Ipilimumab for the treatment of metastatic prostate cancer

Introduction: Immunotherapy with checkpoint inhibitors is beginning to be recognized as a valid weapon for the treatment of metastatic prostate cancer (PCa) when chemotherapy fails. Ipilimumab (ipi) is a fully humanized monoclonal antibody that blocks the activity of CTLA4. It also has a molecular weight of 148 kDa and is water-soluble at physiological pH. Ipi was first approved by the FDA for the treatment of malignant melanoma and is currently being studied in metastatic castration-resistant prostate cancer, with promising early results.

Areas covered: The aim of this review is to collate the most significant preclinical and clinical studies available that look at ipi to propose new strategies for the future.

Expert opinion: Additional studies are required to reduce toxicity and increase the activity of ipi in PCa. A possible strategy is to combine ipi with standard anti-cancer therapeutics such as vaccines, PDL1 inhibitors, antiandrogen drugs, and chemotherapy agents. Several initial results have suggested that combination strategies are useful to increase the activity in mCRPC, even if the toxicity of the treatment can increase. The activity of combined treatments is still not predictable, but considering the ongoing studies, we believe that they have good potential that will lead to the discovery of an optimal therapeutic strategy.     

Ipilimumab in combination with nivolumab for the treatment of renal cell carcinoma

Introduction: Renal cell carcinoma (RCC) is a highly immunogenic neoplasm, and cytokine-based immunotherapies have been used for decades with limited success. In recent years, antibody-based immunotherapies targeting immune checkpoint receptors PD-1 and CTLA-4 have demonstrated clinical efficacy in metastatic RCC (mRCC) patients, leading to FDA approval of the combination of nivolumab and ipilimumab in treatment-naïve patients with intermediate- or poor-risk disease in April 2018.

Areas covered: The pharmacodynamics and pharmacokinetics of nivolumab and ipilimumab are reviewed. Clinical safety and efficacy results from pivotal phase I and III trials of the combination of nivolumab plus ipilimumab in mRCC are summarized, and the combination is reviewed in the context of other available systemic therapies for RCC. Ongoing clinical studies involving the combination of nivolumab plus ipilimumab in RCC are discussed.

Expert opinion: The combination of nivolumab and ipilimumab has demonstrated superior efficacy for treatment-naïve patients with intermediate- and poor-risk mRCC with clear cell histology and is likely to replace anti-angiogenic therapies as the treatment-of-choice in this patient population in the United States. Development of additional combination strategies, novel trial designs, and predictive biomarkers of response will be important to further optimize therapeutic selection and clinical outcomes.     

Ipilimumab increases activated T cells and enhances humoral immunity in patients with advanced melanoma

Ipilimumab, a fully human monoclonal antibody, which blocks cytotoxic T-lymphocyte antigen-4, has demonstrated an improvement in overall survival in 2 phase III trials of patients with advanced melanoma. To gain an understanding of its mechanism of action, the effects of ipilimumab on T-cell populations and on humoral immune responses were studied in patients with advanced melanoma from 2 phase II trials. Antibody levels against 5 tumor antigens were assessed at baseline and up to 12 weeks after ipilimumab treatment. Serologic reactivity to the cancer-testis antigen NY-ESO-1 increased by at least 5-fold at week 12 of treatment in 10% to 13% of patients. Increased antibody levels were also observed to the tumor antigens Melan-A, MAGE-A4, SSX2, and p53. Immunocompetence was evaluated with tetanus boosters administered before ipilimumab and pneumococcal and influenza vaccines given 5 days after ipilimumab treatment. At week 7, most patients who received ipilimumab and vaccine showed greater humoral responses relative to baseline titers. For peripheral T-cell populations, statistically significant increases in the percent of activated (HLA-DR) CD4 and CD8 T cells with concomitant decreases in naive CD4 and CD8 T cells were observed after ipilimumab treatment. These changes were evident by week 4 of treatment. Increases were also observed in central memory, effector memory, and activated ICOS CD4 T cells, but not in ICOS CD8 T cells or in FoxP3 CD4 regulatory T cells. These results suggest that ipilimumab can enhance immune responses mediated by different T-cell populations, and humoral immunity, in melanoma patients.     

Ipilimumab (MDX-010) in the treatment of non-small cell lung cancer

Respiratory syncytial virus (RSV) is a major cause of bronchiolitis and pneumonia in young children and the elderly. Despite its clinical importance, there is no licensed vaccine available at present. Vaccine development has been hampered by observations of increased pathology after RSV infection in infants vaccinated with formalin-inactivated RSV; incomplete immunity following natural infection; and the need to be effective during the neonatal period when levels of maternal antibody are high. Four categories of RSV vaccine carriers – live-attenuated RSVs, recombinant vectors expressing the protective antigens of RSV, DNA vaccines and subunit vaccines – have been evaluated in animal models and/or clinical trials. So far, studies with live-attenuated virus vaccines highlight the need to improve immunogenicity whilst maintaining a suitable level of attenuation. Studies with recombinant vectors, DNA and subunit vaccines illustrate the pivotal nature of the vaccine carrier in determining the balance between immune-mediated protection against infection and the induction of immune-mediated pulmonary pathology.     

Ipilimumab (MDX-010) in the treatment of non-small cell lung cancer

INTRODUCTION: Non-small cell lung cancer (NSCLC) is one of the main causes of cancer-related deaths worldwide. Although new therapies have become available, innovative treatments are still needed for advanced disease. Ipilimumab , a monoclonal antibody targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), enhances the immune response against the tumor mass and has been proven effective against malignant melanoma. AREAS COVERED: The authors explored the role of ipilimumab in NSCLC using a literature review. The clinical trials involving ipilimumab for lung cancer have shown progression-free survival (PFS) benefits. The use of ipilimumab is related to unusual adverse events resulting from increased or excessive immune activity. Because ipilimumab shows unique response patterns, more suitable criteria known as immune-related response criteria (ir-RC), different from RECIST and WHO criteria, are required. EXPERT OPINION: Although NSCLC is not known as an immunogenic-mediated malignancy, in the past few years, the authors have observed an increasing interest in the development of therapies able to modulate the immune response including vaccines and non-specific immunoregulatory drugs (such as ipilimumab). Ipilimumab may become a new, powerful strategy for the management of NSCLC patients. Further investigation is needed to confirm the optimal treatment schedule and determine the potential predictors of response to the CTLA-4 blockade.     

Ipilimumab in prostate cancer

Introduction: Immune checkpoint inhibitors, such as ipilimumab, are a new class of immunotherapeutic agents that have shown significant efficacy in melanoma. A number of ongoing clinical trials are investigating the role of ipilimumab in prostate cancer, either alone or in combination with immunomodulating agents such as radiation and chemotherapy, and in combination with cancer vaccines.

Areas covered: This article reviews the molecular basis, preclinical and clinical evidence on the safety and efficacy of ipilimumab in prostate cancer. Medical literature search using MEDLINE and online abstracts database of national meetings form the basis of this article.

Expert opinion: A number of preliminary clinical studies suggest the potential therapeutic utility of immune checkpoint inhibitors such as ipilimumab in prostate cancer. Pending the results of large-scale studies, the rationale of combining ipilimumab with standard anticancer therapeutics such as radiation, cytotoxic chemotherapy and other immunotherapeutic agents can be of great value in reducing mortality and morbidity in prostate cancer.     

Talimogene laherparepvec in the treatment of melanoma

Introduction: Metastatic melanoma continues to present a significant therapeutic challenge, with an incidence rate rising faster than that of any other cancer. The last 5 years have seen a revolution in the development of new treatments for advanced melanoma, with oncogene targeted agents and checkpoint inhibitor immunotherapies providing the first convincing evidence of a positive shift in overall survival. The role of oncolytic virotherapy in this rapidly evolving field has long been the subject of debate. However, it is with the development of Talimogene Laheparepvec (T-Vec), an intratumourally administered, genetically modified clinical herpes simplex virus-1 strain that has shown positive results in Phase III testing, that the potential for the use of OV may be realised.

Areas covered: This review will outline some of the recent advances in the treatment of advanced melanoma, with a detailed overview of evidence surrounding the development of T-Vec. A literature search was conducted using the databases ‘Medline’ and ‘Pubmed’, including a subsequent manual search of references to identify papers of further relevance.

Expert opinion: As the pivotal OPTiM trial concludes, we outline some of the potential new directions for T-Vec and OV therapy and evaluate the ever-increasing role these novel agents are likely to play in the future landscape of cancer immunotherapy.     

Toripalimab for the treatment of melanoma

ABSTRACT

Introduction

Immune therapies have dramatically changed the treatment landscape for melanoma in the past decade. Ipilimumab, nivolumab, and pembrolizumab have been approved by U.S. Food and Drug Administration for the treatment of metastatic melanoma sequentially. Toripalimab, a humanized IgG4 monoclonal antibody against programmed cell death protein-1 (PD-1), was approved by National Medical Product Administration in China in 2018 as second-line therapy for metastatic melanoma.     

Ipilimumab in treatment-naive and previously treated patients with metastatic melanoma: retrospective analysis of efficacy and safety data from a phase II trial

Ipilimumab is a fully human, monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 to potentiate antitumor T-cell responses. In a phase III trial, ipilimumab monotherapy at 3 mg/kg demonstrated an improvement in overall survival (OS) in patients with previously treated, metastatic melanoma. Here, we conducted a retrospective analysis of efficacy and safety data from a phase II clinical trial in which treatment-naive and previously treated patients with metastatic melanoma received ipilimumab at an investigational dose of 10 mg/kg. Patients were randomized 1:1 to receive oral budesonide or placebo, and ipilimumab at 10 mg/kg every 3 weeks for 4 doses, to determine whether prophylactic budesonide affected the rate of grade ≥2 diarrhea. One hundred fifteen patients were randomized and treated: 62 had received prior systemic therapy for metastatic disease and 53 had not. No efficacy endpoint was affected by budesonide therapy, and the efficacy data were therefore pooled for budesonide and placebo subgroups. Median OS was 30.5 months for treatment-naive patients who received ipilimumab, with survival rates of 69.4%, 62.9%, and 56.9% at 12, 18, and 24 months. In previously treated patients who received ipilimumab, median OS was 13.6 months, with survival rates of 50.0%, 37.7%, and 28.5% at 12, 18, and 24 months. There were no meaningful differences in the number of objective responses or rate of grade ≥2 diarrhea between groups. These retrospective analyses are the first to provide survival data for ipilimumab in treatment-naive and previously treated patients within the same clinical trial.     

Association Between Ipilimumab and Celiac Disease

A 62-year-old man with chemotherapy-naive, castration-resistant metastatic prostate cancer presented with refractory diarrhea despite prolonged high-dose corticosteroid treatment after receiving 3 doses of ipilimumab as part of a phase 3 clinical trial. The investigative work-up and response to a gluten-free diet essentially confirm celiac disease. Although ipilimumab-induced enterocolitis is a well-reported complication, there have been no reported cases of celiac disease with ipilimumab therapy, to our knowledge. We suspect that ipilimumab may have amplified the symptomatic presentation of previously unrecognized celiac disease or perhaps even triggered the disease itself. With ipilimumab being used more commonly in the treatment of melanoma and prostate cancer, we believe that physicians should be aware of this potential adverse outcome when evaluating a patient who experiences persistent diarrhea during or after ipilimumab treatment.     

Pembrolizumab use for the treatment of advanced melanoma

Introduction: Until recently, overall long term survival in patients with stage IV melanoma was lower than 10%. However, the treatment of melanoma has evolved rapidly over the last few years, with the advent of inhibitors of BRAF and MEK and of immunotherapeutic agents including ipilimumab, nivolumab, and pembrolizumab.

Areas covered: This is a comprehensive review of the literature on the role of pembrolizumab in melanoma. Pembrolizumab is a Programmed Death Receptor 1 (PD-1) directed monoclonal antibody which is approved by FDA and EMA for the treatment of patients with metastatic melanoma.

Expert opinion: Phase II and III trials demonstrated that pembrolizumab is superior to ipilimumab in previously untreated patients and to chemotherapy in ipilimumab pre-treated patients. Unfortunately, prospectively validated predictive markers are lacking. Immune-related adverse events are particularly interesting and should be managed per the published guidelines. There are still many issues that remain unresolved including: when to stop treatment, biomarkers for choosing a single agent or combination therapy, the optimal schedule of ipilimumab in combination with anti-PD1 monoclonal antibodies, optimal management of adverse events, the role of immunotherapy in specific populations, the optimal sequence of immunotherapy and the BRAF/MEK inhibitor combination in patients.