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Chimeric antigen receptor T-cell therapies: Optimising the dose. | LitMetric

Chimeric antigen receptor T-cell therapies: Optimising the dose.

Br J Clin Pharmacol

Cancer Immunotherapy Programme, Malaghan Institute of Medical Research, Wellington, New Zealand.

Published: September 2020

AI Article Synopsis

  • Lymphocytes, like T-cells, can be modified to carry chimeric antigen receptors (CARs) that allow them to target and attack specific cancer cells, leading to effective treatments for certain tough-to-treat B-cell cancers.
  • These genetically altered CAR T-cells can proliferate quickly for the first two weeks post-administration and may persist in the body long-term, but their numbers and effectiveness can vary based on numerous factors such as the design of the CAR, the patient’s immune status, and related treatments.
  • Determining the right dosage of CAR T-cells is complex and often requires adjustments based on factors like disease severity and prior treatments, prompting researchers to explore innovative trial designs for better safety and effectiveness outcomes

Article 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.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444796PMC
http://dx.doi.org/10.1111/bcp.14281DOI Listing

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