Summary Non-small-cell lung cancer and mesothelioma are thoracic malignancies, which in their advanced stages are incurable and have poor prognosis. Advances in our understanding of immune responses ...to tumours, tumour immunosuppression mechanisms, and tumour-specific shared antigens enabled successful early clinical trials of several specific and non-specific immunotherapies. For non-small-cell lung cancer, phase 3 clinical trial results of Toll-like receptor agonists show little promise. However, ongoing phase 3 trials are assessing melanoma-associated antigen A3 vaccine, liposomal BLP25, belagenpumatucel-L, and talactoferrin. In mesothelioma, immunotherapies being investigated include dendritic cell-based and Listeria -based vaccines, and allogeneic tumour cell and WT1 analogue peptide vaccines. Selection of appropriate patients and disease stages for immunotherapy, measurement of tumour-specific immune responses, and understanding the association between immune and clinical responses are some of the major challenges for the development of immunotherapies for these malignancies.
Highlights • Mesothelin, a cell surface antigen is a target for tumor-directed therapy. • Thymic carcinomas frequently demonstrate strong mesothelin expression. • High mesothelin expression in thymic ...carcinoma is associated with longer survival. • Mesothelin-directed therapy should be evaluated in advanced thymic carcinoma.
Abstract Objective To present our single-institution experience with management of seven patients with mesothelioma of the tunica vaginalis. Materials and Methods Our institution database was queried ...from 2003 to 2014. Clinical, surgical and pathological features were retrospectively collected and evaluated. Results Seven patients were identified with tunica vaginalis mesothelioma. Average age at the time of diagnosis was 63.6 years. Four patients presented with hydrocele, one with scrotal mass, one with inguinal mass, and one with spermatocele. Two (28.6%) patients reported possible asbestos exposure. Radical orchiectomy was performed in all patients. Two patients received adjuvant radiotherapy, one patient received both chemotherapy and radiation. All patients were followed up postoperatively with serial imaging detect for recurrence. One of 7 patients in our cohort experienced recurrence at 12 months. Our mean follow-up time on these patients is 52.2 months. Conclusion Previous reported cases have described poor prognosis of tunica vaginalis mesothelioma despite aggressive surgery and systemic therapy. Our single-institution experience suggests relatively good outcomes with surgery and limited adjuvant therapies. Post treatment surveillance is also imperative and should include imaging routinely within the first 2 years. Negative asbestos exposure screening during history should not eliminate clinical suspicion.
PARP inhibition may enhance antitumor responses in BAP1-associated mesothelioma by inducing synthetic lethality.
A single-center, nonrandomized, phase 2 trial was conducted, in which patients with ...refractory mesothelioma were given olaparib 300 mg twice daily in a 21-day cycle until disease progression or intolerable toxicity. The primary objective was to determine the objective response rate on the basis of somatic or germline mutation status of DNA repair genes. The secondary objectives were to assess safety and tolerability and to determine progression-free survival (PFS) and overall survival (OS). Whole-exome sequencing was performed on blood and tumor.
A total of 23 previously treated patients with pleural and peritoneal mesothelioma were enrolled and treated (germline BAP1, n = 4; germline MRE11A, n = 1; somatic BAP1, n = 8 mutations). There was one (4%) partial response, 18 (78%) with stable disease at 6 weeks, and four (17%) with progressive disease. The median overall PFS and OS were 3.6 months (95% confidence interval CI: 2.7–4.2 mo) and 8.7 months (95% CI: 4.7 mo–not estimable), respectively. The median PFS of germline BAP1 mutants (n = 4) was 2.3 months (95% CI: 1.3–3.6 mo) versus 4.1 months (95% CI: 2.7–5.5 mo) for wild-type (n = 19; p = 0.019). The median OS was 4.6 months (95% CI: 3.1–4.9 mo) for germline BAP1 mutation versus 9.6 months (95% CI: 5.5 mo–not estimable) in no germline mutation (p = 0.0040). Olaparib was safe with no new safety concerns.
Olaparib has limited activity in previously treated mesothelioma including patients with BAP1 mutations. Germline BAP1 mutations were associated with decreased PFS and OS.
JNJ-64041757 (JNJ-757) is a live, attenuated, double-deleted Listeria monocytogenes–based immunotherapy expressing human mesothelin. JNJ-757 was evaluated in patients with advanced NSCLC as ...monotherapy (phase 1) and in combination with nivolumab (phase 1b/2).
Patients with stage IIIB/IV NSCLC who had received previous therapy were treated with JNJ-757 (1 × 108 or 1 × 109 colony-forming units CFUs) alone (NCT02592967) or JNJ-757 (1 × 109 CFU) plus intravenous nivolumab 240 mg (NCT03371381). Study objectives included the assessment of immunogenicity, safety, and efficacy.
In the monotherapy study, 18 patients (median age 63.5 y; women 61%) were treated with JNJ-757 (1 × 108 or 1 × 109 CFU) with a median duration of 1.4 months (range: 0–29). The most common adverse events (AEs) were pyrexia (72%) and chills (61%), which were usually mild and resolved within 48 hours. Peripheral proinflammatory cytokines and lymphocyte activation were induced posttreatment with transient mesothelin-specific T-cell responses in 10 of 13 biomarker-evaluable patients. With monotherapy, four of 18 response-evaluable patients had stable disease of 16 or more weeks, including one patient with a reduction in target lesions. In the combination study, 12 patients were enrolled (median age 63.5 y; women 33%). The most common AEs with combination therapy were pyrexia (67%) and chills (58%); six patients had grade 3 AEs or greater, including two cases of treatment-related fatal pneumonitis. The best overall response for the combination was stable disease in four of nine response-evaluable patients.
As monotherapy, JNJ-757 was immunogenic and tolerable, with mild infusion-related fever and chills. The limited efficacy of JNJ-757, alone or with nivolumab, did not warrant further investigation of the combination.
Antibody–drug conjugates for cancer therapy Thomas, Anish, MD; Teicher, Beverly A, PhD; Hassan, Raffit, Dr
The lancet oncology,
06/2016, Letnik:
17, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Summary Antibody–drug conjugates are monoclonal antibodies conjugated to cytotoxic agents. They use antibodies that are specific to tumour cell-surface proteins and, thus, have tumour specificity and ...potency not achievable with traditional drugs. Design of effective antibody–drug conjugates for cancer therapy requires selection of an appropriate target, a monoclonal antibody against the target, potent cytotoxic effector molecules, and conjugation of the monoclonal antibody to cytotoxic agents. Substantial advances in all these aspects in the past decade have resulted in regulatory approval of ado-trastuzumab emtansine and brentuximab vedotin for clinical use. Several promising antibody–drug conjugates are now in late-phase clinical testing. Ongoing efforts are focused on identifying better targets, more effective cytotoxic payloads, and further improvements in antibody–drug linker technology. Improved understanding of the mechanistic basis of antibody–drug conjugate activity will enable design of rational combination therapies with other agents, including immunotherapy.
PDF
