Ipilimumab: Developmental History, Clinical Considerations, and Future Perspectives

Michael A. Postow, MD1,2
Medical Oncology Fellow
Melanoma/Sarcoma Service
Memorial Sloan-Kettering Cancer Center

Jedd D. Wolchok, MD, PhD1,2,3,4
Melanoma/Sarcoma Service
Memorial Sloan-Kettering Cancer Center

1Department of Medicine
Memorial Sloan-Kettering Cancer Center
New York, NY

2Weill Medical College of Cornell
University, New York, NY

3Associate Director
Ludwig Center for Cancer Immunotherapy Memorial Sloan-Kettering Cancer Center New York, NY

4Ludwig Institute for Cancer Research
New York Branch, New York, NY

Development of a Novel Immune-Modulating Therapy

Ipilimumab (commercial name YervoyTM, Bristol-Myers Squibb, Princeton, NJ) was approved on March 25, 2011 by the US Food and Drug Administration (FDA) for the treatment of advanced melanoma. Its approval was a landmark event in the history of melanoma treatment, as it was the first therapy ever to demonstrate improved overall survival in a randomized phase III trial for patients with metastatic melanoma.1 Ipilimumab is a monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4 (CTLA-4). Since CTLA-4 is normally expressed on the surface of T-cells as a negative regulator of T-cell function, ipilimumab releases T-cells from this inhibitory mechanism, enabling the uninhibited T-cells to exert their full potential in creating antitumor immunity (Figure 1).

Figure 1: Panel “A” shows that T-cell activation involves binding of the T-Cell Receptor (TCR) to a peptide antigen bound to the major histocompatibility complex (MHC) on the surface of an antigen-presenting cell (APC). This process also involves the interaction of CD28 on T-cells with the B7 molecules on APC. Following T-cell activation, panel “B” shows that CTLA-4 is up-regulated and expressed on the cell surface of effector T-cells and functions as an inhibitory molecule, outcompeting CD28 in the binding to B7, and causing inhibition of T-cell activation and function. Ipilimumab binds to and inhibits the function of CTLA-4, thus enhancing T-cell function as shown in panel “C.”

Over 15 years of research have established the foundations for the therapeutic potential of ipilimumab. Preclinical development was led by Dr. James Allison, who initially demonstrated that antibodies directed at CTLA-4 could result in tumor regressions in mice.2 Pilot clinical studies of ipilimumab followed, with the Over 15 years of research have established the foundations for the therapeutic potential of ipilimumab. Preclinical development was led by Dr. James Allison, who initially demonstrated that antibodies directed at CTLA-4 could result in tumor regressions in mice.2 Pilot clinical studies of ipilimumab followed, with the first human phase I study of ipilimumab reported in 2002, demonstrating
tolerability with early hints of clinical activity.3 Subsequent phase II studies focused on establishing appropriate dosing (0.3mg/kg vs. 3mg/kg vs. 10mg/kg) and schedule, suggesting that the dose of ipilimumab was relevant. The highest administered dose, 10mg/kg, resulted in a higher response rate compared to the 3mg/kg dose, albeit with increased side effects.4

Ultimately, FDA approval at the 3mg/kg dose was based upon an overall survival benefit seen in a randomized phase III trial comparing ipilimumab (3mg/kg) with or without the gp100 peptide vaccine compared to gp100 alone for patients with previously treated, unresectable stage III or stage IV melanoma.1 More recently, the benefit of ipilimumab was also established for treatment-naïve patients through a second randomized phase III trial.5 Patients who received a higher dose of ipilimumab (10mg/kg) with dacarbazine had improved overall survival compared to those receiving dacarbazine alone.

Unique Spectrum of Side Effects: Immune-Related Adverse Events

Ipilimumab is generally well tolerated but can be associated with a host of novel side effects, presumably due to the immune system activation by CTLA-4 blockade. Collectively the spectrum of side effects is described as immune-related adverse events (irAEs). Though rates of irAEs differ in various trials, in the large, phase III trial reported by Hodi, et al (2010), irAEs most commonly affected the skin (rash/vitiligo/pruritis; 43.5% any grade, 1.5% grade 3-4); the liver (hepatitis/rise in liver enzymes; 3.8% any grade, 0% grade 3-4); the bowel (diarrhea/colitis; 29.0% any grade, 7.6% grade 3-4), and the endocrine system (hypophysitis, thyroiditis, adrenal insufficiency; 7.6% any grade, 3.8% grade 3-4).1

More rarely, uveitis, conjunctivitis, neuropathy, myopathy, and nephritis have been known to occur. IrAEs are typically responsive to interruption or discontinuation of CTLA-4 blockade in combination with immunosuppressive drugs such as steroids or occasionally tumor necrosis factor-blocking antibodies. At present, there is no clear preventive strategy to avoid irAEs. A randomized, double-blind, placebo- controlled trial assessing the role of prophylactic budesonide in reducing ipilimumab-associated diarrhea showed no benefit.6 IrAEs are not believed to be true autoimmune diseases, as they typically resolve with cessation of ipilimumab and appropriate immunosuppressive therapy. Given this side effect profile, however, ipilimumab is not recommended for patients with underlying autoimmune diseases, particularly inflammatory bowel diseases and autoimmune hepatitis. Patients with underlying autoimmune conditions were excluded from clinical trials in the development of ipilimumab, and its safety has not been assessed in this patient population.

Retrospective analysis suggests that patients who experience irAEs may be more likely to benefit from anti-CTLA-4 therapy. Serious irAEs, however, are not required for an anti-tumor response, nor does the development of irAEs guarantee clinical benefit. Monitoring for predisposition to irAEs and attempting to separate the therapeutic benefits of anti-CTLA-4 therapy from irAEs are areas of ongoing investigation.

Rethinking Radiographic Disease Assessment:  The Immune-Related Response Criteria

In addition to the unique side effect profile, ipilimumab is associated with novel patterns of clinical response, distinct from those observed with traditional cytotoxic chemotherapy. Cytotoxic chemotherapy typically is characterized by prompt responses. The “Response Evaluation Criteria in Solid Tumors” (RECIST) criteria were developed to standardize assessment of responses to chemotherapy in clinical trials. Patients treated with ipilimumab, however, experience alternative patterns and kinetics of response. In some cases, patients may have a period of early apparent disease progression before a profound disease response, or regression of initial lesions despite development of additional, smaller lesions.

A study evaluating the novel patterns of disease responses to ipilimumab across three phase II studies determined that improved survival was associated with a variety of radiographic response patterns.7 Consequently, the immune-related response criteria (irRC) were proposed to evaluate the benefits of ipilimumab and other related immunotherapeutic approaches. In general, the irRC considers the patient’s “total tumor burden” and requires confirmation of suspected disease progression with a subsequent radiographic test, approximately four weeks later. IrRC are already being used in tandem with traditional response criteria, such as RECIST, in current clinical protocols for prospective validation of immunotherapeutic agents such as ipilimumab.

Patient Selection: Biomarker Analyses

Considerable efforts have been directed towards understanding immunologic biomarkers associated with disease response to ipilimumab, to help determine which patients might be the best candidates for therapy. Monitoring of immunological parameters of patients undergoing therapy with ipilimumab has therefore been an integral component of completed and ongoing clinical trials. In one retrospective study of 51 patients treated with ipilimumab (10mg/kg), an absolute lymphocyte count (ALC) that exceeded 1000/µL at the time of the third ipilimumab dose (week 7 of therapy) was associated with an overall survival benefit.8

Additional work has investigated antigen-specific immune responses to a number of cancer-related antigens. Specifically, immune responses to the cancer-testis antigen NY-ESO-1 before or during ipilimumab therapy have been the most extensively characterized to correlate with clinical activity following therapy. In one recent study of 144 patients, those with detectable serum antibodies to NY-ESO-1 by ELISA prior to or during the course of ipilimumab therapy were more likely to achieve disease control (stable disease or disease response) from ipilimumab than those who did not have the serum antibodies.9 Seropositive patients treated at Memorial Sloan-Kettering Cancer Center who also had a detectable NY-ESO-1-specific CD8+ T-cell response showed a significant survival advantage compared to seropositive patients without a detectable CD8+ T-cell response. Though immunity to NY-ESO-1 was correlated with clinical benefit from ipilimumab, NY-ESO-1-specific immunity is likely a surrogate marker for the broader mechanisms of ipilimumab’s antitumor effects, rather than a direct mediator. Studies of ALC and NY-ESO-1 have identified them as potential biomarkers in retrospective analyses, and prospective validation is an area of active research. 

Future Directions: Combination Strategies To Increase the Number of Patients Who Benefit

Research leading to the approval of ipilimumab highlighted the importance of immune regulatory circuits and provided insights into how immunomodulatory antibodies that manipulate these mechanisms can dramatically improve clinical outcomes. Ipilimumab has fundamentally changed the landscape of melanoma treatment, with a substantial subset of patients now achieving long-term disease control and survival. Current research into understanding the pathophysiology of ipilimumab’s unique side effect profile and analyzing biomarkers predictive of response will ultimately lead to improved patient selection and clinical care.

Despite the therapy’s ability to create durable, long-lasting responses, there is a clear need to increase the number of patients who benefit. One study in treatment-naïve patients showed a trend towards a higher response rate when ipilimumab was combined with dacarbazine compared to ipilimumab alone.10 Despite the possibility of an additive effect in this study, further studies are necessary. Current and planned clinical trials are combining ipilimumab with chemotherapy, other immunotherapy, radiotherapy, and targeted therapy, such as BRAF inhibition (Table 1). Ipilimumab is also being investigated in the adjuvant setting after surgical resection of high-risk disease. We believe therapeutic strategies combining ipilimumab with other immunotherapeutic agents such as vaccines or other immunomodulatory antibodies that enhance T-cell responses may add to the benefit of ipilimumab, and we are conducting clinical trials to assess this promising possibility. 

Table 1. Selected Ipilimumab Combination Clinical Trials for Patients with Melanoma (Source: www.clinicaltrials.gov)

Ipilimumab and Radiotherapy

One promising combination therapeutic approach deserving of further investigation involves administering ipilimumab with radiotherapy. We recently reported on a patient treated with ipilimumab who had slowly progressive disease. After she received localized palliative radiotherapy, disease outside of the irradiated area remarkably regressed, possibly related to enhancement of the immune system by the radiation.11 This rare phenomenon has been described in the medical literature as the “abscopal effect” and refers to tumor regression outside of the irradiated field. Since we believe the immune system may be activated by radiotherapy, we are excited about the prospect of combining it with ipilimumab. We are actively designing a multi-institutional clinical trial to test this hypothesis.


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