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Labcorp Drug Development临床前肿瘤学生物安全性2级能力与持续扩展

作者:

Melissa Andrews, PhD | Research Associate II, In Vivo Operations

Sarah Clark, DVM, DACLAM | Attending Veterinarian, Animal Welfare and Veterinary Services

Justin Snider | Senior Scientist, Scientific Development

Ashley Weiser | EHS Manager, Environmental Health & Safety

Date: October 2021


Viruses and bacteria have a bad reputation. As we continue to deal with a global pandemic that is caused by a virus, there is heightened awareness to the potential negative impact of viruses. However, it is also true that both viruses and bacteria are powerful tools in treating many diseases. Their ability to infect quickly and rapid dividing potential also makes them a great asset to the research community. Since the early 20th century, viruses, bacteria and other biosafety level 2 (BSL2) materials have been recognized as potential treatments for various cancers. More concerted efforts have been put forth in recent years to research these materials. There are currently two BSL2 materials approved by the FDA for use: T-VEC (Imlygic®), an oncolytic virus (OV) therapy against advanced melanoma, and Bacillus Calmette-Guerin, a bacterial therapy against non-muscle invasive bladder cancer. BSL2 materials differ from more traditional cancer therapies due to the moderate risk they pose to humans and/or animals as infectious agents or toxins.1 Due to the nature of some BSL2 materials, an animal biosafety level 2 (ABSL2) suite is practically preferable to perform in vivo work within a vivarium. ABSL2 suites allow for containment and separation of animals, materials and staff from the general vivarium and animal populations to contain the potentially infectious material. BSL2 material can be used as a monotherapy or in a combination therapy approach. As a monotherapy, an OV can replicate and kill cancer cells, without harming normal tissue.2 In a combination approach, OVs have allowed for local delivery of multiple immunomodulators to the tumor environment, even crossing the blood-brain barrier, which has been shown to decrease non-target toxicity.3 OVs have also been combined with Chimeric Antigen Receptor T (CAR T) cell therapy in solid tumors to make the tumor microenvironment more suitable for T-cell infiltration.4

At Labcorp Drug Development Preclinical Oncology (PCO), we strive to stay current on modern technologies and look to collaborate with clients to optimize our service offerings and advance research opportunities. Considering the renewed interest in BSL2 materials, PCO has recently renovated or is in the process of expanding our ABSL2 suites at both the Ann Arbor, Michigan and Greenfield, Indiana PCO sites. We believe that our preclinical oncology expertise, our vast experience in the use of checkpoint inhibitors, cell therapies and BSL2 materials and our revamped ABSL2 suites place us in a great position to serve our clients in their exploration to find an effective and novel treatment in either a non-GLP or GLP setting (Table 1). Both PCO sites have experience working with several modified BSL2 viral and bacterial vectors and have entered discussions to perform studies with additional materials (Table 2). These materials have been administered via traditional dosing routes, but also, via direct intracranial injections and intratumoral injections. We have vast surgical experience that allows us to implant cancer cells or tumor fragments orthotopically or inject BSL2 materials into specific tissues. If in vivo or ex vivo imaging is of interest, our IVIS (In Vivo Imaging System) BLI (Bioluminescence Imaging) systems allow us to monitor and track cancer cell lines transfected with luciferase for disease progression or track fluorescent-tagged BSL2 materials for biodistribution evaluation. We also have the capability to assess disease burden with digital caliper measurements. We offer a number of other in vivo and in vitro services to aid our clients in their pursuit of further developing anti-cancer BSL2 materials (Table 3).  

Our employees and animals are of utmost importance to us at PCO, which lead us to our policy that any biological component that may pose a risk to the health of our employees and animals or the vivarium environment requires review by the PCO site’s biosafety committee. This allows us to prevent exposure and to appropriately identify containment level and handling procedures. The U.S. Centers for Disease Control and Prevention (CDC) and National Institutes of Health (NIH) Biosafety in Microbiological and Biomedical Laboratories (BMBL 6th edition) is referenced for best practices.5 The BMBL is only a guiding document and other resources will be referenced as needed. All animal work is reviewed and approved by the site’s Institutional Animal Care and Use Committee or Animal Welfare Ethical Review Board.  Both PCO sites meet or exceed local animal welfare regulations and have their programs accredited by AAALAC. Minimum information that the biosafety committee requests to assess risk is a draft study design, the type of agent and any associated agent documents. The biosafety committee also evaluates risks of splash, laceration/needle stick and aerosols either from formulation, dosing or indirectly from animal bedding to determine the need for engineering controls in accordance with OSHA’s Bloodborne pathogen Standard as well as the general duty clause for ensuring safety of our employees. We protect our staff, animals and vivarium via controls that include, but are not limited to, separate ABSL2 HVAC units, biosafety cabinets, disinfectants, personal protective equipment and other mitigation efforts to ensure employees are safe from hazards. If an agent requires vaccination prior to handling, the committee will communicate and offer vaccines to staff as needed. All waste is considered biohazardous and collected for off-site treatment by a licensed waste vendor. 

Table 1 – Number of Different Study Types Performed at Labcorp PCO

Studies Performed at Labcorp PCO

Study Type

Number of Studies Run at PCO

CAR T or CAR NK studies

425+ 

Studies with ABSL2 agents 

40+ 

BLI studies

650+ 

Checkpoint inhibitor studies

300+ 

Biologic test article studies

1200+ 

Small molecule test article studies

1900+ 

Combination studies

1100+ 

GLP and non-GLP studies

 4100+

Table 2 – Different BSL2 Materials Used or Discussed by Labcorp PCO

BSL2 Test Materials

Materials - Previous Experience

Materials - Ongoing Discussions

Adenovirus constructs 

Bacteriophages 

Herpes simplex virus constructs 

Lentiviral constructs 

Vaccinia virus constructs 

Lymphocytic choriomeningitis (LCMV) constructs  

Escherichia coli constructs 

  

Salmonella Typhi constructs 

  

Salmonella Typhimurium constructs 

 

Table 3 – Labcorp ABSL2 Capacity and Capabilities Overview

ABSL2 Capacity and Capabilities

In Vivo Capacity and Capabilities

In Vitro Capabilities

Physical space: 9 rooms
• Room capacity: ~150-500 cages/room
• GLP and non-GLP capabilities
• BLI imaging (in vivo & ex vivo)
• Surgical support capabilities for implants and treatment
• Toxicology support capabilities
• Ultra-clean necropsy capabilities
• ABSL2 engineering controls:
    ◦Separate HVAC systems
    ◦Dedicated BSCs for BSL2 materials
    ◦Dedicated ABSL2 equipment
    ◦Restricted access to ABSL2 suite
    ◦Strict decontamination procedures

• 流式细胞计量术
• ELISpot/FluoroSpot
• ELISA
• Luminex
• MSD (MesoScale Discovery)
• Tissue specific 3D models
• Western blots
• qPCR
• 组织学
• IHC and IF
• Custom assay development

* In vitro capabilities are dependent on the BSL2 material being used

Additional Information on Capabilities

• BLI imaging:

https://drugdevelopment.labcorp.com/industry-solutions/oncology/preclinical/tumor-spotlights/Bioluminescence-imaging-spotlight.html

 

• CAR T-cell persistence analysis via flow cytometry:

https://drugdevelopment.labcorp.com/industry-solutions/oncology/preclinical/tumor-spotlights/determining-preclinical-car-t-cell-persistence-by-flow-cytometry.html

• ELISpot and FluoroSpot analysis:

https://drugdevelopment.labcorp.com/industry-solutions/oncology/preclinical/tumor-spotlights/measuring-tumor-anitgen-specific-immunity.html

Contact the preclinical oncology scientific team to learn more.


参考资料

1 https://www.phe.gov/s3/BioriskManagement/biocontainment/Pages/BSL-Requirements.aspx

2 Chiocca A, Rabkin S. Oncolytic viruses and their application to cancer immunotherapy. Cancer Immunology Research, 2014; 4: 295-300.

3 Haddad A, Young J, Aghi M. Using viral vectors to deliver local immunotherapy to glioblastoma. Journal of Neurosurgery, 2021; 2.

4 https://www.fiercebiotech.com/biotech/bluebird-psioxus-show-oncolytic-virus-boosts-car-t-solid-tumors

5 https://www.cdc.gov/labs/pdf/SF__19_308133-A_BMBL6_00-BOOK-WEB-final-3.pdf

 
请注意,所有动物护理和使用均根据动物福利法规在AAALAC认可的研究中心进行,并经过IACUC协议审查和批准。

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