Phase I study of samalizumab in chronic lymphocytic leukemia and multiple myeloma: blockade of the immune checkpoint CD200

Autor: Camille L. Bedrosian, Xiaoping Zhang, Maria Whelden, Mark C. Lanasa, Lan Li, Charles M. Farber, Terrie L Ulery, Susan J. Faas, Manjari Pandey, Anjli Kukreja, Leonard T. Heffner, Daruka Mahadevan
Rok vydání: 2019
Předmět:
Male
0301 basic medicine
Oncology
Cancer Research
T-Lymphocytes
Chronic lymphocytic leukemia
Immune checkpoint inhibitor
Samalizumab
Cohort Studies
0302 clinical medicine
Circulating tumor cell
Multiple myeloma
hemic and lymphatic diseases
Immunology and Allergy
Tissue Distribution
Aged
80 and over
Middle Aged
Prognosis
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
030220 oncology & carcinogenesis
Molecular Medicine
Female
Research Article
Adult
medicine.medical_specialty
Maximum Tolerated Dose
medicine.drug_class
Immunology
Antibodies
Monoclonal
Humanized
Monoclonal antibody
lcsh:RC254-282
03 medical and health sciences
Immune system
Antigens
CD
Internal medicine
medicine
Humans
Adverse effect
Aged
Pharmacology
business.industry
medicine.disease
Leukemia
Lymphocytic
Chronic
B-Cell
Immune checkpoint
030104 developmental biology
CD200
Pharmacodynamics
business
CLL
Follow-Up Studies
Zdroj: Journal for ImmunoTherapy of Cancer, Vol 7, Iss 1, Pp 1-13 (2019)
Journal for Immunotherapy of Cancer
ISSN: 2051-1426
DOI: 10.1186/s40425-019-0710-1
Popis: Purpose Samalizumab is a novel recombinant humanized monoclonal antibody that targets CD200, an immunoregulatory cell surface member of the immunoglobulin superfamily that dampens excessive immune responses and maintains self-tolerance. This first-in-human study investigated the therapeutic use of samalizumab as a CD200 immune checkpoint inhibitor in chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). Experimental design Twenty-three patients with advanced CLL and 3 patients with MM were enrolled in an open-label phase 1 study (NCT00648739). Patients were assigned sequentially to one of 7 dose level cohorts (50 to 600 mg/m2) in a 3 + 3 study design, receiving a single dose of samalizumab intravenously once every 28 days. Primary endpoints were safety, identification of the maximum tolerated dose (MTD), and pharmacokinetics. Secondary endpoints were samalizumab binding to CD200, pharmacodynamic effects on circulating tumor cells and leukocyte subsets, and clinical responses. Results Twenty-one patients received > 1 treatment cycle. Adverse events (AEs) were generally mild to moderate in severity. Samalizumab produced dose-dependent decreases in CD200 expression on CLL cells and decreased frequencies of circulating CD200 + CD4+ T cells that were sustained at higher doses. The MTD was not reached. Decreased tumor burden was observed in 14 CLL patients. One CLL patient achieved a durable partial response and 16 patients had stable disease. All MM patients had disease progression. Conclusions Samalizumab had a good safety profile and treatment was associated with reduced tumor burden in a majority of patients with advanced CLL. These preliminary positive results support further development of samalizumab as an immune checkpoint inhibitor. Trial registration ClinicalTrials.gov, NCT00648739 registered April 1, 2008. Electronic supplementary material The online version of this article (10.1186/s40425-019-0710-1) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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