The role of sipuleucel-T in therapy for castration-resistant prostate cancer: a critical analysis of the literature

Context

Sipuleucel-T, an autologous antigen-presenting cell vaccine loaded with prostate acid phosphatase conjugated with granulocyte-macrophage colony-stimulating factor (GM-CSF), yielded a survival advantage in men with metastatic castration-resistant prostate cancer (mCRPC).

Objective

Critically analyze the role of sipuleucel-T in therapy for mCRPC.

Evidence acquisition

A systematic review of the literature was performed in June 2011 using Medline and an abstract search of major cancer conferences. The search strategy included the terms sipuleucel-T, APC-8015, castration-resistant, prostate cancer, and immunotherapy.

Evidence synthesis

The era of targeted immunotherapy was initiated with the regulatory approval in 2010 of sipuleucel-T for asymptomatic and minimally symptomatic mCRPC. The median survival was prolonged by 4.1 mo (25.8 vs 21.7 mo; hazard ratio: 0.78; 95% confidence interval, 0.61–0.98; p = 0.03), coupled with an improvement in 3-yr survival (31.7% vs 23.0%). Outcomes were characterized by the lack of tumor regression or delay in progression. Further development is proceeding in earlier stages of prostate cancer and in the context of a host of emerging agents.

Conclusions

The addition of sipuleucel-T, an immunotherapeutic agent, to the armamentarium represents a paradigm shift in therapy for mCRPC. The rational combination and proper sequencing of sipuleucel-T with other newly approved agents (abiraterone acetate, cabazitaxel) and emerging agents (MDV3100, TAK-700, ipilimumab) will be important to evaluate.     

Efficacy of ipilimumab after anti-PD-1 therapy in sequential treatment of metastatic melanoma patients - Real world evidence

PurposeImmunotherapy has become a standard treatment option for patients with metastatic melanoma, and the use of checkpoint inhibitors significantly improves the treatment outcomes in this group.Patients and methodsA total of 116 patients with metastatic melanoma were enrolled in the study. In the first line, they were treated with an anti-PD-1 inhibitor (nivolumab or pembrolizumab), following which ipilimumab was used as the second-line therapy.ResultsBRAF mutation was detected in 12 patients (10%). The median progression-free survival (PFS) of ipilimumab treatment was 2.8 months, the overall survival (OS) was 5.1 months. The rate of 6-month survival was 45%, 1-year survival was 24%, and 2-year survival was 3%. The responses to treatment were: complete response in 2 cases (2%), partial response in 7 cases (6%), stable disease in 39 cases (34%). In multivariate analysis, normal levels of lactate dehydrogenase (LDH) were associated with a longer median OS and PFS (p = 0.02 and p = 0.009, respectively), while 2 or less number of metastatic locations and the presence of BRAF mutations were correlated with a longer OS (p = 0.041 and p = 0.024, respectively).ConclusionsIpilimumab could be considered after anti-PD-1 treatment. Treatment with ipilimumab following anti-PD-1 therapy showed beneficial effects in patients with normal levels of LDH, 2 or less number of metastatic locations, and BRAF-mutated melanoma. However, further studies are required to confirm our results as the study included a low number of patients with BRAF mutation-positive melanoma. No significant increase in toxicity was detected with the use of ipilimumab after anti-PD-1 therapy.     

Immunotherapy for advanced melanoma: Fulfilling the promise

The incidence of melanoma is increasing worldwide and despite early detection and intervention, the number of patients dying from metastatic disease continues to rise. The prognosis of advanced melanoma remains poor, with median survival between 6 and 9 months. Over the past thirty years and despite extensive clinical research, the treatment options for metastatic disease were limited and melanoma is still considered as one of the most therapy-resistant malignancies. Single-agent and combination chemotherapy, hormonal therapy, biochemotherapy, immunotherapy, targeted agent therapy and combination regimes failed to show significant improvement in overall survival.     

Ipilimumab associated colitis: An Ipi Colitis case series at Med Star Georgetown University Hospital

Although ipilimumab has been shown to improve survival in patients with metastatic melanoma and cause regression of metastatic renal cell carcinoma, the associated immune-related toxicities are of concern. The resultant T cell activation by this monoclonal antibody causes an increased immune response, which has been associated with many immune-regulated adverse effects. One of the most concerning effects is the development of colitis. Upwards to 8% of patients have been reported to develop colitis, with 5% being severe(Grades 3-4). While initial treatment of such adverse effects is generally comprised of supportive and symptomatic treatment, more severe cases warrant the use of high dose steroids. Furthermore, use of anti-TNF agents is usually reserved for those cases that prove to be refractory to steroids. We describe a systematic case review of seven patients who developed gastrointestinal symptoms following initiation of ipilimumab immunotherapy, and present the steps in their evaluation, treatment and outcomes at our institution.     

Prognostic factors and outcomes in metastatic uveal melanoma treated with programmed cell death-1 or combined PD-1/cytotoxic T-lymphocyte antigen-4 inhibition

BackgroundUveal melanoma (UM) is an ocular malignancy with high potential for metastatic spread. In contrast to cutaneous melanoma, immunotherapy has not yet shown convincing efficacy in patients with UM. Combined immune checkpoint blockade with checkpoint programmed cell death-1 (PD-1) and checkpoint cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibition has not been systematically assessed for UM to date.Patients and methodsPatients with metastatic UM treated with either PD-1 inhibitor monotherapy or combined PD-1 inhibitor and ipilimumab (an anti-CTLA-4 monoclonal antibody) were included from 20 German skin cancer centres. Records from 96 cases were analysed for treatment outcomes. Clinical and blood parameters associated with overall survival (OS) or treatment response were identified with multivariate Cox regression and binary logistic regression.ResultsEighty-six patients were treated with PD-1 inhibitors only (n = 54 for pembrolizumab, n = 32 for nivolumab) with a centrally confirmed response rate of 4.7%. Median OS was 14 months for pembrolizumab-treated and 10 months for nivolumab-treated patients (p = 0.765). Fifteen patients were treated with combined immune checkpoint blockade with partial response observed in two cases. Median OS was not reached in this group. Multivariate Cox regression identified Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.002), elevated serum levels of lactate dehydrogenase (LDH) (p = 0.002) and C-reactive protein (CRP) (p = 0.001), and a relative eosinophil count (REC) <1.5% (p = 0.002) as independent risk factors for poor survival. Patients with elevated CRP and LDH and a REC <1.5% were at highest risk for disease progression and death (p = 0.001).ConclusionsBlood markers predict survival in metastatic UM treated with immune checkpoint blockade. Normal serum levels of LDH and CRP and a high REC may help identify patients with better prognosis.     

Endoscopic evaluation of immunotherapy-induced gastrointestinal toxicity

Immunotherapy is any treatment aimed at boosting or enhancing the immune system. It includes a wide range of options, from vaccines to treatment for conditions such as allergy and cancer. In the case of cancer, unlike other available treatments, immunotherapy is not aimed at destroying the tumor cells but at stimulating the patient's immune system so that it attacks the tumor. In cancer,immunotherapy provides a series of advantages. Nevertheless, immunotherapy administered for treatment of cancer is associated with immune-mediated enterocolitis. Colitis mediated by monoclonal anti-cytotoxic T lymphocyte–associated antigen 4 and to programmed cell death protein 1 and its ligand PDL1 shares characteristics with chronic inflammatory bowel disease(IBD), and similar findings have been reported for both the endoscopy images and the segment involved. The most frequent lesions on endoscopy are ulcer and erythema, and the most frequently affected site is the sigmoid colon. A segmental pattern has been reported to be slightly more frequent than a continuous pattern.In addition, upper gastrointestinal lesions have been reported in up to half of patients, with the most frequent findings being gastritis and erosive duodenitis.As is the case in IBD, systemic corticosteroids and immunosuppressive treatment(anti-TNF agents) are the approaches used in patients with a more unfavorable progression. Immunotherapy must be suspended completely in some cases.     

Clinical Development of Immunotherapy for Deficient Mismatch Repair Colorectal Cancer

Colorectal cancer (CRC) is the second most common cause of cancer-related death in the United States. Despite excellent prognosis for early stage disease, 5-year survival rates in metastatic disease remain low. A small subset of CRC is defined by a deficiency in mismatch repair (dMMR) resulting in high levels of microsatellite instability and are responsive to immunotherapy. Immune checkpoint inhibitors (ICIs) targeting the programmed death 1 (PD-1)/programmed death ligand 1 axis and cytotoxic T-lymphocyte antigen 4 have been explored and show robust clinical outcomes with prolonged progression-free survivals in nonrandomized single-arm clinical trials. On the basis of these data, single-agent therapy with pembrolizumab and nivolumab and combination therapy with nivolumab/ipilimumab have been approved by the US Food and Drug Administration for metastatic CRC that has progressed after treatment with fluoropyrimidine, oxaliplatin, and irinotecan. Ongoing clinical trials are exploring the use of these agents in earlier lines of therapy such as first-line metastatic therapy and adjuvant therapy for stage III CRC. However, resistance to ICIs does occur in a subset of patients and ongoing clinical trials are exploring novel approaches in these PD–1-refractory patients. The aim of this review is to outline the development and decision-making of ICIs in the treatment of dMMR CRC and to discuss ongoing clinical trials in this therapeutic space.     

食管癌免疫治疗研究进展

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