Chimeric antigen receptor T-cell therapies: Optimising the dose

Abstract

Lymphocytes such as T-cells can be genetically transduced to express a synthetic chimeric antigen receptor (CAR) that re-directs their cytotoxic activity against a tumour-expressed antigen of choice. Autologous (patient-derived) CAR T-cells have been licensed to treat certain relapsed and refractory B-cell malignancies, and numerous CAR T-cell products are in clinical development. As living gene-modified cells, CAR T-cells exhibit unique pharmacokinetics, typically proliferating within the recipient during the first 14 days after administration before contracting in number, and sometimes exhibiting long-term persistence. The relationship between CAR T-cell dose and exposure is highly variable, and may be influenced by CAR design, patient immune function at the time of T-cell harvest, phenotype of the CAR T-cell product, disease burden, lymphodepleting chemotherapy and subsequent immunomodulatory therapies. Recommended CAR T-cell doses are typically established for a specific product and indication, although for some products, stratification of dose based on disease burden may mitigate toxicity while maintaining efficacy. Re-evaluation of CAR T-cell dosing may be necessary following changes to the lymphodepleting regimen, for different disease indications, and following significant manufacturing changes, if product comparability cannot be demonstrated. Dose escalation trials have typically employed 3 + 3 designs, although this approach has limitations, and alternative phase I trial designs may facilitate the identification of CAR T-cell doses that strike an optimal balance of safety, efficacy and manufacturing feasibility.

Trial registration: ClinicalTrials.gov NCT04049513.

Keywords: chimeric antigen receptor therapy; drug interactions; drug toxicity; immunologic dose-response relationship; pharmacokinetics; phase 1 clinical trials.

Conflict of interest statement

N.D., P.G. and R.W. are employees of the Malaghan Institute of Medical Research, which is the Sponsor of an investigator‐initiated phase I CAR T‐cell trial(ClinicalTrials.gov reference NCT04049513), of which R.W. is the Principal Investigator. The authors have no proprietary or financial interest in the trial or the investigational product. R.W. is in receipt of a ClinicalPractitioner Research Fellowship from the Health Research Council of NewZealand (HRC), is Principal Investigator of an HRC grant to investigate the mechanism of CAR T‐cell co‐stimulatory domains, and has received honoraria from Janssen and AbbVie.

© 2020 The British Pharmacological Society.

Figures

FIGURE 1

Schematic representation of chimeric antigen receptors. (A) First‐generation chimeric antigen receptors (CARs) signal via CD3ζ only, and elicit limited T‐cell effector function against target antigen. (B) Second‐generation CARs, employed in the licensed CAR T‐cell products tisagenlecleucel and axicabtagene–ciloleucel, employ a single intracellular costimulatory domain such as 4‐1BB or CD28. (C) Third‐generation CARs employ 2 costimulatory domains in sequence. (D) Bicistronic constructs allow expression of a second protein, such as the T‐cell stimulatory cytokine interleukin (IL)‐12, alongside a CAR. scFv, single chain variable fragment

FIGURE 2

Manufacture of chimeric antigen receptor (CAR) T‐cells. Manufacture of autologous CAR T‐cells typically begins with patient blood leucocytes obtained by leukapheresis. A sample of this input product is sent for screening tests, while T‐cells are purified and activated using immunomagnetic beads or plate‐bound antibodies. In‐process controls may include purity checks by flow cytometry. A transgene is introduced using a lentiviral or retroviral vector, or a transposon/transposase system. CAR T‐cells are expanded in vitro using optimised cell culture conditions and in the presence of cytokines. Product release testing is required before CAR T‐cells are released for administration to the patient, typically following lymphodepleting chemotherapy

FIGURE 3

Chimeric antigen receptor (CAR) T‐cell pharmacokinetics. For second‐generation anti‐CD19 CAR T‐cells for B‐cell malignancies, an initial drop in CAR T‐cell levels after infusion is followed by a period of CAR T‐cell expansion. Peak levels (Cmax), typically occur within 14 days (tmax); t1/2 represents the half‐life, tlast represents the time at which the last measurable level (Clast) was recorded. AUC0‐28d represents the area under the concentration‐time curve during the first 28 days after CAR T‐cell administration. The y‐axis represents a log‐scale in terms of differences in the CAR T‐cell concentrations

FIGURE 4

Selecting an optimal chimeric antigen receptor (CAR) T‐cell dose. Beneath a certain dose threshold, CAR T‐cells may fail to expand within the recipient, and both response and severe toxicity are unlikely. Above this threshold, clinical efficacy may increase rapidly until a minimum effective dose is reached, beyond which there may be little further improvement in response rate with increasing dose. In contrast, the rate of severe toxicities may continue to rise as the dose is increased. Phase I trial designs that seek to determine the minimum effective dose as well as the maximum tolerated dose may facilitate selection of a dose that maximises response rate without undue toxicity risk