In vivo CAR-T cell generation: a production-rate framework linking vector and cellular pharmacology

In vivo CAR-T cell generation is advancing rapidly within gene and cell therapy, but it is often framed as an “in-body” version of ex vivo CAR-T—a view that obscures fundamental pharmacological differences. We propose that in vivo CAR-T is better understood as a vector-to-cell pharmacological transition, in which vector pharmacology directly shapes cellular pharmacology: vector dose is only the administered input, whereas therapeutic cellular exposure is hypothesized to depend jointly on the rate, duration, and functional quality of CAR-T cells generated within the patient. Three generation-phase constraints — niche competition without lymphodepletion, founding-state lock-in, and antigen-encounter timing mismatch — define this transition and inform platform–indication matching. We develop this as a testable organizing hypothesis rather than a validated pharmacokinetic model, specifying which quantities are observed, which are inferred, and which are derived, together with four falsifiable predictions and the measurements required to evaluate them. “Production rate × functional window” is retained as a mnemonic for the two axes involved — the kinetics and duration of cellular generation, and the functional quality of the cells generated — rather than as an arithmetic product.