Ipilimumab in melanoma

Ipilimumab is a fully human monoclonal antibody directed against the cytotoxic T-lymphocyte antigen-4 receptor. Blocking cytotoxic T-lymphocyte antigen-4 signaling has been shown to enhance T-cell activation and to amplify T-cell-mediated immunity. Ipilimumab, either as a single agent or in combination with gp100 vaccination, significantly prolonged overall survival in a randomized Phase III trial in patients with disease progression after prior treatment when compared with gp100 alone. In previously untreated patients, the addition of ipilimumab to dacarbazine also significantly prolonged overall survival. The most common adverse events are immune related. Adherence to established treatment algorithms in patients with immune-related adverse events is advocated. Predictive factors for the activity of ipilimumab have not been identified but would be of great value in the selection of patients who are most likely to benefit from this innovative immunotherapy. Outstanding issues include the role of ipilimumab in the adjuvant treatment of patients who are at high risk for relapse, and the optimal treatment sequence for patients with BRAFV600 mutant melanoma, as small-molecule BRAF inhibitors have also been shown to improve the survival for this subgroup of patients.     

Ipilimumab in melanoma

Introduction: The treatment of melanoma is evolving rapidly over the past few years. Patients with BRAFv600 mutations can be treated with a combination of a BRAF-inhibitor and an MEK-inhibitor. Patients with BRAF wild-type tumors and BRAFv600 mutated tumors can be treated with immunotherapy i.e. check point inhibitors.

Areas covered: We conducted a comprehensive review of the literature on the efficacy and predictive markers, safety, and pharmacoeconomics of ipilimumab in melanoma

Expert commentary: Ipilimumab was the first check point inhibitor reaching the clinic, gaining FDA and EMA approval for metastatic melanoma in 2011. Ipilimumab was also approved by FDA in the adjuvant setting for patients with high risk, stage III melanoma. The anti-PD1 directed antibodies pembrolizumab and nivolumab are superior to single agent ipilimumab, which is no longer considered the standard first line treatment in metastatic melanoma.

The addition ipilimumab to nivolumab is associated with a higher response rate and a better PFS, particularly in patients with PD-L1 negative tumors, albeit at the cost of a steep increase in grade 3–4 adverse event rate. Definitive survival data on this combination are pending and the selection of patients potentially requiring the combination and its pharmacoeconomic implications are to be elucidated.     

Ferroptosis: a promising target for cancer immunotherapy

Ferroptosis is a recently recognized type of programmed cell death and emerges to play an important role in cancer biology and therapies. This unique form of cell death, characterized by iron-dependent lipid peroxidation, is exquisitely regulated by the cellular metabolic networks such as lipid, iron and amino acid metabolism. The sensitivity to ferroptosis varies among different tumors. Recent evidence reveals that triple-negative breast cancer (TNBC), a highly aggressive disease with limited effective targeted therapies is particularly vulnerable to ferroptosis inducers, suggesting this new form of non-apoptotic cell death as an attractive target for the treatment of the “difficult-to-treat” tumor. Intriguingly, ferroptosis has recently been implicated to be involved in T cell-mediated anti-tumor immunity and affect the efficacy of cancer immunotherapy. Better understanding of this ferroptotic cell death will shed light on the discovery of novel combination therapeutic strategies for cancer treatment. Herein, we provide an overview of the key hallmarks of ferroptosis, use TNBC as a model to characterize the regulation of ferroptosis in cancer, and highlight ferroptosis-modulating combination therapeutic strategies in the context of cancer immunotherapy.     

Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma

Ipilimumab (MDX-010, Yervoy; Bristol-Myers Squibb), a fully human monoclonal antibody against CTL antigen 4 (CTLA-4), was recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic melanoma. In both early- and late-phase trials, ipilimumab has shown consistent activity against melanoma. For example, in a randomized phase III trial that enrolled patients with previously treated metastatic disease, ipilimumab, with or without a peptide vaccine, improved overall survival: Median overall survival was 10.1 and 10.0 months in the ipilimumab and ipilimumab plus vaccine arms, respectively, versus 6.4 months in the vaccine-alone group (hazard ratio, 0.68; P ≤ 0.003). Serious (grade 3-5) immune-related adverse events occurred in 10% to 15% of patients. Thus, although it provides a clear survival benefit, ipilimumab administration requires careful patient monitoring and sometimes necessitates treatment with immune-suppressive therapy. Here, we review the mechanism of action, preclinical data, and multiple clinical trials that led to FDA approval of ipilimumab for metastatic melanoma.     

Dendritic cells: still a promising tool for cancer immunotherapy

Abstract Dendritic cells are bone marrow-derived professional antigen-presenting cells that exert critical functions in innate and adaptive immune responses. Depending on their functional maturation status, dendritic cells trigger primary immune responses or promote immunological tolerance. This functional ambivalence has taken dendritic cells into the focus of attention of immunotherapy protocols for both vaccination and tolerance induction. The capacity of dendritic cells to generate anti-tumour immune responses has already been demonstrated, and numerous clinical trials are currently in progress to assess their therapeutic potential. In the present review we will briefly outline the types and effector functions of dendritic cells in the human system, and summarise the present state of anti-tumour immunotherapy protocols, emphasising the most relevant parameters currently evaluated in preclinical and clinical assays. *Supported by an unrestricted educational grant from Pfizer.     

Ipilimumab: showing survival benefit in metastatic melanoma

Ipilimumab is a fully humanized monoclonal antibody to cytotoxic T-lymphocyte-associated antigen 4. Data from preclinical and clinical studies have shown that ipilimumab can cause tumor regression in patients with metastatic melanoma with response rates of 5.8-22%. Phase III trials have demonstrated a benefit in median overall survival in the first-line setting in combination with dacarbazine versus dacarbazine alone (11.2 vs 9.1 months) and in the second-line setting in combination with gp100 versus gp100 alone (10.1 vs 6.4 months). The main toxicities of ipilimumab are immune related, most commonly skin and gastrointestinal. Bowel perforation and treatment-related deaths have occurred, although prompt use of steroids and other immunosuppressive agents can minimize this risk.     

Dendritic cell-based vaccine: a promising approach for cancer immunotherapy.

The unique ability of dendritic cells to pick up antigens and to activate naive and memory CD4+ and CD8+ T cells raised the possibility of using them to trigger a specific anti-tumor immunity. If numerous studies have shown a major interest in dendritic cell-based vaccines for cancer immunotherapy in animal models, only a few have been carried out in human cancers. In this review, we describe recent findings in the biology of dendritic cells that are important to generate anti-tumor cytotoxic T cells in vitro and we also detail clinical studies reporting the obtention of specific immunity to human cancers in vivo using reinfusion of dendritic cells pulsed with tumor antigens.     

Ipilimumab in advanced melanoma: reports of long-lasting responses

Patients with metastatic melanoma have a poor prognosis; the results of chemotherapy remain unsatisfactory. Ipilimumab, an anticytotoxic T lymphocyte-associated antigen-4 antibody, has shown promising results in several clinical trials. In this report, advanced melanoma patients receiving ipilimumab were scored according to novel immune-related response criteria (irRC) in an attempt to capture additional response patterns and to avoid premature treatment cessation. Thirty-six heavily pretreated metastatic melanoma patients recieved ipilimumab within five international clinical trials at our Institution from May 2006 to August 2008. Disease progression was defined as an increase in tumor burden by at least 25% compared with the nadir, irrespective of any initial increase in baseline lesions or the appearance of new lesions. We report unusually long-lasting responses in patients treated with ipilimumab 10 mg/kg. An overall response was observed in six out of 30 patients (20%), a complete response in three (10%), and disease control in 11 (37%), which seemed to be of a long duration (median of 16 months; complete response 36+, 34+, and 41+ months). All irRC patterns seemed to be strongly associated with an improvement in overall survival. Interestingly, we found a correlation between the presence of a grade 3/4 immune-related adverse event and responses, time to progression, and overall survival. Ipilimumab therapy resulted in clinically meaningful responses in advanced melanoma patients, supporting the need for further irRC validation.     

Adjuvant immunotherapy for melanoma

Adjuvant immunotherapy was administered to 84 lymph-node-negative and 25 lymph-node-positive melanoma patients. This active specific homologous cell protein preparation was given after aggressive surgery and given over 2 years. Projected and observed survival rates are presented as well as other clinical and pathologic characteristics such as female-to-male ratio, site of primary, level and depth of invasion. The projected 5-year survival rates are 90% for all stage I with 89% for females and 94% for males. Lower extremity stage I projected 5-year survival rate was 88% for all, 87% for females, and 100% for males. The projected 5-year survival rate for stage II was 68% overall and 100% for lower extremity. Only two of five patients with an unknown primary have expired. All of these results are improved over expected survival. Hopefully a randomized prospective study will be stimulated to ascertain the basis for this improvement.     

Active-specific immunotherapy for melanoma

Twenty-five patients with metastatic melanoma were treated with a therapeutic vaccine ("theraccine") consisting of allogeneic melanoma lysates and a novel adjuvant, DETOX (Ribi ImmunoChem Research, Inc, Hamilton, MT). Each patient received 200 antigenic units (20 x 10(6) tumor cell equivalents) subcutaneously on weeks 1, 2, 3, 4, and 6. Clinical responses included one complete remission, three partial remissions, and a long-term (17-month) stability. Two other patients had mixed responses, with partial remissions of numerous subcutaneous nodules. Sites of responsive disease included primarily the skin, but ileal, breast, and a liver metastasis also responded. Removal of residual lesions in patients with partial remissions, whose other lesions had disappeared during treatment, led to long disease-free survivals. The median duration of remission was 17 months, with four of the five responders alive for at least 24 months after treatment. An increase in precursors of cytolytic T cells (CTLs) correlated with clinical outcome, when complete, partial, and mixed responses and long-term stability were considered. The CTLs recognized melanoma-associated antigens on many cell lines, but not other types of tumor or normal lymphocytes. Skin-test reactivity to melanoma antigens and serum antibodies against the melanoma cells was unrelated to clinical response. Toxicity was minimal, restricted largely to minor soreness at the site of injection. Only five patients, four of whom were treated with repeated courses, developed severe granulomas. These results confirm that active-specific immunization with allogeneic lysates of melanoma administered with the adjuvant DETOX can induce immunity to melanoma, and can induce regressions of disease in a proportion of patients with metastatic disease with little toxicity.     

Personalized immunotherapy for the treatment of non-Hodgkin's lymphoma: a promising approach

The efficacy of immunotherapeutic strategies for the treatment of lymphoid malignancies has been demonstrated in recent years. In patients with B-cell lymphomas, particularly indolent lymphoma, the use of passive immunotherapy, such as the anti-CD20 monoclonal antibody rituximab, has made an impressive impact on patient outcome. Personalized immunotherapy, a method that triggers the immune system to mount a response against tumor cells, has shown promising results in early clinical trials in hematologic malignancies. This therapeutic modality appears safe, with the most common adverse events being transient, local reactions at the site of injection. Furthermore, personalized immunotherapy has the potential to generate immunologic memory, which could provide prolonged remission. Currently, 3 large phase III studies are evaluating the efficacy and safety of personalized immunotherapy in patients with follicular lymphoma. It is hoped that the results of these studies will lead to the incorporation of this promising approach into the standard treatment of patients with lymphoma.     

Review: dendritic cell immunotherapy for melanoma

Melanoma is a particularly aggressive malignant tumour of the skin that is influenced by genetic, environmental and physiological elements. Since current therapy for melanoma is limited and associated with high toxicity and side effects, development of alternative approaches is imperative. The importance of dendritic cells (DCs) in immunity against tumours is now well established. DC immunotherapy for melanoma is possible but must be considered in terms of effectiveness and clinical viability. The source of DCs to be used in adoptive therapy as well as the nature and method of delivery of the priming antigen are important factors. The most suitable DC appears to be cells derived by culture from hemopoietic progenitor cells (HPC) in bone marrow or DC progenitors in peripheral blood. Generation of an effective anti-tumour immune response will be dependent upon the presentation of multiple melanoma-specific antigens by both major histocompatibility complex (MHC) class I and class II molecules and stimulation of both tumour-specific cytotoxic T lymphocytes (Tc) and T helper type 1 (Thl) cells. Different techniques for delivery of the priming antigen offer different advantages. DCs can be pulsed with peptide, protein or tumour cell lysate, transfected with viral vectors or naked nucleic acid and tumour/DC hybridomas can also be generated. Repeated antigen administration into neighbouring lymph nodes appears to be the most effective method for promoting a systemic anti-tumour response. Adjuvant therapies can also enhance immune responses and lead to total tumour clearance. The importance of DC immunotherapy in clinically different stages of disease will also be an important consideration.     

Betting on immunotherapy for melanoma

Immunotherapy is an effective treatment option for a small percentage of patients with advanced melanoma or at high risk for recurrence after resection of the primary tumor. However, a long period of unsuccessful immune modulation trials involving new cytokines, antibodies, cancer vaccines, adoptive immunotherapy, and combinations generated doubts that benefit could be extended to a larger group of patients. Renewed optimism for the therapeutic potential of immune therapy is currently driven by key advances in tumor immunobiology, including the potential to manipulate and disrupt immune activation checkpoints and tumor defense mechanisms; newer approaches to antigen presentation for immune activation; refinements to procedures for antigen-specific T-cell expansions in vitro and preparative regimens to support their expansion and activity in vivo; gene transfer to alter lymphocyte specificity and function; and the potential for discovery of improved predictive biomarkers to select patients for individual treatments. Proof of concept is provided by durable remissions observed in patients with advanced melanoma enrolled in clinical trials of anti-CTLA-4 and in new studies of adoptively transferred tumor antigen-specific lymphocytes combined with lymphocyte ablation conditioning regimens. Many agents now being developed are predicted to produce broader, more potent, and more effective antitumor immune responses.