Immune Checkpoint Blockade in Cancer: Inhibiting CTLA-4 and PD-1/PD-L1 With Monoclonal Antibodies

Abstract

Inhibitory receptors such as anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1) expressed on tumor-specific T cells lead to compromised activation and suppressed effector functions such as proliferation, cytokine secretion, and tumor cell lysis. Modulating these receptors using monoclonal antibodies, an approach termed “immune checkpoint blockade,” has gained momentum as a new approach in cancer immunotherapy. This treatment concept was first introduced in patients with advanced melanoma: in this patient population, the anti-CTLA-4 antibody ipilimumab was the first drug ever to show improved overall survival in phase III trials. Antibodies directed against PD-1 and its ligand, PD-L1, have shown much promise in the treatment of melanoma, renal cell cancer, non-small cell lung cancer, and other tumors, as evident by encouraging rates and durability of tumor responses. Because of the successes with immune checkpoint inhibitors in cancer immunotherapy, many new agents and strategies, including combination approaches, are being developed at a fast pace.

Figure. T-Cell Interaction With Dendritic Cells and Tumor Cells: The Immune Checkpoints CTLA-4 and PD-1/PD-L1

Introduction

Tumor mutations give rise to tumor-specific neoantigens that can be recognized by the immune system, leading to elimination of cancer cells. To defend themselves from immune attack, tumors can employ a host of mechanisms such as local immune suppression in the tumor microenvironment, induction of T cell tolerance, and immune editing.^1-3 Many previous cancer immunotherapies have likely been limited by these suppressive mechanisms. A novel therapeutic strategy that tackles a critical immune-modulating mechanism has recently risen to the forefront of cancer immunotherapy: the blockade of the inhibitory receptors cytotoxic T-lymphocyte—associated antigen 4 (anti-CTLA-4) and programmed death-1 (PD-1) and its ligand, PD-L1, an approach termed immune-checkpoint blockade. This treatment is designed to improve activation and effector function of tumor-specific T cells.

Evidence that immune-checkpoint blockade is an effective cancer therapy was first documented in patients with advanced melanoma. In this patient population, the anti-CTLA-4—specific monoclonal antibody ipilimumab led to overall survival (OS) benefit in phase III trials, resulting in FDA approval for this agent in 2010.^4,5 Recently reported data from large phase I studies have indicated that targeting the inhibitory receptors PD-1 and PD-L1 may be even more powerful. The observation that PD-1 and PD-L1 inhibition seem to induce tumor regression in patients with non-small cell lung cancer (NSCLC) and other tumor types (in addition to melanoma and renal cell cancer [RCC]) has attracted particular attention by the oncology community since these cancers have traditionally not been considered susceptible to any form of immunotherapy.^6-8 The documented tumor activity of immune checkpoint blockade has validated this therapeutic approach and has brought the field of cancer immunotherapy to the forefront of novel cancer therapeutics.

Ipilimumab

CTLA-4 is an inhibitory receptor expressed on T cells. It has much higher binding affinity to the co-stimulatory receptor B7 than the co-stimulatory receptor CD28, and therefore tips the balance from the T cell activating interaction between CD28 and B7 to inhibitory signaling between CTLA-4 and B-7, leading to suppression of T cell activation.⁹ The biological role of CTLA-4 is the modulation of T cell responses, predominantly during initial activation in the lymph node and the prevention of autoimmunity, which is impressively illustrated by the development of lethal massive lymphoproliferation in CTLA-4 knock-out mice.^10,11 Ipilimumab and tremelimumab are fully-human monoclonal antibodies targeting CTLA-4.

Clinical activity of ipilimumab in patients with advanced melanoma was first shown in a series of phase II studies, in which the drug was given at dosages between 0.3 mg/kg and 10 mg/kg every 3 weeks for four doses, followed by maintenance therapy.^12-14 Two phase III trials revealed improved OS. Response rates were relatively low (11%-15%), however, a large proportion of patients whose tumors did respond experienced durable responses or disease stabilization for many years. The durability of responses is also reflected in the consistent separation of the OS curves by approximately 10% after up to 4 years of follow-up.¹⁵ In a recent pooled analysis of outcomes in phase II and III clinical trials as well as observational data on almost 5000 patients with advanced melanoma, ipilimumab was shown to result in a survival plateau that begins after 3 years and extends through the 10th year; approximately 17%-25% of patients benefited from this long-term disease control.¹⁶ Of note, continued treatment with ipilimumab is not required to achieve this effect, and most patients received only a small number of treatments.

PD-1/PD-L1 Pathway

The inhibitory receptor PD-1 is expressed on activated T cells and modulates T cell function mainly during the effector phase in peripheral tissues including tumors (as opposed to the upregulation of CTLA-4 during the early activation phase in the lymph node). The PD-1 ligand, PD-L1, is expressed on epithelial and endothelial cells, in addition to different types of immune cells such as antigen-presenting cells (dendritic cells, macrophages, B cells). PD-L1 can be both constitutively expressed and upregulated by interferons present in an inflammatory condition such as a chronic tissue infection. It is thought that tumors “exploit” this regulatory function to evade a tumor-directed T cell response.

PD-L1 expression in tumors has been associated with poor prognosis in many tumor types, which has been interpreted as consistent with its role in immune evasion. However, recent reports have challenged this notion to some extent, documenting favorable outcomes in melanoma patients with PDL1 positive tumors.¹⁷ PD-L1 expression in the tumors was colocalized with tumor T cell infiltration and interferon-γ mRNA expression, suggesting an “adaptive resistance” mechanism in which PD-L1 expression is a reflection for the melanoma being actively attacked by presumably melanoma-specific T cells, explaining the improved prognosis.¹⁷ Based on encouraging results from phase I studies, fastpaced clinical trial programs developing agents targeting both PD-1 and PD-L1 are ongoing. To date, results have been reported for the PD-1—specific antibodies nivolumab (also known as MDX-1106; ONO-4538) and MK3475 and the PDL1– specific antibodies BMS936559 (also known as MDX- 1105) and MPDL3280A (Table).

Nivolumab

Nivolumab is a fully-human IgG4 PD-1 receptor blocking antibody with no antibody-dependent cell death activity (consistent with its IgG4 Fc-domain). In a large phase I study, 26 of 94 patients (28%) with melanoma, 14 of 76 patients (18%) with NSCLC, and 9 of 33 patients (27%) with RCC had objective responses, which were durable in a large proportion of patients.⁸ The onset of RECIST responses was rapid: 15 of 33 patients (45%) had a complete response (CR) or partial response (PR) at the time of the first tumor assessment at 8 weeks. One hundred and twenty-two patients (41%) had adverse events (AEs) with suspected immune-related etiology such as pneumonitis, vitiligo, colitis, hepatitis, hypophysitis, and thyroiditis. The majority of the toxicities were reversible with treatment interruption, treatment discontinuation, or the administration of glucocorticoids. Treatment algorithms have been developed to guide treatment of inflammatory events associated with PD-1/PD-L1 blockade.

Table. CTLA-4 and PD-1 Pathway Inhibition: Clinical Studies in Different Tumor Types

Agent

Phase

Tumor Type

N

Efficacy

anti-CTLA-4

Ipilimumab (BMS)

III

(Ipilimumab + gp100 vs ipilimumab vs. gp100 3:1:1)

Melanoma

676

OS 10.1 months, RR 10.9% (ipilimumab) vs OS 6.4 months, RR 1.5% (gp100)

Ipilimumab (BMS)

III

(Ipilimumamb + DTCI versus DTIC)

Melanoma

502

OS 11.2 months, RR 15.2% (ipilimumab + dacarbazine) vs 9.2 months; RR 10.3% (dacarbazine)

anti-PD-1

Nivolumab (BMS)

I

Melanoma

107

RR: 31%

I

NSCLC

127

RR: 16%

I

RCC

34

RR: 29%

MK-3475 (Merck)

I

Melanoma

135

RR: 37%

anti-PD-L1

BMS936559

I

Melanoma

52

RR: 17%; SD 27%

NSCLC

49

RR: 10%; SD 10%

RCC

17

RR: 12%; SD 41%

Ovarian

17

RR: 6%; SD 18%

MPDL-3280A (Genentech/Roche)

I

Melanoma

45

RR: 26%

NSCLC

37

RR: 23%

NSCLC, non-small cell lung cancer; OS, overall survival; RCC, renal cell carcinoma; RR, relative risk; SD, stable disease.

The outcomes for patients with melanoma, NSCLC, and RCC were updated at the American Society of Clinical Oncology (ASCO) 2013 Annual Meeting. In melanoma, the median OS was 16.8 months; 1-year OS and 2-year OS were 61% and 44%, respectively. The objective response rate (ORR) was 31% (33/106). In the 3-mg/kg dosage cohort, the median OS was 20 months and ORR was 41% (7/17).¹⁸ The median duration of responses was 104 weeks. In addition to patients with ORRs, seven melanoma patients (7%) had stable disease (SD) for ≥24 weeks and four patients had a response with an unconventional (immune-related) pattern. For patients with NSCLC, the ORR was 20 of 122 patients (16%) in the updated data set; OS was 9.6 months. One-year OS and 2-year OS were 43% and 32%, respectively. In RCC, median OS was >22 months, with 70% and 52% 1-year and 2-year OS, respectively.

MK-3475

In a large phase I study, 135 patients with advanced melanoma were treated with the humanized anti-PD-1 monoclonal antibody MK-3475 at dosages of 10 mg every 2 weeks, 2 mg very 3 weeks, or 10 mg every 3 weeks.¹⁹ A large proportion of patients had visceral metastases including brain metastases. Generalized symptoms included fatigue, fever, chills, myalgias, and headaches, which were almost exclusively grade 1 or 2. Grade 3 or 4 drug-related AEs were seen in 17 patients (13%). Treatment-related pneumonitis, all grade 1 or 2 occurred, in six patients (4%). The ORR for all dosage cohorts evaluated by RECIST 1.1 was 38% and 52% in the highest (10 mg/kg every 2 weeks) dosage cohort. An additional eight unconfirmed responses were seen, resulting in a response rate including confirmed and unconfirmed responses of 44%. No difference in response rate was observed between prior treatment with ipilimumab versus no prior treatment with ipilimumab. The majority of objective responses were seen at the time of the first tumor assessment at 12 weeks. Importantly, the median duration of responses and median OS had not been reached after 11 months of follow-up, suggesting encouraging durability of these responses. Phase II and III trials using MK-3475 are ongoing in melanoma and NSCLC, whereas other tumor types are under investigation in phase I and II studies. No clinical efficacy data have been reported to date from these studies.

PD-L1 Blockade

BMS936559

The fully human anti-PD-L1 monoclonal antibody BMS936559 (MDX-1105) was assessed in patients with NSCLC, melanoma, RCC, ovarian cancer, gastric cancer, pancreatic cancer, and colorectal cancer, most of which were refractory to one or more lines of prior systemic treatment.⁷ Grades 1 and 2 inflammatory/ immune-mediated toxicities such as rash, diarrhea, hypothyroidism, and hepatitis were observed in 39% of patients, and 9% of patients had treatment-related grade 3 or 4 AEs. Objective tumor responses were seen in patients with melanoma (9/52; 17%), NSCLC (5/49; 10%), RCC (2/17; 12%), and ovarian cancer (1/17; 6%). Furthermore, 12% to 41% of patients in these cohorts experienced stable disease lasting ≥24 weeks.

MPDL-3280A

MPDL-3280A is a fully-human monoclonal PD-L1—specific antibody of the IgG4 isotype. Clinical safety and efficacy data have been reported on 38 patients with advanced melanoma and 85 patients with heavily pretreated locally advanced and metastatic NSCLC, which were cohorts of a phase IA dose escalation study.²⁰ Six of 38 melanoma patients (14%) had treatment- related grade 3 and 4 AEs, and two patients (5%) had immune-related grade 3 and 4 events. Eleven of 38 patients (29%) with advanced melanoma had a CR or PR, while two of 38 patients (5%) had stable disease lasting ≥24 weeks.

In another study, 12 of 53 patients (23%) with NSCLC who were evaluable for responses achieved an objective response after treatment with single-agent MPDL-3280A.²¹ Interestingly, the response rate was higher in smokers compared with nonsmokers, suggesting that the higher tumor mutation rate in smokers leads to the expression of a higher number of neoantigens, which may make tumors in smokers more immunogenic, and therefore more sensitive to an immune checkpoint-blocking approach.

Concurrent PD-1 and CTLA-4 Blockade

There is preclinical evidence in the B16 melanoma model for synergy between CTLA-4 and PD-1/PD-L1, which is consistent with the distinct and complementary roles of the two molecules in the regulation of T cell responses, providing the rationale for combination treatment of patients with advanced melanoma in a phase I trial.²² Fifty-three patients received concurrent treatment with nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4)23 followed by nivolumab as a single agent given every 3 weeks for four doses, and maintenance with nivolumab and ipilimumab administered every 12 weeks for up to eight doses. Twenty-eight of 53 patients (53%) had grade 3 or 4 treatment-related AEs, including elevated transaminases, diarrhea, rash, elevated lipase, and emesis. Common grade 1 and 2 events were rash, pruritus, fatigue, diarrhea, fever, nausea, and elevated transaminases. Most of these toxicities were reversible and could be managed using standard protocol algorithms. Twenty-one of 52 patients (40%) had a confirmed response according to modified WHO criteria. There were four more responses as measured by immune-related response criteria and two patients had an unconfirmed tumor. Importantly, the majority of these responses were rapid in onset and deep as defined as ≥80% tumor reduction at 12 weeks. Notably, tumor responses were seen in patients with extensive and bulky disease, and 19 of 21 responses were ongoing at the time of data-cutoff, with response duration ranging up to 72 weeks.²³

Conclusion and Outlook

The clinical efficacy seen with PD-1/PD-L1 pathway blockade in patients with multiple different tumor types, most of whom were heavily pretreated, suggests that the B7-H1/ PD-1 pathway is an important target that many cancers may utilize to evade destruction by the host immune response. This observation in conjunction with the favorable toxicity profile of PD-1 and B7-H1 inhibition indicates potential broad applicability in patients with advanced cancers. Even more meaningful may be the durability of tumor responses observed with both CTLA-4 and PD-1/ PD-L1 pathway inhibition, which has reached the 10- year mark for some melanoma patients treated with ipilimumab who have not required any treatment for many years. The stunning tumor activity seen with concurrent PD-1 and CTLA-4 blockade in patients with advanced melanoma, many of whom had bulky metastatic disease, has led to rapidly expanding clinical trial programs that include the entire spectrum of solid tumor types. Many other combinatorial approaches including combinations of checkpoint blockade with novel vaccines, angiogenesis inhibition, molecular targeted therapies such as MAPK inhibition, and direct targeting of other immunosuppressive pathways are ongoing.

ABOUT THE AUTHOR

Affiliation:Patrick A. Ott, MD, PhD, is assistant professor of Medicine, Harvard Medical School, and clinical director, Melanoma Disease Center and Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA.

Disclosure: Dr. Ott reports no conflicts of interest to disclose.

Address correspondence to:Patrick_Ott@DFCI.harvard.edu

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