable or metastatic gastric cancer following chemotherapy (NCT01585987), and in combination with chemotherapy in metastatic bladder cancer (NCT01524991).

Another CTLA-4 Inhibitor in Development: Tremelimumab Tremelimumab is another anti-CTLA-4 mAb in development. Similar to data seen with ipilimumab, tremelimumab demonstrated encouraging antitumor activity with durable responses in phase I and phase II studies in patients with metastatic melanoma15,17 (Table 1). Based on these findings, a phase III study comparing tremelimumab (15 mg/ kg once every 90 days) with physician’s choice of chemotherapy (temozolomide or dacarbazine) was conducted in patients with newly diagnosed metastatic melanoma19 (Table 1). Tremelimumab failed to improve OS compared to that achieved with chemotherapy (12.6 months v 10.7 months; HR ¼ 0.88; P ¼ .127), and clinical development in melanoma was discontinued. More recently, tremelimumab has demonstrated activity in malignant mesothelioma, metastatic colorectal cancer, and hepatocellular carcinoma.14,16,18

NEXT-GENERATION IMMUNE CHECKPOINT INHIBITORS The unprecedented activity of ipilimumab in achieving durable objective responses and significantly improving PFS and OS in advanced melanoma has spurred the clinical development of other immune checkpoint inhibitors. The agents farthest

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along in clinical development are antibodies that block programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1). The primary role of the PD-1/PD-L1 pathway is to limit T-cell effector function in peripheral tissues. PD-1 engagement on T cells results in T-cell exhaustion. Tumors often express PD-L1, which binds to PD-1 on activated cytotoxic T cells and natural killer cells in the tumor microenvironment, thereby inducing T-cell dysfunction.27–35 At present, the most mature data available for antibodies targeting this pathway are from phase I/II clinical trials.

Early Trials of Anti-PD-1/Anti-PD-L1 in Melanoma In 2013, anti-PD-1/anti-PD-L1 antibodies were named “drug of the year”.36 This was due, in a large part, to the exciting data reported from early phase trials of nivolumab, pembrolizumab, and MPDL3280A for treatment of patients with advanced melanoma (Table 2).37–49 These studies demonstrated impressive rates of response and prolonged duration of response. Nivolumab, a fully human immunoglobulin G4 (IgG4) anti-PD-1 mAb, was the first to be assessed in patients with metastatic melanoma. Nivolumab was evaluated in a phase I study in patients with a variety of malignancies (n ¼ 296), including 107 with advanced melanoma37–39,50 (Table 2). The objective response rate (ORR) for the melanoma cohort was 31% (33 of 106), and OS rates were 61% at 1 year, 44% at 2 years, and 41% at 3 years. Grade 3 or grade 4 drug-related AEs occurred in 21% of patients, with the most common being lymphopenia (3%), and fatigue, increased lipase, diarrhea, and endocrine disorders (2% each); no grade Z3 drug-related pneumonitis was reported in the melanoma cohort. In a phase I trial in patients with melanoma (N ¼ 105) who were ipilimumab-naı¨ve or had progressed on ipilimumab, treatment with nivolumab (1, 3, or 10 mg/kg) resulted in a median PFS of 4.2 months, an estimated median OS of 16.7 months, and a 1-year OS rate of 65%40 (Table 2). Of the 20 patients with prior ipilimumab-induced grade 3/4 irAEs, only one had a subsequent grade 3/4 irAE with nivolumab, which was different from the toxicity seen with ipilimumab. However, treatment-emergent grade 1/2 rash and injection reactions were more frequent. In general, agents targeting PD-1/PD-L1 appear to have a more favorable toxicity profile compared to the toxicity profile of anti-CTLA-4, likely due to the distinct biologic characteristics of the two pathways (ie, PD-1/PD-L1 checkpoint interaction occurs primarily at the tumor site and focuses on activated T cells, whereas the CTLA-4/B7 interaction occurs mainly in lymphoid organs).36,51 Results from

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Table 2. Key Published Monotherapy Clinical Trials of PD-1/PD-L1 Checkpoint Inhibitors in Solid Tumors37–49 Target/Agent PD-1/ Nivolumab

PD-1/ Pembrolizumab

Phase Tumor Type I

I

Treatment Arms

Primary N Endpoint

Melanoma

Nivolumab

107

ORR

Melanoma

Nivolumab

105

ORR

NSCLC

Nivolumab

127

ORR

Renal cell Nivolumab carcinoma

34

ORR

Melanoma

Pembrolizumab 135

ORR

Melanoma

Pembrolizumab 221

ORR

Efficacy Results 31% ORR; median OS 16.8 mos; 1-year OS 61%; 2-year OS 44%; 3-year OS 41% Median PFS 4.2 mos; estimated median OS 16.7 mos; 1-year OS 65%

Grade 3/4 AEs

Status

21% pts (3% lymphopenia; Ongoing37–39 2% fatigue, increase lipase, diarrhea, hepatitis, and endocrine disorders) Of 20 pts with prior ipiCurrently induced grade 3/4 irAEs, recruiting40 1 had a subsequent nivolumab-induced grade 3/4 irAE 2% each of fatigue, Ongoing38,41 pneumonitis, and elevated AST*

Ongoing38,42 Completed43

Currently recruiting44–46

J.S. Weber

16% ORR; median OS 9.2 and 9.6 mos (squamous and nonsquamous); 1 year OS rate 44% and 41% (squamous and nonsquamous) 29% ORR; median 21% pts (including 6% OS 422 mos; 1 year hypophosphatemia, 6% OS rate 70% respiratory disorders) 38% ORR; median 13% pts, with 3 pts rash (2%), 1 pt pruritus (1%), PFS 47 mos; 8 pts SD; 77% had tumor 2 pts fatigue (1%) shrinkage during study 2 mg/kg Q3W: 33% ORR; 14% pts experienced grade median PFS 27 weeks; 3/4 AEs 24-week PFS 51% 10 mg/kg Q3W: 40% ORR; median PFS 23 weeks; 24-week PFS 48% Ipi-naïve; combined dose groups: 40% ORR; median PFS 24 weeks; 24-week PFS 51%

I

PD-L1/ BMS936559

I

PD-L1/ MPDL3280A

I

Hematologic Pidilizumab malignancies Melanoma BMS-936559

17

ORR

52

ORR

NSCLC

BMS-936559

49

ORR

Ovarian

BMS-936559

17

ORR

Renal cell BMS-936559 carcinoma

17

ORR

Solid tumors MPDL3280A

171

ORR

Completed47

17% ORR (9 pts); 27% SD 3% (7 pts): 1 adrenaline Completed48 (14 pts); 42% PFS at 24 insufficiency, weeks 1 pancreatitis, 1 vomiting, 10% ORR (5 pts); 12% SD 1 chest pain, 1 sarcoidosis, (6 pts); 31% PFS at 24 1 endophthalmitis, weeks 1 elevated aspartate, 6% ORR (1 pt); 18% SD (3 1 myasthenia gravis* pts); 22% PFS at 24 weeks 12% ORR (2 pts); 41% SD (7 pts); 53% PFS at 24 weeks 21% ORR (based on 122 39% of pts (including Ongoing49 pts); 24-week PFS: 44% hepatitis, rash, colitis)

Current perspectives on immunotherapy

PD-1/ Pidilizumab

Ipi-treated; combined dose groups: 28% ORR; median PFS 23 weeks; 24-week PFS 44% 33% ORR (1 CR, 4 SD, None 1 minimal response)

n Grade 3/4 irAEs presented are for all tumor types included. Abbreviations: AEs, adverse events; AST, aspartate aminotransferase; CR, complete response; ipi, ipilimumab; mos, months; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; pt, patient; SD, stable disease; Q3W, every 3 weeks.

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ongoing, randomized, phase III trials of nivolumab versus physician’s choice (dacarbazine or carboplatin with paclitaxel) in advanced melanoma (NCT01721746), nivolumab versus dacarbazine in untreated or advanced melanoma (NCT01721772), and nivolumab or nivolumab plus ipilimumab versus ipilimumab in untreated advanced melanoma (NCT01844505) are eagerly awaited. Pembrolizumab, a humanized IgG4 anti-PD-1 mAb, is being studied in both ipilimumab-naı¨ve patients with melanoma and those previously treated with ipilimumab. The ORR was 38% in a phase I study of 135 patients with advanced melanoma, and response rates did not differ between patients who had (37%) or had not (38%) received prior ipilimumab43 (Table 2). Responses were durable and over 81% of patients who had a response were still receiving treatment at the time of the analysis. Common treatment-related AEs included fatigue, rash, pruritus, and diarrhea; most of the AEs were low grade. The phase I KEYNOTE-001 study evaluated three doses of pembrolizumab (10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, and 2 mg/kg every 3 weeks) in ipilimumab-naı¨ve and ipilimumab-treated patients with melanoma (N ¼ 221)44–46 (Table 2). Initial results showed that the ORR was higher in patients treated with pembrolizumab 10 mg/kg every 3 weeks compared to patients treated with pembrolizumab 2 mg/kg every 3 weeks (40% v 33%), and ORR was higher in ipilimumab-naı¨ve patients compared to that of ipilimumab-treated patients (40% v 28%). Approximately 14% of patients experienced drug-related grade 3/4 AEs. Randomized phase II (NCT01704287) and phase III (NCT01866319) studies evaluating pembrolizumab versus chemotherapy and ipilimumab, respectively, are currently ongoing. BMS-936559, a fully human IgG4 anti-PD-L1 mAb, also was evaluated in patients with advanced melanoma. In a phase I study of 207 patients with advanced malignancies, including 55 patients with melanoma48 (Table 2), an objective response was observed in nine of the 52 evaluable patients with melanoma (17%), and five had a duration of response of at least 1 year. Common treatment-related AEs were fatigue, infusion reactions, diarrhea, arthralgia, rash, nausea, pruritus, and headache; most of the AEs were low grade. As of June 2014, however, no phase II or phase III trials of BMS-936559 were listed on clinicaltrials.gov. MPDL3280A, a humanized anti-PD-L1 mAb, was evaluated in a phase I dose-escalation study in patients with solid tumors, including melanoma49 (Table 2). Of the patients evaluable for efficacy (N ¼ 122), an ORR of 21% was observed. Of those evaluable for safety (N ¼ 171), none experienced dose limiting toxicities and a maximum tolerated dose was not identified.

J.S. Weber

Although no phase I or phase III trials of MPDL3280A in melanoma were listed on clinicaltrials.gov as of June 2014, a phase III study in NSCLC is currently recruiting (NCT02008227).

Comparison of Anti-PD-1/Anti-PD-L1 to Anti-CTLA-4 Although there are currently no completed randomized, head-to-head studies comparing antiPD-1/anti-PD-L1 and anti-CTLA-4 mAbs, the fact that they both target immune checkpoint molecules prompts a natural comparison. PD-1/PD-L1 and CTLA-4 have distinct biologic properties, and preclinical studies also suggest that the combination of CTLA-4 and PD-1 blockade is more effective than either alone. The CTLA-4 and PD-1 blockade approach52 is currently being explored in a clinical setting for treatment of advanced melanoma (NCT01024231). Given a more tumor-specific mechanism of immune activation, existing data suggest that PD-1/PD-L1 inhibitors may be more active and less toxic than CTLA-4 inhibitors.53 The growing body of data on expression of PD-1/PD-L1 as potential prognostic and predictive biomarkers also adds to the rising interest in targeting this pathway for cancer therapy.54

Ongoing Clinical Trials of Anti-PD-1/Anti-PDL1 in Multiple Tumor Types In addition to the promising early phase results in melanoma, nivolumab and BMS-936559 have demonstrated impressive activity in NSCLC and renal cell carcinoma, and pidilizumab has shown promising results in hematologic malignancies38,41,42,47,48 (Table 2). Overall, these results suggest that targeting the PD-1/PD-L1 pathway has broad potential across multiple tumor types.

DEVELOPMENT OF SIPULEUCEL-T FOR PROSTATE CANCER AND CURRENT USE Sipuleucel-T is distinct from other marketed antitumor treatments because it is an individually tailored immunotherapeutic vaccine manufactured from immune cells specific to each patient.55 In 2010, sipuleucel-T was approved by the FDA based on a demonstrated survival benefit in men with asymptomatic/minimally symptomatic mCRPC.56 It is the first approved autologous cellular immunotherapy to improve OS in patients with advanced cancer.57 Developing sipuleucel-T for each patient involves a multistep process57 (Figure 2). First, the patient’s own peripheral blood mononuclear cells, including autologous antigen-presenting cells (APCs) and T cells, are harvested via leukapheresis. The harvested cells are then cultured ex vivo with PA2024, a

Current perspectives on immunotherapy

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Figure 2. Process of sipuleucel-t administration. Production of sipuleucel-T begins at an approved apheresis center. The unprocessed cells from the leukapheresis procedure are then shipped to one of three manufacturer’s facilities for product preparation. During a standard processing procedure, the cells are activated through co-culturing with PA2024. The activated cells are then shipped back to the physician’s infusion center. This process is repeated three times for a standard course of treatment.57

recombinant fusion protein composed of prostatic acid phosphatase (PAP), a prostate cancer-associated antigen, and granulocyte-macrophage colony-stimulating factor (GM-CSF). The GM-CSF component stimulates maturation of APCs into mature DCs. Following ex vivo activation, the mature APCs loaded with PAP peptides in the context of the patient’s type 1 and type 2 human leukocyte antigens are reinfused into the patient where they can stimulate CD4þ and CD8þ cells, thus potentially triggering an immune response specifically against PAP-positive PC cells. A complete treatment course consists of three doses administered at approximately 2-week intervals57 (Figure 2). Each dose is manufactured approximately 3 days prior to infusion. The first infusion serves to prime the anti-tumor immune response, and the two subsequent infusions boost that response, which may result in long-lasting antigenspecific cellular and humoral immune responses to PAP.

Clinical Trials Resulting in Approval of Sipuleucel-T To date, three randomized, double-blind, placebocontrolled phase III trials of sipuleucel-T have been completed in patients with mCRPC. The first two trials, D9901 and D9902A, had identical designs.55,58 Patients with asymptomatic mCRPC were randomized 2:1 to receive sipuleucel-T or placebo, and were followed for 36 months. In study D9901 (N ¼ 127) there was a statistically nonsignificant improvement in time to disease progression (TTP) for the sipuleucel-T group compared to the TTP found with the control group (HR 1.45; P ¼ .05). However, at 36

months, there was a statistically significant 4.5month prolongation in OS with sipuleucel-T compared to that of the control (25.9 months v 21.4 months, HR 1.71; P ¼ .01).55 Although study D9902A was discontinued prematurely based on the primary analysis of study D9901, it also demonstrated a similar improvement in OS in the sipuleucel-T group compared to the OS of the control group (19.0 months v 15.7 months; HR 0.79; P ¼ .33), but the OS benefit did not reach statistical significance.55 As a result, a third phase III trial was conducted to confirm the OS benefit. Approval of sipuleucel-T was supported mainly by data from the pivotal phase III IMPACT trial (D9902B).59 A total of 512 men with asymptomatic/minimally symptomatic mCRPC were randomized 2:1 to receive sipuleucel-T or control infusions of nonantigen-treated APCs. The primary endpoint was met with a 22% reduction in risk of death (HR 0.78; P ¼ .03) in patients treated with sipuleucel-T and a 4.1-month prolongation in median OS in patients treated with sipuleucel-T compared to the median OS in the control group (25.8 months v 21.7 months). The 3-year survival rate in the sipuleucel-T group was 31.7% and 23.0% in the control group. The side effects of sipuleucel-T are generally infusion-related and self-limiting. Based on an integrated safety analysis of 601 sipuleucel-T–treated patients and 303 control patients treated in four randomized phase III trials, the most frequently reported AEs associated with sipuleucel-T were chills, pyrexia, headache, myalgia, influenza-like illness, and hyperhidrosis.60 In general, these events were mild or moderate in severity, occurred within 1 day of infusion, and resolved within 2 days. Given the favorable toxicity profile and convenient route of

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administration, the success of sipuleucel-T has paved the way for new vaccine treatment paradigms in prostate cancer and other oncology indications.

CURRENT THERAPEUTIC VACCINES IN PHASE III DEVELOPMENT The success of sipuleucel-T has encouraged the development of other therapeutic prostate cancer vaccines, including the tumor-cell based GVAX-PCa and the viral vaccine Prostvac (Bavarian Nordic, Mountain View, CA). GVAX-PCa contains a mixture of two irradiated allogeneic prostate cancer cell lines (LNCaP and PC-3) that have been genetically modified to constitutively express GM-CSF.61,62 Although GVAX-PCa appeared to have promising activity in early phase trials, two phase III trials, known as VITAL-1 (NCT00089856) and VITAL-2 (NCT00133224), were prematurely terminated due to a lack of therapeutic effect and increased mortality, respectively. Studies combining GVAX-PCa with immune checkpoint inhibitors are ongoing. Rilimogene-galvacirepvec/Prostvac, also known as PSA-TRICOM, is a recombinant viral vaccine. The primary vaccination includes a recombinant vaccinia vector, which is followed by multiple booster vaccinations with a recombinant fowlpox vector. Both vectors contain transgenes for PSA and three co-stimulatory molecules (LFA-3 [CD58], ICAM-1 [CD54], and B7-1 [CD80]).63 The clinical potential of rilimogenegalvacirepvec in patients with mCRPC has been demonstrated in two phase II studies.64,65 Although the first study (N ¼ 125) did not meet its primary endpoint of improved PFS, there was a statistically significant increase in OS among patients treated with rilimogene-galvacirepvec compared to patients treated with placebo (25.1 months v 16.6 months; HR 0.56; P ¼ .006).64 The survival outcome was subsequently confirmed in a smaller study (N ¼ 32) in which median OS among rilimogene-galvacirepvec–treated patients was 26.6 months.65 Rilimogenegalvacirepvec is currently being evaluated in the phase III PROSPECT study (NCT01322490; Table 3). Algenpantucel-L is currently the most clinically advanced vaccine for pancreatic cancer. This cellbased vaccine contains two irradiated human allogeneic pancreatic cancer cell lines that are engineered to express the murine enzyme α-1,3-galactosyl transferase (αGT). This enzyme directs the synthesis of α-galactosyl (αGal) epitopes on surface proteins and glycolipids, which can boost immune responses to tumor cells by making them appear as “foreign” to the immune system.66 Binding of naturally occurring anti-αGal antibodies to αGal epitopes on the tumor cell lines activates complement-mediated lysis and antibody-dependent cell-mediated toxicity. In a

J.S. Weber

phase II study of algenpantucel-L plus standard of care (SOC) treatment in patients (N ¼ 70) with resected pancreatic cancer, the 1-year disease-free survival (DFS) and OS rates were 62% and 86%, respectively, and 3year DFS and OS rates were 26% and 39%, respectively.67–68 The most common AEs were induration and pruritus at the sites of injection, which typically resolved spontaneously within a week of onset. Algenpantucel-L is currently being evaluated in two phase III trials, IMPRESS (NCT01072981; Table 3) and PILLAR (NCT01836432; Table 3). The lipopeptide vaccine tecemotide is designed to induce an immune response against cancer cells expressing the cell-surface glycoprotein MUC1, which is expressed on numerous cancers, including NSCLC, and is involved in tumor growth and survival.69,70 Tecemotide is composed of the BLP25 lipopeptide, the immunoadjuvant monophosphoryl lipid A, and several other lipids. It is being evaluated in multiple tumor types, and to date the most advanced results are from the phase III START trial in patients (N ¼ 1513) with unresectable stage III NSCLC.71 In a phase IIb trial of previously treated patients with stage IIIb/IV NSCLC, tecemotide demonstrated a nonsignificant improvement in OS compared to the OS of best supportive care in patients with locoregional disease,70–72 and this led to a phase III trial in stage III NSCLC. Although the START trial did not meet the primary endpoint of improved OS in the overall patient population, a prespecified exploratory analysis demonstrated a statistically significant improvement in patients who received tecemotide after concurrent chemoradiotherapy compared to that of patients who received placebo (30.8 months v 20.6 months; HR 0.78; P ¼ .016). Of note, the FDA placed a clinical hold on tecemotide after a patient with multiple myeloma developed encephalitis in a phase II study. The clinical hold has since been lifted, and phase III development in NSCLC is continuing (START2 [NCT02049151] and INSPIRE [NCT01015443]; Table 3); however, a phase III study (STRIDE; NCT00925548) in women with advanced breast cancer was terminated.73 Another peptide vaccine being investigated in NSCLC and melanoma targets the gene MAGEA3. Unlike MUC1, MAGEA3 is expressed almost exclusively on tumor cells. The MAGE-A3 vaccine, administered intramuscularly with the AS02B immunostimulant, was being investigated as adjuvant therapy in the MAGRIT trial (NCT00480025) in patients with completely resected NSCLC that expressed the MAGEA3 gene. This was the largest adjuvant lung cancer trial ever conducted. Unfortunately, this trial was recently closed because an interim analysis showed that the vaccine failed to significantly improve DFS. This vaccine also recently failed in a phase III adjuvant trial in melanoma. These failures highlight the challenges facing vaccines that

NCT Number/Trial Name

Treatment Arms

NCT01322490/ PROSPECT Rilimogene-galvacirepvec þ GMCSF Rilimogenegalvacirepvec þ placebo Placebo þ placebo NCT01072981/ IMPRESS Algenpantucel-L þ GEM ⫾ 5-FU chemoradiation GEM ⫾ 5-FU chemoradiation NCT01836432/ PILLAR Algenpantucel-L þ FOLFIRINOX FOLFIRINOX Algenpantucel-L þ GEM/Nab-PAC GEM/Nab-PAC NCT02049151/ START2 Tecemotide Placebo NCT01015443/ INSPIRE NCT01480479/ ACT IV n

Tecemotide þ BSC Placebo þ BSC Rindopepimut þ TMZ KLH (control) þ TMZ

N*

Primary Endpoint

Asymptomatic/minimally symptomatic mCRPC

1200

OS

Currently recruiting

Surgically resected pancreatic cancer

722

OS

Ongoing

Borderline resectable or locally advanced unresectable pancreatic cancer

280

OS

Currently recruiting

Completed concurrent chemoradiotherapy for unresectable stage III NSCLC Asian patients with unresectable stage III NSCLC Newly diagnosed, surgically resected, EGFRvIII-positive GBM

1002

OS

Currently recruiting

500

OS

700

OS

Currently recruiting Currently recruiting

Target Population

Status

Current perspectives on immunotherapy

Table 3. Selected Ongoing Phase III Clinical Trials of Vaccines in Solid Tumors

Planned enrollment. Abbreviations: 5-FU, fluorouracil; BSC, best supportive care; EGFR, epidermal growth factor receptor; FOLFIRINOX, 5-flourouracil, leucovorin, oxaliplatin, and irinotecan; GBM, glioblastoma multiforme; GEM, gemcitabine; GM-CSF, granulocyte-macrophage colony-stimulating factor; KLH, keyhole limpet hemocyanin; mCRPC, metastatic castration-resistant prostate cancer; NabPac, nab-paclitaxel; NCT, national clinical trial; NSCLC, non-small cell lung cancer; OS, overall survival; TMZ, temozolomide. Source: clinicaltrials.gov

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do not incorporate a strategy to overcome tumorinduced immune suppression. Rindopepimut, which is being evaluated in glioblastoma multiforme (GBM), is an epidermal growth factor receptor variant III (EGFRvIII)-targeted peptide vaccine.74 EGFRvIII is expressed in approximately one-third of primary GBM, but not in normal tissue, and it is associated with poor long-term survival.75,76 In three phase II trials (ACTIVATE [N ¼ 18], ACT II [N ¼ 22], and ACT III [N ¼ 65]), significantly higher PFS and OS were demonstrated in patients with newly diagnosed GBM who were treated with rindopepimut in combination with SOC (temozolomide) compared with patients treated with historic controls, as well as in comparison with previous phase III trials. ACTIVATE, ACT II, and ACT III demonstrated a PFS of 14.2 months, 15.2 months, and 12.3 months, respectively, in the rindopepimut/ SOC groups and 6.3 months in the historic control group, and an OS of 26.0 months, 23.6 months, and 24.6 months in the rindopepimut/SOC groups and 15.0 months in the historic control group.71,77–79 Toxicity was mainly limited to injection site reactions, and was typically grade 2 or less. Rindopepimut is currently being evaluated in the phase III ACT IV study (NCT01480479; Table 3).

CONCLUSIONS The regulatory approvals of ipilimumab and sipuleucel-T, and the encouraging data from early clinical trials of other immune checkpoint inhibitors and novel vaccine strategies, have brought immunotherapy to the forefront of cancer therapeutics and made the goal of long-term tumor control seem achievable by immunologic manipulation. Results from phase III studies of mAbs targeting PD-1/PD-L1 and numerous cancer vaccines in development are eagerly awaited. The potential addition of these strategies to the anticancer armamentarium is anticipated to provide important benefits to patients. Emerging strategies for cancer immunotherapy are reviewed within the article by Brian Rini within this supplement.

Acknowledgments The author would like to thank Marithea Goberville, PhD, and Chelsey Goins, PhD, for their assistance in drafting the manuscript, and Christi Gray for her assistance with preparing the manuscript for submission.

REFERENCES 1. Krummel MF, Allison JP. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med. 1995;182:459–65.

J.S. Weber

2. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271:1734–6. 3. Wolchok JD, Hodi FS, Weber JS, Allison JP, Urba WJ, Robert C, et al. Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma. Ann N Y Acad Sci. 2013;1291:1–13. 4. Yervoy (ipilimumab) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; 2013. 5. Sharma P, Wagner K, Wolchok JD, Allison JP. Novel cancer immunotherapy agents with survival benefit: recent successes and next steps. Nat Rev Cancer. 2011;11:805–12. 6. Small EJ, Tchekmedyian NS, Rini BI, Fong L, Lowy I, Allison JP. A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer. Clin Cancer Res. 2007;13:1810–5. 7. Slovin SF, Higano CS, Hamid O, Tejwani S, Harzstark A, Alumkal JJ, et al. Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study. Ann Oncol. 2013;24:1813–21. 8. Reck M, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. Ann Oncol. 2013;24:75–83. 9. Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012;30:2046–54. 10. Yang JC, Hughes M, Kammula U, Royal R, Sherry RM, Topalian SL, et al. Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J Immunother. 2007;30:825–30. 11. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23. 12. Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517–26. 13. Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, et al. Ipilimumab versus placebo after complete resection of stage III melanoma: Initial efficacy and safety results from the EORTC 18071 phase III trial [abstract]. J Clin Oncol (Meeting Abstracts). 2014;32(5s):LBA9008. ˜ arrairaegui 14. Sangro B, Gomez-Martin C, de la Mata M, In M, Garralda E, Barrera P, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol. 2013;59:81–8. 15. Camacho LH, Antonia S, Sosman J, Kirkwood JM, Gajewski TF, Redman B, et al. Phase I/II trial of tremelimumab in patients with metastatic melanoma. J Clin Oncol. 2009;27:1075–81.

Current perspectives on immunotherapy

16. Chung KY, Gore I, Fong L, Venook A, Beck SB, Dorazio P, et al. Phase II study of the anti-cytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, tremelimumab, in patients with refractory metastatic colorectal cancer. J Clin Oncol. 2010;28: 3485–90. 17. Kirkwood JM, Lorigan P, Hersey P, Hauschild A, Robert C, McDermott D, et al. Phase II trial of tremelimumab (CP-675,206) in patients with advanced refractory or relapsed melanoma. Clin Cancer Res. 2010;16:1042–8. 18. Calabro L, Morra A, Fonsatti E, Cutaia O, Amato G, Giannarelli D, et al. Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol. 2013;14:1104–11. 19. Ribas A, Kefford R, Marshall MA, Punt CJ, Haanen JB, Marmol M, et al. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol. 2013;31:616–22. 20. Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res. 2013;19:5300–9. 21. Weber JS, Ka¨hler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30: 2691–7. 22. Kaehler KC, Piel S, Livingstone E, Schilling B, Hauschild A, Schadendorf D. Update on immunologic therapy with anti-CTLA-4 antibodies in melanoma: identification of clinical and biological response patterns, immune-related adverse events, and their management. Semin Oncol. 2010;37:485–98. 23. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47. 24. Pennock GK, Waterfield W, Wolchok JD. Patient responses to ipilimumab, a novel immunopotentiator for metastatic melanoma: how different are these from conventional treatment responses? Am J Clin Oncol. 2012;35:606–11. 25. Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, ´ C, et al. Guidelines for the evaluation of Lebbe immune therapy activity in solid tumors: immunerelated response criteria. Clin Cancer Res. 2009;15: 7412–7420. 26. Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. Developing a common language for tumor response to immunotherapy: immunerelated response criteria using unidimensional measurements. Clin Cancer Res. 2013;19:3936–43. 27. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8:793–800. 28. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member

S27

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192:1027–34. Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992;11:3887–95. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704. Keir ME, Liang SC, Guleria I, Latchman YE, Qipo A, Albacker LA, et al. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med. 2006;203:883–95. Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motifcarrying immunoreceptor. Immunity. 1999;11: 141–51. Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science. 2001;291:319–22. Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol. 2007;19:813–24. Parsa AT, Waldron JS, Panner A, Crane CA, Parney IF, Barry JJ, et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med. 2007;13:84–8. Robert C, Soria JC, Eggermont AM. Drug of the year: programmed death-1 receptor/programmed death-1 ligand-1 receptor monoclonal antibodies. Eur J Cancer. 2013;49:2968–71. Sznol M, Kluger HM, Hodi FS, McDermott DF, Carvajal RD, Lawrence DP, et al. Survival and long-term followup of safety and response in patients (pts) with advanced melanoma (MEL) in a phase I trial of nivolumab (anti-PD-1; BMS-936558; ONO-4538) [abstract]. J Clin Oncol (Meeting Abstracts). 2013;31:CRA9006. Topalian SL, Sznol M, Brahmer JR, McDermott DF, Smith DC, Gettinger SN, et al. Nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients with advanced solid tumors: Survival and long-term safety in a phase I trial [abstract]. J Clin Oncol (Meeting Abstracts). 2013;31:3002. Hodi FS, Sznol M, Kluger HM, McDermott DF, Carvajal RD, Lawrence DP, et al. Long-term survival of ipilimumab-naive patients (pts) with advanced melanoma (MEL) treated with nivolumab (anti-PD-1, BMS936558, ONO-4538) in a phase I trial [abstract]. J Clin Oncol (Meeting Abstracts). 2014;32(5s):9002. Weber JS, Kudchadkar RR, Gibney GT, Yu B, Cheng PY, Martinez A, et al. Updated survival, toxicity, and biomarkers of nivolumab with/without peptide vaccine in patients naive to, or progressed on, ipilimumab (IPI) [abstract]. J Clin Oncol (Meeting Abstracts). 2014;32(5s):3009. Brahmer JR, Horn L, Antonia SJ, Spigel DR, Gandhi L, Sequist LV, et al. Survival and long-term follow-up of the phase I trial of nivolumab (Anti-PD-1; BMS-936558; ONO4538) in patients (pts) with previously treated advanced

J.S. Weber

S28

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

non-small cell lung cancer (NSCLC) [abstract]. J Clin Oncol (Meeting Abstracts). 2013;31:8030. Drake CG, McDermott DF, Sznol M, Choueiri TK, Kluger HM, Powderly JD, et al. Survival, safety, and response duration results of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in a phase I trial in patients with previously treated metastatic renal cell carcinoma (mRCC): Long-term patient follow-up [abstract]. J Clin Oncol (Meeting Abstracts). 2013;31:4514. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369:134–44. Ribas A, Hodi FS, Kefford R, Hamid O, Daud A, Wolchok JD, et al. Efficacy and safety of the anti-PD1 monoclonal antibody MK-3475 in 411 patients (pts) with melanoma (MEL) [abstract]. J Clin Oncol (Meeting Abstracts). 2014;32(5s):LBA9000. Hamid O, Robert C, Ribas A, Wolchok JD, Hodi FS, Kefford R, et al. Randomized comparison of two doses of the anti-PD-1 monoclonal antibody MK-3475 for ipilimumabrefractory (IPI-R) and IPI-naive (IPI-N) melanoma (MEL) [abstract]. J Clin Oncol (Meeting Abstracts). 2014;32(5s):3000. Kefford R, Ribas A, Hamid O, Robert C, Daud A, Wolchok JD, et al. Clinical efficacy and correlation with tumor PD-L1 expression in patients (pts) with melanoma (MEL) treated with the anti-PD-1 monoclonal antibody MK-3475 [abstract]. J Clin Oncol (Meeting Abstracts). 2014;32(5s):3005. Berger R, Rotem-Yehudar R, Slama G, Landes S, Kneller A, Leiba M, et al. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res. 2008;14:3044–51. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65. Herbst RS, Gordon MS, Fine GD, Sosman JA, Soria J-C, Hamid O, et al. A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors [abstract]. J Clin Oncol (Meeting Abstracts). 2013;31:3000. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54. Gelao L, Criscitiello C, Esposito A, Goldhirsch A, Curigliano G. Immune checkpoint blockade in cancer treatment: a double-edged sword cross-targeting the host as an "innocent bystander". Toxins (Basel). 2014;6:914–33. Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A. 2010;107:4275–80. Menzies AM, Long GV. New combinations and immunotherapies for melanoma: latest evidence and clinical utility. Ther Adv Med Oncol. 2013;5:278–85.

54. Kyi C, Postow MA. Checkpoint blocking antibodies in cancer immunotherapy. FEBS Lett. 2014;588:368–76. 55. Higano CS, Schellhammer PF, Small EJ, Burch PA, Nemunaitis J, Yuh L, et al. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer. 2009;115:3670–9. 56. Provenge (sipuleucel-T) [prescribing information]. Seattle, WA: Dendreon Corporation; 2011. 57. Sims RB. Development of sipuleucel-T: autologous cellular immunotherapy for the treatment of metastatic castrate resistant prostate cancer. Vaccine. 2012;30:4394–7. 58. Small EJ, Schellhammer PF, Higano CS, Redfern CH, Nemunaitis JJ, Valone FH, et al. Placebo-controlled phase III trial of immunologic therapy with sipuleucelT (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol. 2006;24:3089–94. 59. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411–22. 60. Hall SJ, Klotz L, Pantuck AJ, George DJ, Whitmore JB, Frohlich MW, et al. Integrated safety data from 4 randomized, double-blind, controlled trials of autologous cellular immunotherapy with sipuleucel-T in patients with prostate cancer. J Urol. 2011;186:877–81. 61. Geary SM, Salem AK. Prostate cancer vaccines: update on clinical development. Oncoimmunology. 2013;2:e24523. 62. Le DT, Pardoll DM, Jaffee EM. Cellular vaccine approaches. Cancer J. 2010;16:304–10. 63. Shore ND. PROSTVACR targeted immunotherapy candidate for prostate cancer. Immunotherapy. 2014;6:235–47. 64. Kantoff PW, Schuetz TJ, Blumenstein BA, Glode LM, Bilhartz DL, Wyand M, et al. Overall survival analysis of a phase II randomized controlled trial of a Poxviralbased PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol. 2010;28:1099–105. 65. Gulley JL, Arlen PM, Madan RA, Tsang KY, Pazdur MP, Skarupa L, et al. Immunologic and prognostic factors associated with overall survival employing a poxviralbased PSA vaccine in metastatic castrate-resistant prostate cancer. Cancer Immunol Immunother. 2010;59:663–74. 66. Gunturu KS, Rossi GR, Saif MW. Immunotherapy updates in pancreatic cancer: are we there yet? Ther Adv Med Oncol. 2013;5:81–9. 67. Hardacre JM, Mulcahy M, Small W, Talamonti M, Obel J, Krishnamurthi S, et al. Addition of algenpantucel-L immunotherapy to standard adjuvant therapy for pancreatic cancer: a phase 2 study. J Gastrointest Surg. 2013;17(1):94–100;discussion p. 100-1. 68. Rossi GR, Hardacre JM, Mulcahy MF, Talamonti MS, Obel JC, Lima CR, et al. Effect of algenpantucel-L immunotherapy for pancreatic cancer on antimesothelin antibody (Ab) titers and correlation with improved overall survival [abstract]. J Clin Oncol (Meeting Abstracts). 2013;31:3007.

Current perspectives on immunotherapy

69. Agrawal B, Krantz MJ, Reddish MA, Longenecker BM. Rapid induction of primary human CD4þ and CD8þ T cell responses against cancer-associated MUC1 peptide epitopes. Int Immunol. 1998;10:1907–16. 70. Sangha R, Butts C. L-BLP25: a peptide vaccine strategy in non small cell lung cancer. Clin Cancer Res. 2007;13:s4652–4. 71. Butts C, Socinski MA, Mitchell PL, Thatcher N, Havel L, Krzakowski M, et al. Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III nonsmall-cell lung cancer (START): a randomised, doubleblind, phase 3 trial. Lancet Oncol. 2014;15:59–68. 72. Butts C, Murray N, Maksymiuk A, Goss G, Marshall E, Soulie`res D, et al. Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small-cell lung cancer. J Clin Oncol. 2005;23:6674–81. 73. Vansteenkiste J, Zielinski, Linder A, Dahabreh J, Gonzalez EE, Malinowski W, et al. Adjuvant MAGE-A3 immunotherapy in resected non-small-cell lung cancer: phase II randomized study results. J Clin Oncol. 2013;31:2396–403. 74. Babu R, Adamson DC. Rindopepimut: an evidencebased review of its therapeutic potential in the treatment of EGFRvIII-positive glioblastoma. Core Evid. 2012;7:93–103.

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75. Pelloski CE, Ballman KV, Furth AF, Zhang L, Lin E, Sulman EP, et al. Epidermal growth factor receptor variant III status defines clinically distinct subtypes of glioblastoma. J Clin Oncol. 2007;25:2288–94. 76. Tang CK, Gong XQ, Moscatello DK, Wong AJ, Lippman ME. Epidermal growth factor receptor vIII enhances tumorigenicity in human breast cancer. Cancer Res. 2000;60:3081–7. 77. Lai RK, Recht LD, Reardon DA, Paleologos N, Groves M, Rosenfeld MR, et al. Long-term follow-up of ACT III: A Phase II trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma [abstract]. Neuro Oncol (Meeting Abstracts). 2011;13(Suppl 3) (IM-03). 78. Sampson JH, Aldape KD, Archer GE, Coan A, Desjardins A, Friedman AH, et al. Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIIIexpressing tumor cells in patients with glioblastoma. Neuro Oncol. 2011;13:324–33. 79. Sampson JH, Heimberger AB, Archer GE, Aldape KD, Friedman AH, Friedman HS, et al. Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol. 2010;28:4722–9.