Clinical pharmacology of CAR-T cells: Linking cellular pharmacodynamics to pharmacokinetics and antitumor effects

Norelli, Margherita; Casucci, Monica; Bonini, Chiara; Bondanza, Attilio

doi:10.1016/j.bbcan.2015.12.001

Cited by 24 publications

(30 citation statements)

References 111 publications

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“…Smith et al (1980) showed similar results in rats, where exogenous activated lymphocytes accumulated in the lungs up to 4-6 hours and then localized to the spleen and liver over 24 hours. This phenomenon can be attributed to the presence of a reticuloendothelial system within the spleen and liver, which is reported to be significantly involved in the disposition of T cells (Pabst, 1988;Norelli et al, 2016). In addition, lymphoid tissues such as lymph nodes and bone marrow showed high accumulation of T cells over time.…”

Section: Resultsmentioning

confidence: 98%

Measurement and Quantitative Characterization of Whole-Body Pharmacokinetics of Exogenously Administered T Cells in Mice

Khot

Matsueda

Thomas

et al. 2019

J Pharmacol Exp Ther

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Here we have investigated whole-body pharmacokinetics (PK) of exogenously administered T cells in a mouse model of melanoma and have developed a physiologically based pharmacokinetic (PBPK) model to quantitatively characterize the data. T cells were isolated from the spleen of tumor-bearing mice, activated, and labeled with chromium-51 to facilitate the quantification. Labeled T cells were injected in the tumor-bearing mice, and PK was measured in 19 different tissues. It was found that T cells disappear from the blood rapidly after administration and accumulate in the tissues to various extents. Spleen, liver, lung, kidney, bone, and lymph nodes accounted for more than 90% of T cells in the body. The distribution of T cells in solid tumors was found to be very low, hovering below 1%ID/g (percent of injected dose per gram of tissue) during the entire study. However, this observation may differ for targeted TCR-T and CAR-T cells. Observed PK profiles also suggest that T-cellbased therapies may be more successful in treating cancers of the lymphatic system and bone marrow metastases compared to solid tumors. A PBPK model was developed to characterize the whole-body PK of T cells, which incorporated key processes such as extravasation, elimination, and recirculation of T cells via lymph flow. Retention factors were incorporated into the spleen, liver, and kidney compartment to adequately capture the PK profiles. The model was able to characterize observed PK profiles reasonably well, and parameters were estimated with good confidence. The PK data and PBPK model presented here provide unprecedented insight into the biodistribution of exogenously administered T cells.

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Section: Resultsmentioning

confidence: 98%

Measurement and Quantitative Characterization of Whole-Body Pharmacokinetics of Exogenously Administered T Cells in Mice

Khot

Matsueda

Thomas

et al. 2019

J Pharmacol Exp Ther

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“…The pharmacokinetics of gene-editing therapeutics may differ between ex vivo and in vivo strategies 113,114 . For ex vivo gene-editing therapeutics, pharmacokinetic studies of the time-dependent profiles of gene-edited cells must be performed.…”

Section: Regulatory Perspectivesmentioning

confidence: 99%

Therapeutic gene editing: delivery and regulatory perspectives

et al. 2017

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Gene-editing technology is an emerging therapeutic modality for manipulating the eukaryotic genome by using target-sequence-specific engineered nucleases. Because of the exceptional advantages that gene-editing technology offers in facilitating the accurate correction of sequences in a genome, gene editing-based therapy is being aggressively developed as a next-generation therapeutic approach to treat a wide range of diseases. However, strategies for precise engineering and delivery of gene-editing nucleases, including zinc finger nucleases, transcription activator-like effector nuclease, and CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats-associated nuclease Cas9), present major obstacles to the development of gene-editing therapies, as with other gene-targeting therapeutics. Currently, viral and non-viral vectors are being studied for the delivery of these nucleases into cells in the form of DNA, mRNA, or proteins. Clinical trials are already ongoing, and in vivo studies are actively investigating the applicability of CRISPR/Cas9 techniques. However, the concept of correcting the genome poses major concerns from a regulatory perspective, especially in terms of safety. This review addresses current research trends and delivery strategies for gene editing-based therapeutics in non-clinical and clinical settings and considers the associated regulatory issues.

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“…demonstrated that CAR‐T constructs that generated the highest activity in assays measuring specific lysis and cytokine secretion exhibited attenuated anti‐tumour potency in vivo . Consistent with this, an increasing weight of clinical biomarker data suggest improved outcomes are associated with infusion of αCD19 CAR‐Ts with enhanced potential for expansion (Cmax) and persistence (AUC) post‐infusion . Immunological dogma and phenotypic and transcriptomic profiling data support the thesis that less differentiated central memory (CD45RO+, CD62L+, CD95+) and pluripotent stem cell (CD45RA+, CD62L+, CD95+) memory T‐cell subsets may be optimal in this regard .…”

Section: In‐process Control and Release Testingmentioning

confidence: 76%

“…Consistent with this, an increasing weight of clinical biomarker data suggest improved outcomes are associated with infusion of CD19 CAR-Ts with enhanced potential for expansion (Cmax) and persistence (AUC) post-infusion. 116,117 Immunological dogma and phenotypic and transcriptomic profiling data support the thesis that less differentiated central memory (CD45RO+, CD62L+, CD95+) and pluripotent stem cell (CD45RA+, CD62L+, CD95+) memory T-cell subsets may be optimal in this regard. [73][74][75] Fraietta et al 101 investigated biomarkers in 41 Chronic Lymphoid Leukaemia (CLL) patients treated with Kymriah.…”

Section: In-process Control and Release Testingmentioning

confidence: 78%

Cell therapy products: focus on issues with manufacturing and quality control of chimeric antigen receptor T‐cell therapies

Eyles

Vessillier

Jones³

et al. 2018

J of Chemical Tech & Biotech

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Recent accelerated approvals of Chimeric AntigenReceptor T-cell (CAR-T) therapies targeting refractory haematological malignancies underscore the potential for this novel technology platform to provide new therapeutic options for oncology areas with high unmet medical needs. However, these powerful 'living drugs' are markedly different to conventional small molecule and biologic therapies on several levels. The highly complex nature and varied composition of CAR-T based products still requires considerable investigation to resolve the best approaches to ensure reproducible and cost-effective manufacture, clinical development, and application. This review will focus on key issues for manufacturing and quality control of these exciting new therapeutic modalities, preceded by a brief description of CAR principals and clinical development considerations.

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Clinical pharmacology of CAR-T cells: Linking cellular pharmacodynamics to pharmacokinetics and antitumor effects

Cited by 24 publications

References 111 publications

Measurement and Quantitative Characterization of Whole-Body Pharmacokinetics of Exogenously Administered T Cells in Mice

Measurement and Quantitative Characterization of Whole-Body Pharmacokinetics of Exogenously Administered T Cells in Mice

Therapeutic gene editing: delivery and regulatory perspectives

Cell therapy products: focus on issues with manufacturing and quality control of chimeric antigen receptor T‐cell therapies

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