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

被引：284

作者：

Le, Dung T. ^{[1
,2
]}

Brockstedt, Dirk G. ^{[5
]}

Nir-Paz, Ran ^{[6
]}

Hampl, Johannes ^{[7
]}

Mathur, Shruti ^{[7
]}

Nemunaitis, John ^{[8
]}

Sterman, Daniel H. ^{[9
]}

Hassan, Raffit ^{[10
]}

Lutz, Eric ^{[1
,2
]}

Moyer, Bentley ^{[7
]}

Giedlin, Martin ^{[7
]}

Louis, Jana-Lynn ^{[1
,2
]}

Sugar, Elizabeth A. ^{[1
,2
,3
]}

Pons, Alice ^{[1
,2
]}

Cox, Andrea L. ^{[1
,2
,4
]}

Levine, Jordana ^{[4
]}

Murphy, Aimee Luck ^{[5
]}

Illei, Peter ^{[1
,2
]}

Dubensky, Thomas W., Jr. ^{[7
]}

Eiden, Joseph E. ^{[7
]}

Jaffee, Elizabeth M. ^{[1
,2
]}

Laheru, Daniel A. ^{[1
,2
]}

机构：

[1] Johns Hopkins, Sidney Kimmel Canc Ctr, Skip Viragh Clin Pancreat Canc Ctr, Baltimore, MD USA

[2] Johns Hopkins, Sol Goldman Pancreat Canc Ctr, Baltimore, MD USA

[3] Johns Hopkins, Bloomberg Sch Publ Hlth, Baltimore, MD USA

[4] Johns Hopkins Dept Med, Baltimore, MD USA

[5] Aduro BioTech, Berkeley, CA USA

[6] Hadassah Hebrew Univ, Med Ctr, Jerusalem, Israel

[7] Cerus Corp, Concord, CA USA

[8] Mary Crowley Canc Ctr, Dallas, TX USA

[9] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA

[10] NCI, Bethesda, MD 20892 USA

来源：

CLINICAL CANCER RESEARCH | 2012年 / 18卷 / 03期

关键词：

SECRETING TUMOR VACCINE; CELL-MEDIATED-IMMUNITY; PANCREATIC-CANCER; MONOCYTOGENES; IMMUNOTHERAPY; ACTIVATION; INFECTION; TRIAL; ADENOCARCINOMAS; IDENTIFICATION;

D O I：

10.1158/1078-0432.CCR-11-2121

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: Listeria monocytogenes (Lm)-based vaccines stimulate both innate and adaptive immunity. ANZ-100 is a live-attenuated Lm strain (Lm Delta actA/Delta inlB). 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 Delta actA/Delta inlB 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 1 studies test ANZ-100 and CRS-207 in subjects with liver metastases and mesothelin-expressing cancers, respectively. Experimental Design: A single intravenous injection of ANZ-100 was evaluated in a dose escalation study in subjects with liver metastases. Nine subjects received 1 x 10(6), 3 x 10(7), or 3 x 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 x 10(8), 3 x 10(8), 1 x 10(9), or 1 x 10(10) cfu. Results: 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 x 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 0 and mesothelin-specific T-cell responses were detected and 37% of subjects lived >= 15 months. Conclusions: ANZ-100 and CRS-207 administration was safe and resulted in immune activation. Gin Cancer Res; 18(3); 858-68. (C) 2011 AACR.

引用

页码：858 / 868

页数：11

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