Harnessing (and Controlling) L. monocytogenes to Treat. and Prevent Human Disease. Thomas W. Dubensky, Jr., Ph.D. Cerus Corporation Concord, CA
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1 Harnessing (and Controlling) L. monocytogenes to Treat and Prevent Human Disease Thomas W. Dubensky, Jr., Ph.D. Cerus Corporation Concord, CA
2 Presentation Overview Rationale for L. monocytogenes based vaccines Attenuation & potency of Live-Attenuated Listeria vaccine platform strain Clinical trial status of live-attenuated vaccine platform Killed But Metabolically Active (KBMA) Listeria HPV vaccines Rationale and potency Summary and CAVD activity
3 Clinical Translation of L. monocytogenes Vaccine Platforms Wild-Type L. monocytogenes Attenuation Live PrfA-dependent genes Separate immunogenicity & potency KBMA Inactivate by DNA crosslinking DNA repair mutants Similar mechanism to live attenuated Potency Antigen Expression & Secretion prfa-dependent promoter Bacterial protein fusion partner T cell function Role of phagosomal escape after LLO expression Intracellular signaling Toxicity and Potency in Mice and then Primates Human Clinical Trials
4 Live Attenuated Listeria Platform
5 L. Monocytogenes Lifecycle and Attenuated Vaccine Platform Strain Overview Gram-positive bacterium that is ubiquitous in nature (food-borne) Facultative intracellular lifecycle Taken up by and multiplies within phagocytic cells, including macrophages and dendritic cells Potent activator of innate immune effectors Model pathogen for the study of cell-mediated immunity Induces robust CD4 + and CD8 + T- cell immunity Entry Internalins (InIA/InIB) Lysis of the vacuole (LLO) Lifecycle of attenuated vaccine platform strain Intracellular Movement (ActA) Cell to cell spread Lysis of the two-membrane vacuole (plca/plcb)
6 Accelerated Clearance and Diminished Hepatotoxicity of Lm ΔactAΔinlB Pharmacodynamics of vaccine strain in C57Bl/6 mice following IV administration CFU/Liver (log 10 ) wt ΔactA hrs hrs Days Post Infection ΔinlB ΔactA/ΔinlB Serum Liver 24 h (U/L) Listeria Strain HBSS Buffer Control Wild-type Wild-Type Lm Lm Vaccine ΔactA/ΔinlB Strain AST ALT 24 hpi The LD 50 value of Lm ΔactAΔinlB in mice is >1000-fold less than wild-type Lm
7 Minimal Change in Liver Function Tests with Lm ΔactAΔinlB Strains in Cynomolgus Monkeys Serum ALT levels in female animals following IV administration of live-attenuated L. monocytogenes CRS-100 CRS U/L Dose Vehicle 1e7 CFU 3e8 CFU 1e10 CFU U/L Dose Vehicle 3e7 CFU 1e9 CFU 3e10 CFU * * * * * * Study Day
8 Lm ΔactA/ΔinlB-MCMV Elicits Potent CD8+ T Cell Responses in C57BL/6 Mice MCMV-Specific T Cell Kinetic Following Homologous Prime-Boost Vaccination 12 IFN-γ+ CD8+ T cells (%) Lm ΔactA/ΔinlB-MCMV Lm ΔactA/ΔinlB Days Post Primary Vaccination
9 Intramuscular Immunization with Lm Vaccines Elicits Robust CD8+ T Cell Responses in Mice Primary and secondary HIV Gag (AMQMLKETI) CD8+ T cell responses HBSS 5e6 IV 1e7 IM 1e6 IM 1e5 IM 1e4 IM 1e3 IM HBSS 5e6 IV 1e7 IM 1e6 IM 1e5 IM 1e4 IM 1e3 IM % γ-ifn+ CD8 T cells Prime Boost
10 Ad-Prime and Lm-Boost Vaccination Elicits Potent SIV Gag-Specific Cellular Immunity % IFN-γ+ CD8+ T cells Prime: 1e8 Ad IM Boost: HBSS 1e8 Ad IM 1e7 Lm IM 1e7 Lm IV Ad PRIME IM, 1e8 pfu Day 0 Lm or Ad BOOST Day 21 Day 27 ICS K d AAVKNWMTQTL
11 Immunization with Listeria in the Presence of Protective Immunity Comparison with Vaccinia Virus Establish vector-specific immunity Experimental Protocol HBSS Wild-type Listeria (50 or 5e3 cfu) Vaccinia virus (5e3 or 5e6 pfu) 28 days Vaccinate with Ag-containing vectors ΔactAΔinlB-OVA (5e6 cfu) Vaccinia-OVA (5e6 pfu) 7 days ICS
12 Immunization with Listeria in the Presence of Protective Immunity Comparison with Vaccinia Virus Total IFN-γ CD8+ T cells Total IFN-γ CD8+ T cells per spleen Pre-existing immunity: OVA-specific T cells/spleen 50 cfu 5e3 cfu 5e3 pfu 5e6 pfu Pre-existing immunity to: 50 cfu 5e3 cfu 5e3 pfu 5e6 pfu HBSS Listeria Vaccinia Vaccination: Lm ΔactAΔinlB-OVA Vaccinia-OVA
13 Mesothelin-Targeted Vaccine (CRS-207) for Ovarian, Pancreatic and NSCL Cancers
14 Induction of Cytokines and Chemokines by CRS-207 in Cynomoglus Monkeys Peak Cytokine/Chemokine Levels Post First CRS-207 Dose Cytokine/Chemokine (pg/ml) Vehicle cfu cfu cfu MCP-1 (2 hrs) IL-6 (2 hrs) TNF (2 hrs) IFN-γ (24 hrs)
15 Induction of MCP-1 Following CRS-207 Administration in Cynomolgus Monkeys MCP-1 (pg/ml) HBSS cfu CRS cfu CRS cfu CRS-207 Vaccination * * * Study Day
16 Breaking of T Cell Tolerance Against Mesothelin (a Human Tumor Antigen) in Monkeys Intracellular Cytokine Staining IFN-γ ELISPOT Unstimulated Mesothelin IFN-γ CD8+ Peptide Library Unstim Meso Pool mer cmeso mer hmeso mer cmeso mer hmeso mer cmeso Subpools SFU per 1x10 6 cells Individual Peptides
17 Clinical Trial Status of Live-Attenuated Vaccine Platform CRS-100 Lm ΔactAΔinlB (non-ag encoding strain) Ongoing dose escalation Phase 1 study in patients with carcinoma and hepatic metastases Completed first cohort: 10 6 cfu, given IV (N = 3) Treatment well-tolerated Initiated second cohort: 3 x 10 7 cfu CRS-207 Lm ΔactAΔinlB encoding Mesothelin tumor Ag Mesothelin is over-expressed in pancreatic, ovarian, and non-small cell lung cancers and malignant Mesothelioma Demonstrated breaking of tolerance against endogenous Mesothelin in CRS-207 vaccinated cynomolgus monkeys IND filed in June 2007 Establishing clinical sites
18 Early Results from CRS-100 Phase 1 Study No DLT reported for first 5 study patients First cohort completed at 1 x 10 6 (N = 3) No related DLT reported after single intravenous administration CRS-100 not detected in blood, feces, urine or sputum Second cohort enrolling at dose of 3 x 10 7 cfu Increased cytokine response and cellular activation by first patient NK cell activation & cytokine response confirms pre-clinical models Ratio (Post: Pre Cytokine Levels) Cohort 1 1 x 10 6 cfu Ratio (Post: Pre Cytokine Levels) Patient JJM Cohort 2 3 x 10 7 cfu 0 MCP-1 IFN-gamma IP-10 IL-2 IL12-p70 0 MCP-1 IFN-gamma IP-10 IL-2 IL12-p70
19 Preliminary Evidence of Biological Activity in Patients Recruitment and activation of NK cells and T cells from peripheral blood Stimulation of broad array of Th1 cytokines and chemokines Similar profiles observed in mouse and non-human primate Cohort 1 1 x 10 6 cfu Patient JJM Cohort 2 3 x 10 7 cfu CD38 MESF Ratio CD38 MESF (Post: Pre) NK Cell Activation Relative Treatment Day 1 NK CD4 CD8
20 Killed But Metabolically Active (KBMA) Vaccines
21 Killed But Metabolically Active (KBMA) Vaccines Features ΔactA ΔinlB Derived from attenuated Listeria clinical strain Helinx Sensitive Genome Nucleotide ProprietaryExcision Repair Mutation Mutation Killed but able to express genes Host response similar to live organism NH 2. HCl Activates immune system O O O S-59 Psoralen O HPV Viral 16 E6 Antigen 11 HPV Viral 16 E7 Antigen 2 2 Microbial propagation blocked Elicits protective T cell immunity Can expressive several Ags
22 KBMA Vaccines Mechanism of Action Wild-Type Microbe Conventional Inactivation KBMA Immunotherapy DNA Repair Deficient Strain Photochemical Treatment Many Crosslinks To Inactivate X X X X X X X X X X Single Crosslink Inactivates Gene Expression Diminished Gene Expression Preserved
23 Potent Activity of KBMA Vaccines Immunogenicity Therapeutic anti-tumor efficacy % OVA - Specific CD8+ T Cells Live PCT Live Prime Boost PCT Control Lm + Tumor Ag KBMA Lm + Tumor Ag PCT Lm -OVA PCT: KBMA - OVA Photochemical Treatment
24 Summary We have developed live-attenuated and KBMA vaccine platforms based on L. monocytogenes Recombinant Listeria vaccines are efficacious in the presence of protective immunity and can be repeat administered GMP Listeria vaccine preparations can be cheaply and efficiently produced The live-attenuated vaccine platform is currently being evaluated in two Phase 1 FDA-approved clinical studies We are providing HIV & SIV Gag vaccines on the liveattenuated and KBMA strain backgrounds for CAVD consortium (McElrath PI)
25 Acknowledgements Cerus Heather Allen Gary Bolton Keith Bahjat Dirk Brockstedt David Cook Tom Dubensky Joseph Eiden Yi Gao Martin Giedlin Johannes Hampl Bill Hanson Peter Lauer Ed Lemmens Meredith Leong Weiqun Liu Will Luckett Cerus (cont.) Shruti Mathur Anne North Rodney Prell Ellyn Shocron Justin Skoble Hilde Stubdal U.C. Berkeley Dan Portnoy Johns Hopkins University Drew Pardoll Elizabeth Jaffee Richard Schulick
Received 17 October 2008/Returned for modification 20 February 2009/Accepted 3 June 2009
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