In vivo CAR-T therapy, which eliminates the complex manufacturing required for current ex vivo approaches, could represent the next generation of treatment, but early data raise safety concerns, including inflammatory toxicity, according to a presentation by Saar Gill, MD, PhD, an associate professor of medicine, at the University of Pennsylvania.
The presentation was given during a joint American Association for Cancer Research and American Society of Clinical Oncology session on next-generation CAR-T therapies, where Dr. Gill outlined the advantages of in vivo approaches and the questions that remain.
Dr. Gill previously co-founded Interius BioTherapeutics, a University of Pennsylvania spinout focused on in vivo CAR-T therapies. The company was later acquired by Kite. He described the current ex vivo model as effective but limited by complexity, cost, and logistics. By contrast, he said the in vivo approach is designed to function more like gene therapy, using a viral vector or nanoparticle infusion to generate CAR-T cells directly within the patient.
“The idea…was that, as a physician, you’d be able to write a prescription…[and] the patient would get CAR-T cells manufactured in their own organs, their own lymphoid organs being the bioreactor that otherwise would be your GMP facility,” he said.
Early clinical data highlighted both promise and risk. Dr. Gill described a phase 1 study from China of in vivo CAR-T targeting BCMA, in which responses were deep, including MRD-negative remissions. However, safety signals remain a concern. Four patients were observed in this particular study with all patients reported to have grade 3 or higher adverse events.
“I think it’s an assumption that the early toxicity was related to an innate immune response…to the viral particles,” Dr. Gill said, noting that alternative mechanisms, such as CD3-driven T-cell activation, may also contribute.
In an earlier report, Dr. Gill said, one patient died. The death was described during the discussion as possibly inflammatory or cardiac-related, although Dr. Gill said the cause was not clear to him.
An open question is the extent to which in vivo approaches can access T cells beyond the bloodstream. Most T cells reside in lymphoid tissues, which raises the possibility that in vivo delivery could reach a larger and more functionally relevant pool of cells.
“Most of the T cells in your body aren’t in the circulating compartment…they’re in the lymphoid organs…so we may have access to cells that are not blood T cells,” he said.
Some of the main takeaways from the presentation include:
- In vivo approaches aim to turn the patient into the manufacturing site and could reduce complex logistics and increase treatment access.
- Early efficacy signals are encouraging, with early trials showing deep responses, including MRD negativity, but safety remains a concern.
- Several biological questions remain unresolved, including dosing control, immune activation, and the ability to access T cells beyond the bloodstream.
