Clinical production of viral vectors for cancer gene therapy

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

The Surgery Branch Vector Production Facility (SBVPF) was established to provide clinical-grade retroviral and lentiviral vectors to support of gene therapy clinical trials in the Branch with the primary goal of providing clinical grade products while reducing production time and cost. These products, both gamma-retroviral and lentiviral vectors will be used to introduce novel T cell receptors (TCRs) or other transgenes to genetically modify T cells. This lab provides all the clinical viral reagents for the Surgery Branch clinical gene therapy program and currently supports four independent clinical protocols. A major focus in the Branch is to isolate T cell receptors from tumor infiltrating lymphocytes residing within a patient's tumor which target a patient's tumor neoantigens/mutations. We use a gene therapy approach to treat patients by introducing these neoantigen-specific TCRs into autologous PBMC using these viral vectors, expanding the transduced cells ex vivo and administering the modified cells to the patient. We have developed a small scale transient vector production platforms (gamma-retroviral) that supports GMP-compliant transient vector production for single individualized patient treatments targeting neoantigens. Since the opening of a dedicated GMP viral vector production space in October 2019, the SB GMP VPF has produced >100 novel, individual vectors encoding patient specific TCRs meeting the specifications required for clinical use. Specifically, since July of 2024 through July of 2025, the SBVPF has manufactured 25 unique lots of clinical vector supernatants. A significant milestone for the laboratory was the initiation of parallel productions of gamma-retroviral vectors encoding different TCRs for the same patient. The IND allows for parallel manufacturing of up to 5 from the same patient and the SBVPF has successfully manufactured multiples (2, 4 and 5 TCRs) in parallel during this reporting period. An additional capability brought online this reporting period is small-scale volume gamma-retroviral productions for early phase/first-in-human or proof-of-concept protocols where the patient enrolment numbers are expected to 20 or less. This volume is between individualized (1 patient), the current majority of requests to the facility and Phase 2 trial volumes. We have completed the RandD, protocol generation and initiated the IND-enabling runs in July 2025. A major component of the successful production of sequential virus lots without interruption, is the background operation of the aseptic processing facility in compliance with current good manufacturing practices (cGMP). cGMP manufacturing space or aseptic processing facilities operate within defined, regulated parameters and must demonstrate control of temperatures, humidity, pressures, air changes and bioburden appropriate to the risk level and category of product manufactured. Identifying trends early to mitigate mechanical issues, environmental monitoring coupled with a general review of facility health on a daily basis ensures the facility can support the demanding vector production schedule required to provide the products needed in the Surgery Branch trials. The facility remained in operation and control throughout the reporting period despite required mechanical repairs/upgrades due to built-in redundancies.