A live-attenuated Listeria vaccine (ANZ-100) and a live-attenuated Listeria vaccine expressing mesothelin (CRS-207) for advanced cancers: phase I studies of safety and immune induction

Listeria monocytogenes (Lm)-based vaccines stimulate both innate and adaptive immunity. ANZ-100 is a live-attenuated Lm strain (Lm ΔactA/ΔinlB). Uptake by phagocytes in the liver results in local inflammatory responses and activation and recruitment of natural killer (NK) and T cells, in association...

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Vydáno v:Clinical cancer research Ročník 18; číslo 3; s. 858
Hlavní autoři: Le, Dung T, Brockstedt, Dirk G, Nir-Paz, Ran, Hampl, Johannes, Mathur, Shruti, Nemunaitis, John, Sterman, Daniel H, Hassan, Raffit, Lutz, Eric, Moyer, Bentley, Giedlin, Martin, Louis, Jana-Lynn, Sugar, Elizabeth A, Pons, Alice, Cox, Andrea L, Levine, Jordana, Murphy, Aimee Luck, Illei, Peter, Dubensky, Jr, Thomas W, Eiden, Joseph E, Jaffee, Elizabeth M, Laheru, Daniel A
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 01.02.2012
Témata:
Adult
Aged
Bacterial Vaccines - administration & dosage
Bacterial Vaccines - adverse effects
Bacterial Vaccines - immunology
Cancer Vaccines - administration & dosage
Cancer Vaccines - adverse effects
Cancer Vaccines - immunology
Carcinoma - secondary
Carcinoma - therapy
Cytokines - blood
Female
Flow Cytometry
GPI-Linked Proteins - immunology
Humans
Immunohistochemistry
Listeria monocytogenes - immunology
Liver Neoplasms - immunology
Liver Neoplasms - secondary
Liver Neoplasms - therapy
Lung Neoplasms - pathology
Lung Neoplasms - therapy
Lymphocyte Activation - immunology
Lymphocyte Count
Male
Maximum Tolerated Dose
Mesothelin
Mesothelioma - pathology
Mesothelioma - therapy
Middle Aged
Ovarian Neoplasms - pathology
Ovarian Neoplasms - therapy
Pancreatic Neoplasms - pathology
Pancreatic Neoplasms - therapy
Vaccines, Attenuated - administration & dosage
Vaccines, Attenuated - adverse effects
Vaccines, Attenuated - immunology
ISSN:1557-3265, 1557-3265
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Shrnutí:Listeria monocytogenes (Lm)-based vaccines stimulate both innate and adaptive immunity. ANZ-100 is a live-attenuated Lm strain (Lm ΔactA/ΔinlB). Uptake by phagocytes in the liver results in local inflammatory responses and activation and recruitment of natural killer (NK) and T cells, in association with increased survival of mice bearing hepatic metastases. The Lm ΔactA/ΔinlB strain, engineered to express human mesothelin (CRS-207), a tumor-associated antigen expressed by a variety of tumors, induces mesothelin-specific T-cell responses against mesothelin-expressing murine tumors. These two phase I studies test ANZ-100 and CRS-207 in subjects with liver metastases and mesothelin-expressing cancers, respectively. A single intravenous injection of ANZ-100 was evaluated in a dose escalation study in subjects with liver metastases. Nine subjects received 1 × 10(6), 3 × 10(7), or 3 × 10(8) colony-forming units (cfu). CRS-207 was evaluated in a dose-escalation study in subjects with mesothelioma, lung, pancreatic, or ovarian cancers. Seventeen subjects received up to 4 doses of 1 × 10(8), 3 × 10(8), 1 × 10(9), or 1 × 10(10) cfu. A single infusion of ANZ-100 was well tolerated to the maximum planned dose. Adverse events included transient laboratory abnormalities and symptoms associated with cytokine release. Multiple infusions of CRS-207 were well tolerated up to 1 × 10(9) cfu, the determined maximum tolerated dose. Immune activation was observed for both ANZ-100 and CRS-207 as measured by serum cytokine/chemokine levels and NK cell activation. In the CRS-207 study, listeriolysin O and mesothelin-specific T-cell responses were detected and 37% of subjects lived ≥15 months. ANZ-100 and CRS-207 administration was safe and resulted in immune activation.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1557-3265
1557-3265
DOI:10.1158/1078-0432.CCR-11-2121