Such high efficacy of CTL-mediated serial killing, however, is rarely observed in patients receiving adoptive transfer of tumor-specific T cell receptor (TCR)-engineered or chimeric antigen receptor (CAR) T cells 8. As a consequence of multi-hit delivery, single CTLs are capable of eliminating multiple antigenic target cells in vitro and in vivo, ranging from 1 up to 20 kills per CTL and day, as estimated from bulk killing assays and mathematical modeling 6, 7. CTL and natural killer (NK) cells can bind to and attack more than one target cell sequentially 3, 4, 5. This identifies CTL-mediated cytotoxicity by multi-hit delivery as an incremental and tunable process, whereby accelerating damage magnitude and frequency may improve immune efficacy.Ĭytotoxic T lymphocytes (CTLs) execute effector function by a cyclic process of transient cell–cell interaction and paracrine delivery of cytotoxic effector molecules to target cells, followed by target cell death 1, 2.

In live melanoma lesions in vivo, sublethal multi-hit delivery is most effective in interstitial tissue where high CTL densities and swarming support frequent serial CTL-tumor cell encounters.

Statistical modeling reveals that 3 serial hits delivered with decay intervals below 50 min discriminate between tumor cell death or survival after recovery.

Reversible sublethal damage includes perforin-dependent membrane pore formation, nuclear envelope rupture and DNA damage. Here we describe a mechanism of “additive cytotoxicity” by which time-dependent integration of sublethal damage events, delivered by multiple CTL transiting between individual tumor cells, mediates effective elimination. In non-hematologic solid tumors, however, CTL often fail to kill target cells during 1:1 conjugation. Lethal hit delivery by cytotoxic T lymphocytes (CTL) towards B lymphoma cells occurs as a binary, “yes/no” process.

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