Lymphodepletion strategies to potentiate adoptive T-cell immunotherapy - what are we doing; where are we going?

Adoptive immunotherapy of cancer has evolved from the use of ex vivo expanded lymphokine-activated killer cells and tumor-infiltrating lymphocytes to an increasing array of approaches involving genetically engineered T-cells. A pivotal advance in the enablement of these therapies has been the conditioning of patients with lymphodepleting chemotherapy.A broad range of lymphodepleting regimens has been employed in an effort to improve response rates, without any single consistent approach having emerged. Only a limited number of studies involving small numbers of patients has directly compared two or more regimens, making it challenging to infer which are the preferred agents and dosing schedules. This difficulty is compounded by the fact that both response rate and toxicity appear to be disease-, patient- and T-cell product specific.

This article surveys clinical experience with lymphodepleting regimens that have been used in conjunction with adoptive T-cell immunotherapy, focussing in particular on studies where different approaches have been employed. Harnessing this limited and evolving clinical experience, we set out to provide potential insights into how an optimal balance may be achieved between efficacy and safety. Intermediate dose fludarabine-based regimens are emerging as an increasingly popular option in an attempt to achieve this goal, although further studies are required to provide definitive evidence.