Retroviral and Lentiviral Safety Analysis of Gene-Modified T Cell Products and Infused HIV and Oncology Patients.

Replication-competent retrovirus/lentivirus (RCR/L) and insertional oncogenesis are potential safety risks with integrating viruses in gene-modified cell therapies. As such, the Food and Drug Administration guidances outline RCR/L-monitoring methods throughout the entire gene therapy treatment cycle. We present data for 17 vector lots, 375 manufactured T cell products, and 308 patients post-infusion across both HIV and oncology indications, showing no evidence of RCR/L. Given our data, a Poisson probability model estimates that a single patient, or a group of patients, would need to be followed for at least 52.8 years to observe one positive RCR/L event, highlighting the unlikelihood of RCR/L development. Additionally, we estimate the median time for lentivirus-modified T cell products to fall below the 1% vector sequence threshold in peripheral or whole blood that would trigger vector integration site analysis. These estimated times are 1.4 months in hematologic malignancies, 0.66 month in solid tumors, and 0.92 month in HIV. Based on these considerable safety data in HIV and oncology and recent Biologics License Applications filed for lentiviral-modified T cell products for hematologic malignancies, this may be an opportune time to re-evaluate the current guidelines for T cell gene therapy product testing and long-term patient monitoring.

How do i participate in T-cell immunotherapy?

T cells play a key role in the adaptive immune response, and the ability to manipulate T cells for therapeutic uses has advanced in the past decade. Infusion of expanded or engineered T cells can potentially be used to treat cancer, viral infections, graft-versus-host disease, and organ transplant rejection. The role that blood banks play in the manufacture and distribution of T-cell therapeutics is still being defined. Given the regulatory framework of blood banks, they are well positioned to collect raw material for manufacture of T-cell therapies and to distribute finished product to hospitals in support of clinical trials or eventually for licensed products. A deeper level of involvement in manufacture of T-cell therapeutics is also possible, although that requires more substantial investment in physical facilities and personnel with the regulatory and scientific expertise to prepare and produce cellular therapy products. Examples of physical infrastructure needed would be a laboratory with a clean room for culture of T cells, specialized equipment for expansion of the cells, and adequate administrative and storage support space. Processes that would need to be developed to produce T-cell therapeutics would include development of standard operating procedures and an appropriate quality assurance program. As blood banks consider supporting this novel class of therapies, they will need to weigh capital and expertise requirements with the benefits of providing a novel therapy and the potential of growth for their operations.