Emerging Technologies/Treatments Bootcamp Session 2: Gene Therapy Trials and Tribulations (2017)

In this series, we will discuss regulatory considerations for conducting clinical trials in the era of emerging technologies and treatments.


Course Syllabus/Topics

Definition of Gene Therapy:

  • Medical intervention based on modification of genetic material of living cells
  • Ex vivo for subsequent administration to humans
  • In vivo by delivery directly into subject

Overview of Gene Therapy Procedure:

  • Collect cells
  • Gene Modify Cells
  • Conditioning Chemotherapy
  • Re-administer Cells
  • Monitor patient for adverse events

Gene Therapy to Correct Genetic Deficiency:

  • Gene therapy is used to treat Severe Combined Immune Deficiency (SCID)

Gene Therapy to Activate the Immune System to Attack Cancer:

  • Modify immune cells to kill cancer cells
  • Adoptive Cell Therapy (ACT) Clinical Trial Schematic

Coordination of Teams Required for Administration of Gene Modified Cells:

  • Manufacturing Team
  • Quality Assurance Team
  • Manufacturing Team
  • Physicians and Nurses

Adverse Events Monitoring Following Cell Administration:

  • Local – IRB, ISPRC, DSMB, IBC
  • Federal – FDA CBER/OTAT, NIH/RAC
  • Protocol changes
  • Agreements among regulatory bodies
  • SAE attributions can be unclear and can change as information becomes available

Potential Serious Adverse Events Lessons From History

  • Death of Jesse Gelsinger (1999)
  • X-SCID Patients Developed Leukemia Following Gene Therapy Due to Insertional Mutagenesis (2002)

Risk Assessment for Insertional Mutagenesis Now Required:

  • Preclinical risk assessment of new vectors
  • Monitoring included in trials for assessment of gene insertions and early detection of secondary malignancies
  • Long-term follow up required for gene therapy patients
  • Vectors have been modified to decrease the risk of insertional mutagenesis leading to cancer

Additional Testing Required by FDA:

  • Replication Competent Retrovirus (RCR) testing
  • Replication Competent Lentivirus (RCL) testing
  • Virus tested before introduced into cells
  • Manufactured cells banked for testing before administration
  • Subjects’ blood banked for testing at 3, 6 and 12 months post cell administration and annually thereafter

Three Companies Fought for First Approval of Chimeric Antigen Receptor T (CAR-T) Cell Therapy:

  • Novartis
  • Juno Therapeutics
  • Kite Pharma

New Directions in Gene Therapy

  • “Off the shelf” CAR-T cells
  • Safety switches – turn off genes or kill cells
  • Reduce cost

Ackowledgement

Accompanying text created by Yelin (David) Hu | Regulatory Science Student Worker | yelinhu@usc.edu


NIH Funding Acknowledgment: Important - All publications resulting from the utilization of SC CTSI resources are required to credit the SC CTSI grant by including the NIH funding acknowledgment and must comply with the NIH Public Access Policy.