ABSTRACT: Antibody-based targeting of the immune suppressor molecule cytotoxic T-lymphocyte antigen 4 (CTLA-4) with ipilimumab has been studied in metastatic melanoma in a number of clinical trials, including a recent phase III trial. This marks the first randomized clinical trial reporting an overall survival benefit using immune modulation in metastatic melanoma. Along with its therapeutic benefits, ipilimumab presents unique challenges to clinicians; these are related to the monitoring of treatment response and the management of drug-related toxicities. This drug is currently being investigated in various cancers, and its indications are likely to be expanded.
Melanoma is the most aggressive form of skin cancer. The incidence of melanoma has increased considerably in the United States in recent decades and has been accompanied by a rise in mortality from metastatic disease. In 2010, an estimated 68,130 new cases of melanoma will have been diagnosed (38,870 males and 29,260 females), and 8,700 deaths are expected (5,670 male and 3,030 female). Five-year survival rates for patients with metastatic melanoma are less than 10%, with a median survival of approximately 7 months. Despite innumerable clinical trials for advanced melanoma, the options for these patients are limited.
A vast body of literature from clinical and laboratory studies indicates that melanoma cells are relatively resistant to standard chemotherapeutic agents; response rates with single or combined agents are only in the range of 10% to 20%. Dacarbazine(Drug information on dacarbazine) is the only FDA-approved chemotherapy for melanoma, and it has not shown a survival benefit in randomized clinical trials.
Immunological therapies for metastatic melanoma have been heavily studied. Multiple clinical trials of immune modulation strategies—including cytokines, tumor vaccines, adoptive immunotherapy, and combinations of the foregoing—have been conducted over the last few decades. However, until very recently no randomized clinical trial showed an overall survival difference. Treatment with high-dose interleukin-2 (IL-2) results in prolonged responses in a minority of patients.[1,6] Biochemotherapy (combinations of chemotherapy, interferon, and IL-2) is associated with an improved response rate but has not been shown to improve overall survival compared with chemotherapy in randomized trials.[7-11] Because of an unfavorable side effect profile, high-dose IL-2 and biochemotherapy require excellent cardiovascular and pulmonary function; the majority of elderly patients are thus ineligible.[11-13] Given the paucity of well-tolerated, effective therapies for this disease, clinical trials have remained a good choice for the majority of patients.
A recently published phase III trial by Hodi and colleagues clearly offers hope after the multi-decade quest to develop immunotherapy for metastatic melanoma.[5,14] Ipilimumab, a monoclonal antibody to cytotoxic T-lymphocyte antigen 4, CD152 (CTLA-4), is the first agent to show an overall survival benefit in metastatic melanoma in a randomized clinical trial. Ipilimumab is expected to be approved by the FDA. In this article, we provide an overview of the rationale for targeting CTLA-4 as a method for treating melanoma, and we summarize the majority of the clinical trials involving ipilimumab. We have focused on salient issues in the clinical management of patients receiving ipilimumab, including interpretation of scans and management of toxicities.
Melanoma and Immunogenicity: Is Melanoma Unique?
Melanoma is considered an “immunogenic” cancer because of its ability to undergo spontaneous regression.[5,15,16] Melanoma tumors are often associated with lymphocyte infiltration correlating with areas of histologic regression. Furthermore, a higher incidence of melanoma has been reported in organ transplant patients receiving immunosuppressive therapy. Patients with immunosuppression have an increased risk of dying of melanoma, indicating that melanoma cells might be susceptible to surveillance by the immune system.[15,17] Previous clinical studies have shown an association between autoimmunity and survival in patients with resected melanoma.
The most convincing evidence that melanoma can be immunogenic is derived from preclinical research on the fundamental aspects of T-cell biology and antigen recognition. Although the fundamentals of tumor immunology can be broadly applied to all types of tumors, many of these principles were first demonstrated in melanoma, and the clinical application of immunotherapy for cancer has been most widely studied in melanoma. Use of IL-2 and interferon-α result in tumor shrinkage, and a small percentage of patients with metastatic melanoma who are treated with IL-2 have a durable response and possibly a cure. Melanoma is not the only tumor to respond to immune-based therapy; encouraging results have been seen in lung cancer, renal cell carcinoma, prostate cancer, and others.[18-20]
Why CTLA-4 Blockade Enhances Anti-Tumor Immunity
CTLA-4, a member of the immunoglobulin super-family, is a negative regulator of the immune system and plays a key role in endogenous and vaccine-induced antitumor immunity.[21-23] With the exception of T-regulatory cells (CD4+CD25+, Foxp3+), resting lymphocytes do not constitutively express CTLA-4 on their surface; however, expression is transiently up-regulated after the binding of the T-cell receptor. Up-regulation of CTLA-4 on the surface of cytotoxic T cells results in inhibition of proliferation of these cells. Cytotoxic T lymphocytes (CTLs) are key to a melanoma-specific antitumor response, and various melanoma-specific clones of CTLs have been identified.[15,24,25]
CTLA-4, when expressed on the surface of CTLs, binds to both members of the B7-1 and B7-2 (CD80 and CD86) ligand pair, which are expressed on the surface of antigen-presenting cells (APCs). The binding affinity of CTLA-4 for B7-1/B7-2 is higher than the affinity of CD28 for this ligand pair. The interaction between CTLA-4 and B7-1/B7-2 activates a cell-signaling cascade that results in cell cycle arrest of the CTLs.[21,23] This leads to T-cell anergy and interferes with IL-2 secretion and IL-2 receptor expression. This phenomenon leads in turn to inhibition of T-cell priming and immune escape, thereby allowing tumor growth. In contrast, the binding of CD28 on the CTLs to B7-1 and B7-2 leads to stimulation of T-cell proliferation and production of IL-2. Because of its expression on dendritic cells, effecter T cells, and regulatory T cells, CTLA-4 has a multidimensional role in the various stages of immune response; it produces immune homeostasis by inhibiting T-cell responses and contributing to tolerance to self antigens.[27,28] Blocking of CTLA-4 is thought to shift the dynamic balance of the immune response, enhancing recognition of tumor antigens and tumor eradication. Consequently, this strategy also decreases tolerance to self antigens, leading to autoimmunity.[25,29]
Blocking CTLA-4/B7 interactions in preclinical murine models has shown to induce rejection of several types of established transplantable tumors in mice, including colon cancer, prostate cancer, lymphoma, and renal cancer. It has been shown in murine models that blockade of CTLA-4 expressed on CD4+CD25+ regulatory T cells abrogates the function of these cells and induces autoimmune colitis. CTLA-4 blockade causes a dynamic shift in the ratio of Foxp3+ regulatory T cells (Tregs) to CD8+ cytotoxic T cells, culminating in effective immune recognition of tumor. This phenomenon is well documented in vivo in post-treatment tumor biopsies of patients treated with CTLA-4 blockade and correlates with therapy-induced tumor necrosis.[21,30]
Ipilumumab in Clinical Trials
Ipilimumab (MDX-010: Medarex, Inc./Bristol-Myers Squibb Co.) is a fully humanized IgG1 monoclonal antibody to CTLA-4. In Table 1, we have summarized select clinical trials of ipilimumab in metastatic melanoma. Objective response rates (complete response [CR] + partial response [PR]) have been in the range of 5% to 20%. Disease control rates (CR + PR + stable disease [SD]) of 15% to 30% have been reported. Studies involving higher doses of ipilimumab have shown higher response rates with increased toxicities.[3,29,31,32]
Dose and Schedule of Ipilimumab
In most phase II and III clinical trials, induction therapy with doses ranging from 3 mg/kg to 10 mg/kg were given at 3-week intervals for four cycles.[14,29,31-35] Subsequent maintenance and reinduction schedules varied.[12,14, 5] A phase II study with multiple doses of ipilimumab by Wolchok and colleagues demonstrated dose-dependent efficacy; the best overall response rate—11.1%—was seen with the 10-mg/kg dose, compared with 4.2% with the 3-mg/kg dose. Hodi and colleagues used a dose of 3 mg/kg in a phase III trial, with response rates of 11% (for ipilimumab alone) and 5.7% (for ipilimumab with a gp100 vaccine).
Rates of adverse reactions, particularly autoimmune events, appear to be dose- and schedule-dependent.[12,32] Drug-related grade 3-4 toxicities were reported (primarily skin, gastrointestinal, and endocrine) in 20% to 40% of patients. Bowel perforation due to immune colitis, and mortality related to treatment, have been reported in a small percentage of patients (less than 2%) in the majority of trials.
The role of maintenance and reinduction treatment has been explored in phase II and III trials.[12,14,35] In a phase III study, patients with confirmed PR, CR, or SD for 3 months’ duration after completion of initial therapy (12 weeks) were offered reinduction with their assigned treatment regimen if they had experienced progression of disease (PD). Of the 31 patients who were given reinduction therapy in this study, one achieved a CR, five achieved a PR, and 15 had SD. In other studies, patients who responded to induction ipilimumab received maintenance doses every 3 months until PD or development of severe toxicities.[12,29,35] Currently, the role of maintenance therapy is unclear, and further randomized clinical trials are needed to address this issue.
Response Assessment Criteria for Ipilimumab
World Health Organization (WHO) and Response Evaluation Criteria in Solid Tumors (RECIST) criteria are radiological measurement tools developed primarily to define the objective response to cytotoxic chemotherapy.[36-39] Through clinical experience, it has become increasingly clear that these criteria are not suitable tools for assessing response to immune-based therapies. For cytotoxic chemotherapy, the mechanism of action is primarily direct cancer cell death; thus, the effect can typically be quantified by measuring the decrease in tumor size. Hence, SD after cytotoxic chemotherapy is usually transient and does not signify consequential antitumor activity.
The mechanism by which immunotherapy works is complex; in vivo studies and post-treatment biopsies indicate that tumor can be infiltrated by CD8+ CTLs, resulting in tumor inflammation.[21,30] Therefore, tumor size may remain unchanged or may even increase before eventual regression is detectable by objective response criteria.[36,37] In various clinical trials with immune-based therapies, it has been shown that CR, PR, or SD can occur after an obvious increase in the size of the tumor, which would qualify as PD by WHO or RECIST criteria. A measurable response can be more delayed than with conventional chemotherapies. Therefore, SD or even small increases in tumor size can be seen in the setting of a meaningful therapeutic effect.
Wolchok and colleauges have proposed a new set of criteria to assess response in patients treated with ipilimumab; these are called the immune-related response criteria (irRC). irRC include total tumor burden, which is calculated by summation of the product of the perpendicular diameters of measurable index lesions and new lesions. Transient increases in the size of individual lesions and the transient appearance of new lesions are not considered PD. irRC include the following four categories:
• irCR: decrease of total tumor burden from baseline by 100%.
• irPR: decrease from baseline by > 50% but < 100%.
• irPD: increase from nadir by > 25%.
• irSD: < 50% decrease or < 25% increase in tumor burden.
Further details of irRC are described elsewhere.[29,35,36]
Although these proposed definitions have not been tested prospectively in a randomized clinical trial, they are helpful in patient management, as RECIST or WHO criteria can underestimate the antitumor activity of ipilimumab. Treating physicians, however, should also be mindful that irRC can potentially overestimate response to therapy and lead to unnecessary prolongation of potentially toxic treatment without benefit.