Peak Lymphocyte Count after CAR T Infusion Is a Clinically Accessible Test That Correlates with Clinical Response in Axicabtagene Ciloleucel Therapy for Lymphoma

Novo, Mattia; Sidiqi, M Hasib; Paludo, Jonas; Gandhi, Sangeetha; Kubusek, Jilan; Truong, Tuan; Hayne, Justin; Ansell, Stephen M.; Bennani, N. Nora; Villasboas, José C.; Nedved, Adrienne; Lange, Gina; Brandes, Eva; Alkhateeb, Hassan B.; Dingli, David; Hayman, Suzanne R.; Kapoor, Prashant; Kenderian, Saad S.; Kourelis, Taxiarchis; Kumar, Shaji; Shah, Mithun Vinod; Siddiqui, Mustaqueem; Warsame, Rahma; Johnston, Patrick B.; Lin, Yi

doi:10.1182/blood-2019-127094

Cited by 7 publications

(4 citation statements)

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“…In particular, the modeled persistence level of memory CAR-T cells is positively correlated to the CAR-T peak level, in line with recent findings that patients with positive ddPCR (indicative for persistence) at six months had a significantly higher median peak of CAR-T cell copies compared with negative ddPCR [33]. Also, the minimal tumor burden is inversely related to the CAR-T cell peak level, consistent with [34], which reported that higher peaks of CAR-T cells within 15 days are associated with increased likelihood of achieving complete remission.…”

Section: Discussionsupporting

confidence: 88%

Mathematical modeling unveils the timeline of CAR-T cell therapy and macrophage-mediated cytokine release syndrome

Santurio,

Barros,

Glauche

et al. 2024

Preprint

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Chimeric antigen receptor (CAR)-T cell therapy holds significant potential for cancer treatment, although disease recurrence and cytokine release syndrome (CRS) remain as frequent clinical challenges. To better understand the underlying mechanisms and temporal dynamics during CAR-T cell therapy response we developed a novel multi-layer mathematical model that accurately describes 25 patient time-courses with diverse responses and IL-6 cytokine kinetics. We successfully link the dynamic shape of the response to interpretable model parameters and study the influence of CAR-T cell dose and initial tumor burden on CRS occurrence and treatment outcome. Further accounting for three established mechanisms of macrophage activation we identified the CD40-CD40L axis as a clinically feasible target to control the activation process and modulate IL-6 peak height. Our study underscores the utility of mechanistic modeling in deciphering therapy dynamics and guiding clinical interventions, emphasizing the importance of close integration with clinical data.

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Section: Discussionsupporting

confidence: 88%

Mathematical modeling unveils the timeline of CAR-T cell therapy and macrophage-mediated cytokine release syndrome

Santurio,

Barros,

Glauche

et al. 2024

Preprint

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“…The CCR7+:CCR7-T-cell ratio was positively associated with CAR T-cell peak and cumulative expansion during the first month after infusion. More robust CAR T-cell expansion was also associated with a higher likelihood of achieving CR (11), and early expansion of a specific subset of CD4+ CAR T cells (i.e., with high expression of CD45RO, CD57, PD1, and T-bet transcription factor) may help identify patients most likely to maintain CR at 6 months (12).…”

Section: Axi-cel For Aggressive B-cell Lymphoma Efficacy and Predictomentioning

confidence: 98%

CAR T-Cell Therapy for B-Cell non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia: Clinical Trials and Real-World Experiences

Vitale

Strati

2020

Front. Oncol.

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Chimeric antigen receptor-modified (CAR) T cells targeting CD19 have revolutionized the treatment of relapsed or refractory aggressive B-cell lymphomas, and their use has increased the cure rate for these cancers from 10 to 40%. Two second-generation anti-CD19 CAR T-cell products, axicabtagene ciloleucel and tisagenlecleucel, have been approved for use in patients, and the approval of a third product, lisocabtagene maraleucel, is expected in 2020. The commercial availability of the first two products has facilitated the development of real-world experience in treating relapsed or refractory aggressive B-cell lymphomas, shed light on anti-CD19 CAR T-cell products' feasibility in trial-ineligible patients, and raised the need for strategies to mitigate the adverse effects associated with anti-CD19 CAR T-cell therapy, such as cytokine release syndrome, neurotoxicity, and cytopenia. In addition, promising clinical data supporting the use of anti-CD19 CAR T-cell therapy in patients with indolent B-cell lymphomas or chronic lymphocytic leukemia have recently become available, breaking the paradigm that these conditions are not curable. Multiple clinical CAR T-cell therapy-based trials are ongoing. These include studies comparing CAR T-cell therapy to autologous stem cell transplantation or investigating their use at earlier stages of disease, novel combinations, and novel constructs. Here we provide a thorough review on the use of the anti-CD19 CAR T-cell products axicabtagene ciloleucel, tisagenlecleucel and lisocabtagene maraleucel in patients with indolent or aggressive B-cell lymphoma or with chronic lymphocytic leukemia, and present novel CAR T cell-based approaches currently under investigation in these disease settings.

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“…The lymphocyte count captures the magnitude of CAR T-cell proliferation in vivo, an early aspect of CAR T-cell kinetics associated with both durable remission and risk of toxicity. 47 A study conducted by Novo et al 58 determined a statistically significant difference in peak absolute lymphocyte count between those experiencing and not experiencing complete response.…”

Section: Direct Car T-cell Detection Methodsmentioning

confidence: 99%

“…The lymphocyte count captures the magnitude of CAR T‐cell proliferation in vivo, an early aspect of CAR T‐cell kinetics associated with both durable remission and risk of toxicity 47 . A study conducted by Novo et al 58 determined a statistically significant difference in peak absolute lymphocyte count between those experiencing and not experiencing complete response. The measurement of immunoglobulin levels is not frequently utilised, owing to disease‐ and therapy‐ related hypo‐gammaglobulinaemia being an important confounding factor 47 .…”

Section: Evaluation Of Car T‐cellsmentioning

confidence: 99%

Chimeric antigen receptor T‐cells: Properties, production, and quality control

Ramesh

Hui

Brownrigg

et al. 2023

Int J Lab Hematology

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Chimeric antigen receptor (CAR) T‐cell therapy is a novel adoptive T‐cell immunotherapy for haematological malignancies. First introduced into clinical practice in 2017, CAR T‐cell therapy is now finding its place in the management of lymphoid malignancies, primarily of B‐cell lineage, including lymphoblastic leukaemia, non‐Hodgkin lymphoma and plasma cell myeloma, with remarkable therapeutic outcomes. CAR T‐cells are a customised therapeutic product for each patient. Manufacture commences with collection of autologous T‐cells, which are then genetically engineered ex vivo to express transmembrane CARs. These chimeric proteins consist of an antibody‐like extracellular antigen‐binding domain, to recognise specific antigens on the surface of tumour cells (e.g. CD19), linked to the intracellular co‐stimulatory signalling domains of a T‐cell receptor (e.g. CD137). The latter is required for in vivo CAR T‐cell proliferation, survival, and durable efficacy. Following reinfusion, CAR T‐cells harness the cytotoxic capacity of a patient's immune system. They overcome major mechanisms of tumour immuno‐evasion and have potential to generate robust cytotoxic anti‐tumour responses. This review discusses the background to CAR T‐cell therapies, including their molecular design, mechanisms of action, methods of production, clinical applications and established and emerging technologies for CAR T‐cell evaluation. It highlights the need for standardisation, quality control and monitoring of CAR T‐cell therapies, to ensure their safety and efficacy in clinical management.

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Peak Lymphocyte Count after CAR T Infusion Is a Clinically Accessible Test That Correlates with Clinical Response in Axicabtagene Ciloleucel Therapy for Lymphoma

Cited by 7 publications

References 0 publications

Mathematical modeling unveils the timeline of CAR-T cell therapy and macrophage-mediated cytokine release syndrome

Mathematical modeling unveils the timeline of CAR-T cell therapy and macrophage-mediated cytokine release syndrome

CAR T-Cell Therapy for B-Cell non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia: Clinical Trials and Real-World Experiences

Chimeric antigen receptor T‐cells: Properties, production, and quality control

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