Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 3 de 3
Filter
1.
Clin Cancer Res ; 27(10): 2755-2763, 2021 05 15.
Article in English | MEDLINE | ID: mdl-33542073

ABSTRACT

PURPOSE: LTX-315 is a first-in-class, 9-mer membranolytic peptide that has shown potent immunomodulatory properties in preclinical models. We conducted a phase I dose-escalating study of intratumoral LTX-315 administration in patients with advanced solid tumors. PATIENTS AND METHODS: Thirty-nine patients were enrolled, receiving LTX-315 injections into accessible tumors. The primary objective was to assess the safety and tolerability of this approach, with antitumor and immunomodulatory activity as secondary objectives. Tumor biopsies were collected at baseline and posttreatment for analysis of immunologic parameters. RESULTS: The most common treatment-related grade 1-2 adverse events were vascular disorders including transient hypotension (18 patients, 46%), flushing (11 patients, 28%), and injection site reactions in 38% of patients. The most common grade 3 LTX-315-related toxicities were hypersensitivity or anaphylaxis (4 patients, 10%). Analysis of immune endpoints in serial biopsies indicated that LTX-315 induces necrosis and CD8+ T-cell infiltration into the tumor microenvironment. Sequencing of the T-cell receptor repertoire in peripheral blood identified significant expansion of T-cell clones after treatment, of which 49% were present in available tumor biopsies after treatment, suggesting that they were tumor associated. Substantial volume reduction (≥30%) of injected tumors occurred in 29% of the patients, and 86% (12/14 biopsies) had an increase in intralesional CD8+ T cells posttreatment. No partial responses by immune-related response criteria were seen, but evidence of abscopal effect was demonstrated following treatment with LTX-315. CONCLUSIONS: LTX-315 has an acceptable safety profile, is clinically active, induces changes in the tumor microenvironment and contributes to immune-mediated anticancer activity.


Subject(s)
Antineoplastic Agents/administration & dosage , Neoplasms/drug therapy , Oligopeptides/administration & dosage , T-Lymphocytes/drug effects , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Biopsy , Disease Management , Female , Humans , Immunohistochemistry , Injections, Intralesional , Lymphocytes, Tumor-Infiltrating , Male , Middle Aged , Neoplasms/diagnosis , Neoplasms/etiology , Neoplasms/mortality , Oligopeptides/adverse effects , Oligopeptides/pharmacokinetics , Tomography, X-Ray Computed , Treatment Outcome , Tumor Microenvironment/drug effects , Tumor Microenvironment/immunology
2.
J Med Case Rep ; 13(1): 177, 2019 Jun 10.
Article in English | MEDLINE | ID: mdl-31177991

ABSTRACT

BACKGROUND: Desmoid tumors are intermediary malignant, fibrous lesions occurring in various soft tissues. Surgical treatment is relentlessly challenging because of the propensity for local aggressive behavior and high risk of recurrence. Consequently, a wide range of oncological drugs and radiation therapy are being used; however, outcomes are unpredictable. We investigated whether local treatment with an oncolytic peptide could be beneficial in a patient with an unresectable desmoid tumor. CASE PRESENTATION: In a young 29-year-old Caucasian woman who was diagnosed with a retromammary desmoid tumor infiltrating deeply into the anterior thoracic wall, surgery was considered excessively mutilating, and observation was recommended. The lesion progressed, however, and caused debilitating pain, despite nonsteroidal anti-inflammatory medication. Subcutaneous injections of human interferon-α (Multiferon®) resulted in reduced growth kinetics but had to be terminated because of development of symptomatic pneumonitis. Frequently used oncological treatment was withheld because of the toxicity profile, and the patient was instead included in a phase I study investigating transdermal intratumoral injection of LTX-315, an oncolytic peptide that induces anticancer immune responses ( ClinicalTrials.gov , NCT01986426 ). A marked increase of CD8+ tumor-infiltrating T cells in the lesion was complemented by upregulation of immune gene signature (including effector T-cell, T-helper type 1 cell, chemokine, and cytokine genes). These changes were followed by gradual symptom relief and long-term disease stabilization, indicating clinical benefit. LTX-315 was well tolerated until termination in week 16 after a serious allergic reaction. CONCLUSIONS: Our patient was treated with repeated intratumoral injections of LTX-315, resulting in tumor regression accompanied by upregulation of immune genes and T-cell infiltration. Local application of immunotherapy, minimizing systemic side effects, represents a novel treatment modality in desmoid tumors that should be tested in further clinical trials.


Subject(s)
Fibromatosis, Aggressive , Oligopeptides/administration & dosage , Thoracic Wall , Adult , Antineoplastic Agents/administration & dosage , CD8-Positive T-Lymphocytes/immunology , Diagnosis, Differential , Female , Fibromatosis, Aggressive/immunology , Fibromatosis, Aggressive/pathology , Fibromatosis, Aggressive/physiopathology , Fibromatosis, Aggressive/therapy , Humans , Injections, Intralesional , Positron Emission Tomography Computed Tomography/methods , Remission Induction , Thoracic Wall/diagnostic imaging , Thoracic Wall/pathology , Tumor Burden
3.
Acta Oncol ; 56(3): 479-483, 2017 Mar.
Article in English | MEDLINE | ID: mdl-28105885

ABSTRACT

BACKGROUND: Denosumab is a relatively new treatment option for patients with giant-cell tumor of bone (GCTB). The purpose of this study was to report the results for patients treated in Norway. MATERIALS AND METHODS: Patients treated with denosumab for GCTB were identified from the clinical databases at the Norwegian sarcoma reference centers. Data were retrieved from the clinical databases and supplemented by retrospective review of patient records. Denosumab was given as a subcutaneous injection every 4 weeks with loading doses on day 8 and 15 in cycle 1. RESULTS: Eighteen patients treated with denosumab for GCTB were identified. Denosumab was given for recurrent disease in seven cases and as first-line treatment in 11 patients, of which 6 received therapy as part of a neoadjuvant/adjuvant strategy and 5 for surgically unsalvageable primary tumor. Ten of 12 patients with unresectable disease are still on denosumab without progression with median treatment duration of 41 months (range 18-60). Two patients discontinued treatment due to osteonecrosis of the jaw and reduced compliance, respectively. In the adjuvant group, four patients experienced disease recurrence after stopping denosumab. In three of six patients, the extent of surgery was reduced due to neoadjuvant therapy. Seventeen of 18 patients underwent response evaluation with 18F-FDG PET/CT at median 4.7 weeks from starting denosumab. Median baseline SUVmax was 11.0 and median SUVmax at evaluation was 4.9 (p < 0.001). CONCLUSIONS: In a nationwide GCTB patient cohort, denosumab was an effective agent and durable responses were observed. Our results do not support the use of adjuvant therapy in routine clinical practice. 18F-FDG PET/CT could be a valuable tool for early response evaluation.


Subject(s)
Bone Density Conservation Agents/therapeutic use , Bone Neoplasms/drug therapy , Denosumab/therapeutic use , Giant Cell Tumor of Bone/drug therapy , Adolescent , Adult , Bone Neoplasms/epidemiology , Databases, Factual , Female , Giant Cell Tumor of Bone/epidemiology , Humans , Injections, Subcutaneous , Male , Middle Aged , Norway/epidemiology , Retrospective Studies , Treatment Outcome , Young Adult
SELECTION OF CITATIONS
SEARCH DETAIL
...