In Vivo Cellular Expansion of Lisocabtagene Maraleucel and Association With Efficacy and Safety in Relapsed/Refractory Large B‐Cell Lymphoma

Abstract

Lisocabtagene maraleucel (liso‐cel) is an autologous, CD19‐directed, chimeric antigen receptor T‐cell product for the treatment of adult patients with relapsed or refractory large B‐cell lymphoma (LBCL) after 2 or more lines of systemic therapy. In vivo cellular expansion after single‐dose administration of liso‐cel has been characterized. In this article, in vivo liso‐cel expansion in the pivotal study TRANSCEND NHL 001 (ClinicalTrials.gov identifier, NCT02631044) was further characterized to assess the relationship between in vivo cellular expansion after single‐dose administration of liso‐cel and efficacy or safety after adjusting for key baseline characteristics. Two bioanalytical methods, quantitative polymerase chain reaction and flow cytometry, were used for the assessment of cellular kinetics of liso‐cel, which showed high concordance for in vivo cellular expansion. Multivariable logistic regression analyses demonstrated that higher in vivo cellular expansion of liso‐cel was associated with a higher overall response and complete response rate, and a higher incidence of cytokine release syndrome and neurological events in patients with relapsed or refractory LBCL. Age and tumor burden (by sum of the product of perpendicular diameters) were likely to confound the relationship between in vivo cellular expansion and efficacy, where the association became stronger after controlling for these factors. Repeat dosing of liso‐cel was tested in the study; however, in vivo cellular expansion of liso‐cel was lower after repeat dosing than after the initial dose. These findings should enable a comprehensive understanding of the in vivo cellular kinetics of liso‐cel and the association with outcomes in relapsed/refractory LBCL.

Quantitative Clinical Pharmacology of CAR T‐Cell Therapy

“…Although a relationship between cell dose administered and response has been demonstrated, this is generally limited to responses being dependent on a certain dose threshold, and above that threshold dose‐dependency is not consistently seen 9,11–14 . In addition, consistent correlations between dose administered and subsequent expansion have not been observed 3,12,13 . In a previously published population CK analysis of lisocabtagene maraleucel, a discernible dose‐exposure relationship for cellular expansion could not be observed in the tested administered dose range of 44–156 × 10 6 CAR T‐cells 15 .…”

“…The interpretation of the results of exposure‐response analyses for cell therapies like lisocabtagene maraleucel may thus not be entirely analogous to that applicable for small molecules or biologics. Whereas the multivariable exposure‐response relationships described by Ogasawara et al 3 . advance our understanding of the importance of CAR‐T expansion on clinical outcomes in the context of other sources of variability, quantitative translation to dose selection decisions may not be straightforward.…”

“…Ogasawara et al .’s finding that a second administration of lisocabtagene maraleucel 2 weeks after the first dose did not alter C max 3 further highlights the differences between cellular therapy and traditional therapeutics and the need for more extensive exploration of the factors controlling in vivo expansion. Determining the mechanisms for tumor resistance to CAR T‐cell therapy remains an active area of investigation and is likely multifactorial, related to problems with CAR T‐cell persistence and/or long‐term cytotoxic activity, the tumor microenvironment as well as tumor‐intrinsic mechanisms, such as loss of antigen expression or aberrant apoptotic machinery 26,27 …”

“…Sarah A. Holstein 1, *, Karthik Venkatakrishnan 2 and Piet H. van der Graaf 3,4 One of the most significant innovations in personalized cancer medicine over the past decade has been the development of chimeric antigen receptor (CAR) T-cell therapy, in which a patient's own cells are engineered to becoming cancer-fighting weapons (Figure 1). Blending oncology, biotechnology, and immunology, CAR T-cell therapy has revolutionized the management of relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), various B-cell non-Hodgkin's lymphomas (NHLs), and multiple myeloma (MM).…”

“…2 In this issue of Clinical Pharmacology & Therapeutics (CPT) Ogasawara and colleagues contribute to the growing understanding of the relationship between in vivo CAR T-cell expansion, antitumor efficacy, and toxicity. 3 The CKs of lisocabtagene maraleucel from patients treated in the TRANSCEND NHL 001 trial 4 were evaluated using two bioanalytical methods: quantitative polymerase chain reaction to measure the transgene and flow cytometric detection of the nonfunctional truncated epidermal growth factor receptor that is coexpressed along with the CD19-specific CAR from peripheral blood samples. 3 Reported CK parameters included maximum expansion (C max ), time to C max (T max ), and area under the curve (AUC) for both 0-28 and 0-90 days post-infusion (AUC 0-28 days and AUC 0-90 days ).…”