TY - JOUR
T1 - A live-attenuated listeria vaccine (ANZ-100) and a live-attenuated listeria vaccine expressing mesothelin (CRS-207) for advanced cancers
T2 - Phase I studies of safety and immune induction
AU - Le, Dung T.
AU - Brockstedt, Dirk G.
AU - Nir-Paz, Ran
AU - Hampl, Johannes
AU - Mathur, Shruti
AU - Nemunaitis, John
AU - Sterman, Daniel H.
AU - Hassan, Raffit
AU - Lutz, Eric
AU - Moyer, Bentley
AU - Giedlin, Martin
AU - Louis, Jana Lynn
AU - Sugar, Elizabeth A.
AU - Pons, Alice
AU - Cox, Andrea L.
AU - Levine, Jordana
AU - Murphy, Aimee Luck
AU - Illei, Peter
AU - Dubensky, Thomas W.
AU - Eiden, Joseph E.
AU - Jaffee, Elizabeth M.
AU - Laheru, Daniel A.
PY - 2012/2/1
Y1 - 2012/2/1
N2 - Purpose: 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. 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 × 106, 3 × 107, or 3 × 108 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 × 108, 1 × 109, or 1 × 1010 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 × 109 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. Conclusions: ANZ-100 and CRS-207 administration was safe and resulted in immune activation.
AB - Purpose: 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. 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 × 106, 3 × 107, or 3 × 108 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 × 108, 1 × 109, or 1 × 1010 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 × 109 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. Conclusions: ANZ-100 and CRS-207 administration was safe and resulted in immune activation.
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U2 - 10.1158/1078-0432.CCR-11-2121
DO - 10.1158/1078-0432.CCR-11-2121
M3 - Article
C2 - 22147941
AN - SCOPUS:84856519280
SN - 1078-0432
VL - 18
SP - 858
EP - 868
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 3
ER -