Adrenomedullin and cancer Zudaire, E; Martı́nez, A; Cuttitta, F
Regulatory peptides,
04/2003, Letnik:
112, Številka:
1
Journal Article
Recenzirano
Adrenomedullin (AM) is a pluripotent hormone with structural similarities to calcitonin gene-related peptide (CGRP), which is expressed by many tissues in the body and shows a remarkable range of ...effects mediated by paracrine/autocrine and possibly endocrine mechanisms. AM has been implicated as a mediator of several pathologies such as cardiovascular and renal disorders, sepsis, inflammation, diabetes and cancer, among others. AM is expressed in a variety of tumors where it aggravates several of the molecular and physiological features of malignant cells. AM has been shown to be a mitogenic factor stimulating growth in several cancer types and to encourage a more aggressive tumor phenotype. In addition, AM is an apoptosis survival factor for cancer cells and an indirect suppressor of the immune response through its binding protein, complement factor H, and regulation in expression of cytokines. AM plays an important role in environments subjected to low oxygen tensions, which is a typical feature in the proximity of solid tumors. Under these conditions, AM is upregulated through a hypoxia-inducible factor 1 (HIF-1)-dependent pathway and acts as a potent angiogenic factor promoting neovascularization. The collective findings brought together over the last years place AM as a major regulator of carcinogenesis-tumor progression and identifies its autocrine loop as a putative target for developing new strategies against human cancers.
Micro-Abstract There is controversy about the ideal clinical management of small-cell cancer of the urinary tract (SCCUT). The neuron-specific enolase (NSE) serum levels have never been studied in ...patients with SCCUT. Twelve patients diagnosed and treated in our institution during the past 10 years were evaluated. The clinical outcome and NSE levels at diagnosis and during treatment were assessed. Patients with limited disease and/or those with tumors of bladder origin showed a longer progression-free survival and overall survival. NSE levels decreased during chemotherapy administration in all patients with ED and baseline high levels.
CARTITUDE-1 (NCT03548207) is a phase 1b/2 study of ciltacabtagene autoleucel (cilta-cel; JNJ-68284528), a chimeric antigen receptor T cell (CAR-T) therapy with two B-cell maturation antigen ...(BCMA)–targeting single-domain antibodies, in relapsed/refractory multiple myeloma (RRMM). Updated results from a median 18-month follow-up are reported here.
Eligible patients had MM, received ≥3 prior regimens or were double refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), and had received a PI, IMiD, and anti-CD38 antibody. After apheresis, bridging therapy was allowed. Patients received a single cilta-cel infusion (target dose: 0.75×106 CAR+ viable T cells/kg; range 0.5-1.0×106) 5–7 days (d) after lymphodepletion (300 mg/m2 cyclophosphamide, 30 mg/m2 fludarabine daily for 3 d). Primary objectives were to characterize cilta-cel safety, confirm the recommended phase 2 dose (phase 1b), and evaluate efficacy (phase 2). Cytokine release syndrome (CRS) was graded by Lee et al (Blood 2014) and neurotoxicity by CTCAE, v5.0 in phase 1b. CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded by American Society for Transplantation and Cellular Therapy (ASTCT) criteria in phase 2. Lee et al and CTCAE v5.0 were mapped to ASTCT for CRS and ICANS, respectively.
As of February 11, 2021, 97 patients (median of 6 prior lines) received cilta-cel. Overall response rate per independent review committee (primary endpoint) was 97.9% (95% CI, 92.7–99.7); 80.4% achieved stringent complete response (sCR) and 94.8% achieved very good partial response or better. Median time to first response was 1 month (mo) (range, 0.9–10.7), and median time to ≥CR was 2.6 mo (range, 0.9–15.2). Median duration of response was 21.8 mo (95% CI, 21.8–NE). Of 61 minimal residual disease (MRD)-evaluable patients, 91.8% were MRD negative at 10−5. The 18-month progression-free survival (PFS) and overall survival rates (95% CI) were 66% (54.9–75.0) and 80.9% (71.4–87.6), respectively; median PFS was 22.8 mo (95% CI, 22.8–NE) for all patients, and not reached for patients with sCR. Grade 3/4 hematologic AEs ≥20% included neutropenia (95%), anemia (68%), leukopenia (61%), thrombocytopenia (60%), and lymphopenia (50%). CRS occurred in 95% of patients (4% grade 3/4); median time to onset was 7 d (range, 1–12) and median duration was 4 d (range, 1–14, excluding 1 patient with 97-d duration). CRS resolved in all but one with grade 5 CRS/hemophagocytic lymphohistiocytosis. 21% of patients had CAR-T neurotoxicity (grade ≥3, 10%). Twenty-one deaths occurred during the study: none ≤30 days; 2 ≤100 days; and 19 >100 days after infusion, among which, 10 were due to disease progression, 6 were treatment-related as assessed by the investigator, and 5 were due to AEs unrelated to treatment.
Cilta-cel is under further investigation in other MM populations in earlier lines of therapy and in outpatient settings.
At a longer median follow-up of 18 mo, a single cilta-cel infusion yielded early, deep, and durable responses with a manageable safety, in heavily pretreated patients with MM.
Cilta-cel (JNJ-68284528) is a chimeric antigen receptor T cell (CAR-T) therapy with two B-cell maturation antigen (BCMA)-targeting, single-domain antibodies designed to confer high avidity binding. ...CARTITUDE-2 (NCT04133636) is a phase 2, multicohort, open-label study assessing the efficacy and safety of cilta-cel in patients with multiple myeloma (MM) in various clinical settings. We describe the mitigation and management strategies implemented to identify and reduce the risk for neurologic adverse events in patients enrolled in Cohort A (progressive MM after 1-3 prior lines of therapy).
Eligible patients (≥18 years of age) had MM per International Myeloma Working Group criteria, measurable disease, Eastern Cooperative Oncology Group performance status ≤1, progressive disease after 1-3 prior lines of therapy (including a proteasome inhibitor and an immunomodulatory drug), were lenalidomide refractory, and had not received BCMA-targeting agents. Cilta-cel (0.75 × 106 range 0.5– 1.0 × 106 CAR+ viable T cells/kg) was given as a single infusion 5–7 days after start of lymphodepletion (cyclophosphamide 300 mg/m2 + fludarabine 30 mg/m2 daily for 3 days). Monitoring and mitigation strategies for neurologic adverse events include providing more effective bridging therapy to reduce tumor burden prior to lymphodepletion, frequent assessment of CAR-T related immune effector cellassociated neurotoxicity syndrome (ICANS) using the immune effector cellassociated encephalopathy tool, regular handwriting assessments to detect micrographia, and neuroimaging (brain MRI) and electroencephalogram for patients with prior neurologic disease. Management strategies include evaluating infectious and paraneoplastic etiologies upon observation of ICANS ≥grade 1, administration of tocilizumab (if concurrent with cytokine release syndrome CRS, all grade of ICANS) and/or dexamethasone (grade 2/3) or methylprednisolone (grade 4). ICANS and CRS were graded by American Society for Transplantation and Cellular Therapy criteria; neurotoxicities not classified as ICANS were graded per common terminology criteria for adverse events, v5.0.
As of 15 Jan 2021 (median follow-up: 5.8 months range: 2.5–9.8), 20 patients in Cohort A received cilta-cel. Median age was 60 years (range: 38–75) and 65% were male. Neurotoxicities occurred in 4 patients (20%). Three patients had ICANS (grade 1/2); median time to onset of symptoms was 8 days (range: 7–11) and median duration was 2 days (range: 1–2). Two of the 3 patients received supportive measures to treat ICANS, including levetiracetam and steroids; all 3 had concurrent CRS and all recovered. One patient developed isolated facial paralysis (grade 2) on Day 29 after cilta-cel infusion and recovered 51 days after onset following treatment with dexamethasone for 28 days. No movement or neurocognitive disorders were reported.
Early detection and management of neurologic adverse events can lead to better treatment outcomes.
Neurologic adverse events were generally manageable in patients with MM following treatment with cilta-cel. With a median of 5.8 months of follow-up, there were no movement or neurocognitive disorders in patients from Cohort A.
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