August 2014, Vol 3, No 5
Blocking Immune Checkpoints in Metastatic MelanomaImmunotherapy
Dr Puzanov is currently an associate professor of medicine at Vanderbilt University School of Medicine and the director of melanoma clinical research at Vanderbilt-Ingram Cancer Center in Nashville, TN. He received his MD from Charles University in Prague, Czech Republic. His major interests are phase 1 drug development with emphasis on combination immune and targeted therapy development in melanoma and renal cell carcinoma as well as novel drug design. He has published over 30 original articles and serves as a reviewer for major oncology journals and as a section editor for Personalized Medicine in Oncology and associate editor for International Journal of Targeted Therapies in Cancer.
The incidence of metastatic melanoma has been on the rise in the past 3 decades, along with one of the fastest increasing death rates among cancers. In particular from 2006 to 2010, the incidence rates among whites increased by 2.7% per year, and the death rates among white males 50 years or older increased by 1.1%.1 In the United States alone, it is estimated that 76,200 new cases will be diagnosed in 2014, and an estimated 9710 people will die of their disease. For years, few therapeutic options were available for patients with advanced unresectable stage III or stage IV melanoma, the first-line therapy consisting of chemotherapy (paclitaxel with or without a platinum agent), biochemotherapy (temozolomide or dacarbazine), and immunotherapy (high-dose interleukin-2 [HD IL-2]). Less than 20% of patients treated with HD IL-2, the most effective of the treatments, have a response, and only about one-third of them experience a complete response.2 In addition to toxicity and unavailability of this treatment for patients with some preexisting conditions (cardiopulmonary complications, brain metastases), the impact on overall survival (OS) in patients with metastatic melanoma was negligible. With the lacking standard of care for the next step of the therapy, patients were encouraged to enroll in a clinical trial.
With the rising incidence of metastatic melanoma around the world, one of the deadliest cancers with 5-year survival rates of around 16%, recent advances in targeted therapies and immunotherapies are beginning to lift the heavy cloud of this diagnosis and light the way toward potentially curative treatments. For the first time in the history of this disease, there are treatments that significantly improve OS of the patients.
Cancer Immune Evasion
In recent years, the results from early immunotherapy trials ignited a seed of hope in the oncology community.3,4 Cancer immunotherapy was chosen as the breakthrough of the year in 2013 by the American Academy for the Advancement of Science, a recognition usually reserved for exciting advances in the basic sciences, and immune evasion is now being studied extensively as an emerging hallmark of cancer.5,6 Growing understanding of the mechanisms involved in tumor progression has sprouted active research in the area of immunotherapy, and new targets in the immunoregulatory pathways are being validated in laboratories around the world. The big shift from the general view of tumors as homogeneous masses of malignant cells to something more similar to a rapidly growing organ with its own functions and specific, ever-changing microenvironment resulted in many new insights, including the dual role of the immune system in cancer – on the one hand tumor-suppressive and on the other hand tumor-promoting.7,8
This duality can be explained through the concept of immunoediting, in which the immune system is capable of not only destroying malignant cells but also enabling tumor proliferation either by selecting for less immunogenic cells, thus creating tumor variants able to thrive in an immunocompetent host, or by creating conditions in the tumor microenvironment that are favorable for tumor outgrowth.9 Upon the emergence of transformed cells, the immune system is activated via a variety of mechanisms, including activation of receptors on innate immune cells by ligands coexpressed on the nascent transformed cells and recognition of tumor-specific antigens by the immune receptors on lymphocytes of the adaptive immune system, and proceeds to eliminate the tumor before it becomes clinically apparent. From the results of studies in mouse models, the immune components necessary for effective elimination depend on the specific tumor characteristics such as its origin (spontaneous or carcinogen-induced), its location, and its growth rate.8 As is now supported by numerous mouse model studies, some special tumor cell variants may escape the elimination and enter the equilibrium phase in which the adaptive immune system maintains these cell populations in check, often for many years, without clinical detection.10-14 During this process, the immune system “shapes” the tumor cells into viable, potentially highly aggressive tumors with low immunogenicity. Under special circumstances, such as immune system deterioration due to age or environmental effects, changes in the tumor population caused by the immune editing processes, or changes in the immune system functions caused by immunosuppressive activity of the tumor, it is possible for the tumor to escape this maintenance phase and begin to proliferate and manifest clinically.9
The mechanisms of immune evasion by cancer cells include alterations leading to reduced immune recognition, such as loss of antigens or antigen processing function within the tumor cell or loss of major histocompatibility complex (MHC) class I proteins responsible for antigen presentation; secretion of immunosuppressive factors, such as transforming growth factor-?, that are capable of disabling the infiltrating effector immune cells, including natural killer (NK) cells and CD8+ cytotoxic T lymphocytes; recruitment of inflammatory cells that are actively immunosuppressive, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells; expression of immunomodulatory ligands, such as PD-L1 and PD-L2, that inactivate cancer-specific effector T cells via binding to the immune checkpoint receptors such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed death-1 (PD-1) receptor, and B7.1 receptor.8,15-19 From these, the last one termed “immune checkpoint blockade” is the most pertinent to the recent therapeutic successes achieved in the field of immunotherapy.
The Biology of Immune Checkpoints
Most practicing oncologists treating melanoma are familiar with immunotherapy in the form of adjuvant interferon-? (IFN-?) in the early stage of the disease, but IFN-? is not effective in the metastatic setting.20,21 Until recently, the only immune therapeutic option in the progressed disease consisted of administration of HD IL-2, a recombinant form of the powerful T-cell growth factor. This therapy can achieve modest response rates (overall response rates [ORRs] around 16%-20%) and long-lasting responses; however, it is limited to patients with excellent performance status, no preexisting cardiopulmonary complications, and no active brain metastases.2 With these limitations, the new advances in the field of immunotherapy bring exciting options for patients with this deadly disease.
The newest treatments aim to reactivate or unblock immune checkpoints on tumor-specific T cells that are being held in check by the tumor, thus preventing the immune system from destroying it. The most studied checkpoints are the CTLA-4 and PD-1 receptors – both expressed on activated T cells and involved in downregulation of the immune response at separate points of the process (Figure).
To activate naive and memory T cells, 2 simultaneous signals are required – first, antigen-presenting cells, such as dendritic cells, present the antigen on the MHC molecule to the T-cell receptor on the surface of the T cell; second, the CD28 receptor on the surface of the T cells binds B7 protein on the antigen-presenting cell. During normal immune response, CTLA-4 functions as a modulator of the early activation of T cells to prevent overactivation of the immune system.22,23 The rate of the transport of the receptor to the membrane is dependent on the strength of the T-cell receptor signal. Once CTLA-4 is transported to the T-cell surface, it binds B7 protein with higher affinity than CD28, thus effectively hijacking the activation process and dampening of the T-cell activation. Therefore, blocking the CTLA-4 receptor with a monoclonal antibody and preventing its binding of B7 protein would reinstate signal 2, leading to relative restoration of T-cell activation. Experiments with CTLA-4 knockout mice showed early lethal immunotoxicity, demonstrating the importance of this checkpoint in regulating T-cell response and predicting the potentially serious immune-related side effects of treatments involving inhibition of this receptor.24
The second well-studied immune checkpoint target, the PD-1 receptor, is present on T cells in the periphery during ongoing inflammation and in the tissues involved in tumorigenesis. Major roles of PD-1 are limiting the activity of activated, antigen-specific T cells in the periphery and preventing autoimmune reactions.25,26 The 2 ligands for PD-1 are PD-L1 and PD-L2, which are upregulated in tissues during inflammation.27,28 PD-L1 is expressed on many cell types, including hematopoietic, endothelial, and epithelial, in response to proinflammatory cytokines such as IFN-?, while PD-L2 is expressed in dendritic cells and macrophages in response to interleukin-4. The PD-1 receptor and its ligands play an essential role in sustaining the immunosuppressive conditions within the tumor environment.29
Activated T cells express PD-1 to varying degrees, and the concurrent presence of the receptor and upregulation of the ligands at the inflammation site insures protection of the surrounding tissues.29 In addition to PD-L1 upregulation due to inflammation, many solid tumors have been shown to express PD-1 ligands, including melanoma, lung, colon, and breast, and PD-L1 expression also correlates with poor prognosis in many cancers.30-33 Thus, unlike in the case of CTLA-4 blockade, PD-1 blockade targets the tumor site more directly because PD-1 is present on tumor-specific T cells within the tumor microenvironment. In addition, PD-1 and PD-L1 knockout mice do not develop serious spontaneous autoimmune responses in the first year and only exhibit aggravated tissue responses to infection or accelerated disease in autoimmune-prone strains.34-37 These observations point to the possibility of milder immune side effects to be expected with immunotherapy targeting this checkpoint.
TLA-4 Blockade in the Clinic
The first checkpoint blockade therapy approved in the United States was ipilimumab (Yervoy, previously known as MDX-010). Ipilimumab is a fully human monoclonal antibody against CTLA-4; it was approved by the FDA for the treatment of metastatic melanoma in 2011 based on the results of the phase 3 trial that demonstrated for the first time a significant survival benefit in previously treated patients with advanced unresectable metastatic melanoma.38 In this pivotal study, 676 patients with HLA-A*0201–positive, previously treated melanoma were randomized to receive ipilimumab alone, ipilimumab with glycopeptide 100 (gp100) vaccine, or gp100 vaccine alone, where ipilimumab was administered at the dose of 3 mg/kg q3wk for up to 4 doses. The median OS, the primary end point of this study, was significantly higher in groups receiving ipilimumab (10.0 and 10.1 months, respectively) than in the vaccine-alone group (6.4 months; hazard ratio [HR] 0.68; P?.003). Grade 3/4 immune-related adverse events (irAEs) were 10% to 15% for ipilimumab and ipilimumab plus gp100, and 3% for gp100 alone. OS at 2 years was 22% for the ipilimumab group and 24% for the ipilimumab plus gp100 vaccine group, compared with 14% for the gp100-alone group.
Similarly positive results were published a year later in the first-line setting where, in a randomized phase 3 trial, 502 patients with treatment-naive metastatic melanoma were randomized 1:1 to receive either ipilimumab (10 mg/kg) plus dacarbazine (850 mg/m2) or dacarbazine (850 mg/m2) plus placebo, administered at weeks 1, 4, 7, and 10, followed by dacarbazine alone q3wk through week 22.39 OS at 1 year was 47% in the ipilimumab-dacarbazine group versus 36% in the dacarbazine-placebo group. This study brought ipilimumab into the first-line setting and showed differing patterns of toxicity depending on the context of administration. Grade 3/4 adverse events were more frequent for ipilimumab in combination with chemotherapy – 56% for the ipilimumab-dacarbazine combo and 28% for dacarbazine – and the pattern of irAEs also changed to more frequent hepatotoxicity (20%) and less frequent colitis (2%). Notably, despite showing safety and higher efficacy at the 10 mg/kg dose, the FDA approved ipilimumab only at 3 mg/kg.
PD-1/PD-L1 Blockade in the Clinic
Currently, the results from early studies of 3 anti–PD-1 agents have been reported, including nivolumab (formerly known as MDX-1106/BMS-936558/ONO-4538), pembrolizumab (MK-3475), and pidilizumab (CT-011).
Nivolumab, a fully human IgG4 antibody blocking PD-1, has been shown to produce durable responses in patients with melanoma, renal cell carcinoma (RCC), and non–small cell lung cancer (NSCLC). In a phase 1 study in patients with advanced melanoma, NSCLC, castration-resistant prostate cancer, RCC, and colorectal cancer, nivolumab was administered at doses ranging from 0.1 to 10 mg/kg q2wk.40 Objective response rates were observed in 28% of the melanoma patients (26 of 94), with grade 3/4 irAEs occurring in 14% of all patients, the worst being pulmonary toxicity.
In a phase 1 trial of nivolumab in 107 heavily pretreated patients with advanced melanoma, the ORR was 31% in a dose range from 0.1 mg/kg to 10 mg/kg q2wk, with the best ORR of 41% achieved at 3 mg/kg, the dose chosen for phase 3 trials.41 Median duration of response at this dose was 75 weeks, median progression-free survival (PFS) 9.7 months, and median OS 20.3 months. Overall 1-year survival rate was 62%, with median duration of response 24 months and median OS 17.3 months; 2-year OS was 48%, and 3-year OS was 41%. Patients who experienced an immune-related response (best reduction in target lesions from baseline ?30% in the presence of new lesions or after initial progressive disease [PD], or PD for ?3 tumor assessments with best change in tumor burden ?20% from baseline) can achieve similar OS outcomes as those with objective response according to RECIST. Nivolumab monotherapy produced durable responses, with some continuing following the discontinuation of therapy. In a subset of patients, the PD-L1 expression correlated with favorable ORR, PFS, and OS. The most common adverse events were low-grade and manageable. Nivolumab is currently being assessed in 3 ongoing phase 3 studies (NCT01721746, NCT01721772, and NCT01844505).
Even more promising results were reported for another anti–PD-1 agent, pembrolizumab (lambrolizumab, MK-3475), a highly selective, humanized monoclonal IgG kappa isotype antibody against PD-1. In preliminary dose-escalation studies, pembrolizumab was safe and demonstrated clinical responses at all doses tested (1, 3, and 10 mg/kg administered q2wk). The same dosing regimen was further evaluated in 135 patients with advanced melanoma (KEYNOTE-001, NCT01295827).42 The confirmed response rate across all dose cohorts was 38%, and 52% in the cohort receiving 10 mg/kg. The median PFS was 36 weeks, and 1-year OS was 81%. The most common adverse events were low-grade and included fatigue, rash, pruritus, and diarrhea.
In an expansion of the KEYNOTE-001 trial, 411 ipilimumab-naive or -refractory melanoma patients were enrolled and given pembrolizumab either 2 or 10 mg/kg q2wk or q3wk.43-45 The ORR by RECIST v1.1 (central review) was 34%, with durable responses achieved by both ipilimumab-naive and ipilimumab-treated patients. In addition, 88% of responses were still ongoing at the time of the report, with median duration of response not reached at the time of analysis (range, 6+ to 76+ weeks). Median PFS was 5.5 months, and 1-year OS was 69%. No new safety signals were observed, and the toxicity was manageable across all doses. Preliminary analysis of the correlation of the tumor PD-L1 expression and clinical response revealed improved ORR and PFS in patients with higher PD-L1 expression levels; however, antitumor activity was also observed in patients with low baseline PD-L1 expression.46 Currently, pembrolizumab is in clinical development for other advanced solid tumors, including NSCLC, RCC, and hematologic malignancies, as well as in combination trials with other therapies (Table).47
The safety and tolerability of pidilizumab, an anti–PD-1 IgG1k monoclonal antibody, was assessed in phase 1 trials in patients with hematological malignancies at doses ranging from 0.2 to 6 mg/kg q3wk. The maximum tolerated dose (MTD) was not established, and some clinical activity was demonstrated (PFS, ORR) in diffuse large B-cell lymphoma and folicular lymphoma.48,49 In a phase 2 study in patients with progressive stage IV melanoma, 100 patients were randomized to 2 doses of pidilizumab (1.5 and 6.0 mg/kg q2wk) and stratified to ipilimumab-naive and ipilimumab-pretreated.50 The primary end point, ORR, was missed at only 6%, while the 1-year OS was 64%. Even though the treatment was well tolerated at all doses and the outcomes were independent of dose or pretreatment, the study was small and not adjusted for the potential influence of subsequent therapies on OS. Increasing the dose to improve ORR may lead to more serious irAEs due to binding of the complement by the IgG.
The lower immune-related toxicity observed with anti–PD-1 agrees with the immune effects observed in the PD-1 knockout mouse models compared to CTLA-4 knockouts. Furthermore, the localization of PD-1 receptors within the tumor microenvironment confers more specific targeting of T cells. In addition, the PD-1 receptor is induced on the surface of B cells and NK cells, thus the release of PD-1 blockade further reactivates not only the tumor-specific T cells of the adaptive immune system but also the antitumor response of the innate immune system branch. In the case of pembrolizumab, the use of the IgG4 immunoglobulin with a stabilizing S228P Fc alteration may also contribute to the milder irAEs observed with this antibody, since this IgG subtype does not engage Fc receptors and does not activate complement upon binding to T cells during their activation.
Encouraging results are coming out of early trials with anti–PD-L1 antibodies, BMS-936559 (MDX 1105) and MPDL3280A, which prevent the binding of the ligand to its receptor. Among 52 evaluable patients with advanced melanoma treated with BMS-936559, the objective response rate was 17%, and 27% of patients had stable disease at 24 weeks or more.51 In another phase 1 study with the PD-L1 antibody MPDL3280A, patients with metastatic melanoma were given the agent every 3 weeks for up to 1 year.52 Among 43 evaluable patients, the ORR was 28%, and PFS at 24 weeks was 41% by RECIST. Grade 3/4 irAEs included hepatotoxicity, fatigue, and decreased lymphocytes; no high-grade pneumonitis or colitis were observed. Although with similar ORR, the patients with PD-L1–positive tumors had a higher disease control rate (80%) compared with those with PD-L1–negative tumors (60%) by immunohistochemistry. Relative to baseline, the tumor samples of responders showed enhanced immune cell infiltration, PD-L1 induction, and increased granzymes, tumor necrosis factor-?, and IFN-?.
Combination of Checkpoint Immunotherapy
Combining or sequencing of various immunotherapies will require further detailed assessment due to the unique set of potential side effects. The Table lists selected ongoing combination trials of immune checkpoint therapies and other therapies in melanoma. The late onset and long duration of some immune-related side effects of ipilimumab therapy in some patients often require prolonged treatment with multiple steroids, which may disqualify these patients from receiving HD IL-2 in the future. Thus, for patients who qualify to receive HD IL-2, it may be sensible to use it first followed by ipilimumab, as it was shown that CTLA-4 blockade is equally effective in both immunotherapy-treated and -naive patients.53 An ongoing phase 2 trial is evaluating the combination of ipilimumab and HD IL-2 (NCT01856023).
Another combination being tested is the concurrent or sequential blockade of CTLA-4 and PD-1 with ipilimumab and nivolumab (NCT01844505). The rationale behind this combination stems from the fact that many cancers use both receptors at the same time during immune evasion, and immune cells express multiple independent checkpoints. In addition, preclinical studies show that tumor cells are capable of upregulating PD-L1 in response to CTLA-4 checkpoint blockade, thus simultaneous or adequately sequenced blockade of both receptors should ensure maximum restoration of T-cell activity.54
In a phase 1 study in melanoma patients, the MTD was determined to be 3 mg/kg ipilimumab and 1 mg/kg nivolumab q3wk for 4 doses in the concurrent regimen.55 For all patients treated with the concurrent regimen (n=52), the ORR was 40%; in evaluable patients treated at the MTD (n=17), the ORR was 53%. The disease control rate was 65%. Unprecedented in checkpoint blockade monotherapy studies, the concurrent administration of this combination led to a rapid and deep tumor regression in a substantial proportion of patients – tumor reduction of 80% or more was observed in 16 patients at 12 weeks, including 5 with complete response. Grade 3/4 irAEs similar to those observed in monotherapy studies occurred in 53% of patients and were mostly reversible. At a 2-year follow-up of the initial cohorts treated with concurrent therapy (N=53; nivolumab 0.3, 1, or 3 mg/kg; ipilimumab 1 or 3 mg/kg), an unmatched OS of 79% was reported. In the cohort (n=17) treated with 1 mg/kg nivolumab and 3 mg/kg ipilimumab, the dose chosen for phase 2 and 3 trials, the 1-year OS was 94%, and 2-year OS was 88%.56 A phase 3 trial (NCT01927419) evaluating the combination of ipilimumab and nivolumab compared with either agent alone in the treatment of metastatic melanoma is under way.
In an ongoing phase 2 immunotherapy combination study, ipilimumab with granulocyte-macrophage colony-stimulating factor (GM-CSF) versus ipilimumab alone is being evaluated in patients with advanced melanoma (NCT01134614). Preliminary results show that the addition of GM-CSF reduces the incidence of serious adverse immune reactions caused by ipilimumab, especially pulmonary and gastrointestinal toxicity.57
Combination of Immunotherapy With Targeted Therapy
Alongside the recent developments in immunotherapies, other exciting advancements in the treatment of metastatic melanoma are happening in the area of targeted therapies in which small molecule inhibitors target the components of the MAPK pathway, such as oncogenic BRAF V600 (a protein kinase that activates the MAPK pathway) and MEK (the only known substrate of the BRAF V600 protein).58 Constitutive activation of the MAPK pathway results in unchecked proliferation, evasion of senescence and apoptosis, tissue invasion and metastasis, and evasion of immune response.59 Approximately 40% to 50% of melanomas harbor the activating BRAF V600 mutations, making these targets particularly relevant in this disease. Vemurafenib and dabrafenib are oral enzyme inhibitors of the oncogenic BRAF V600 protein kinase. Data from phase 3 clinical trials suggest that both vemurafenib and dabrafenib improve patient outcomes, with vemurafenib showing an OS benefit and dabrafenib showing improved median PFS.60-62 More positive results are seen in the development of trametinib, which inhibits the MEK protein. Inhibition of MEK leads to decreased cell signaling and proliferation in cancer cells. In phase 3 trials, trametinib demonstrated significant improvement in median PFS and median OS compared with chemotherapy treatment.63
While targeted therapies have rapid onset of response, are well tolerated, and result in a clinical benefit to the patient, they don’t produce durable response upon suspending the treatment, and the tumors invariably develop resistance leading to disease progression.64 This is in contrast to immunotherapies, which are characterized by slow onset of clinical benefit, delayed and often long-term side-effects, but also durable responses following the treatment completion. With these facts in mind, a rationale for sequencing or combining these 2 therapeutic approaches emerges. Indeed, in a retrospective study, the sequential use of ipilimumab followed by vemurafenib in BRAF V600–positive melanoma appears to improve the clinical outcomes compared with vemurafenib followed by ipilimumab, in which many patients rapidly progressed without the opportunity to finish the ipilimumab treatment.65 A recently reported extension of this sequencing study in melanoma patients confirms these findings: patients initiated with ipilimumab achieved median OS of 14.5 months compared with 9.9 months for the group receiving vemurafenib first. In patients who received the BRAF inhibitor first and who didn’t complete the ipilimumab treatment, the median OS at the end of BRAF inhibition was 1.2 months compared with 12.7 months for those who did.66
Careful considerations regarding potential combinations must be in place, as some targeted therapies may cause decreased adaptive immunity as seen in preliminary in vitro studies with trametinib but not observed with vemurafenib. Concurrent administration of ipilimumab and vemurafenib in a phase 1 trial (NCT01400451) led to dose-limiting hepatotoxity and early termination of the trial.67 Other combination trials are under way (Table). Combinations of anti–PD-L1 antibodies with vemurafenib or dabrafenib may produce safer, more tolerable treatments, as side effects of these monotherapies appear milder compared with side effects from agents blocking CTLA-4. Combination of trametinib with an anti–PD-L1 agent should be considered to reduce toxicities and to increase targetable tumor types beyond BRAF-mutated ones to possibly RAS as well as others.
Conclusion and Future Directions
In the past 10 years, the treatment of metastatic melanoma has seen a tremendous development, and patients are beginning to experience this exciting progress with more effective treatment becoming accessible at a faster pace. The ongoing clinical trials testing combination immunotherapy with other therapies are summarized in the Table.
The next big questions to answer will be finding good predictive and prognostic markers. One potentially useful predictive marker, PD-L1 expression, appears to predict improved response to checkpoint blockade; however, some proportion of patients with low PD-L1 levels also experience clinical benefit from these treatments. Further clarity into these questions will be gained with additional analysis of factors affecting tumor infiltration by lymphocytes, as these are associated with better prognosis for patients. In addition, changes in response evaluation are needed for patients undergoing immunotherapy; such as changes can be accomplished by adding immune response criteria to RECIST. Furthermore, combination targeting of other immune checkpoint receptors, addition of cytokines (IFN-?), IDO blockade, and use of oncolytic viruses (such as talimogene laherparepvec [T-VEC]) hold a promise to further improve the outcomes of patients with melanoma as well as with other tumors in the near future.
This manuscript was prepared with the help of medical writer Alexandra Hess, PhD.
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In breast cancer patients with bone metastasis, less frequent infusion of zoledronic acid was as effective as the standard monthly dose, the randomized OPTIMIZE-2 study showed. “We found that less frequent treatment may reduce the risk of serious side effects, with the additional benefits of reduced inconvenience to the patient [ Read More ]
Dr Ali received her medical degree from St. George’s University, St. George’s, Grenada, and is currently practicing as a first-year fellow in the Division of Hematology/Oncology at Scripps Clinic. Dr Sigal received his medical degree from the University of California, Los Angeles, and is currently practicing in the Division of [ Read More ]