Modeling Patient-Specific CAR-T Cell Dynamics: Multiphasic Kinetics via Phenotypic Differentiation

Abstract

Chimeric Antigen Receptor (CAR)-T cell immunotherapy revolutionized cancer treatment and consists of the genetic modification of T lymphocytes with a CAR gene, aiming to increase their ability to recognize and kill antigen-specific tumor cells. The dynamics of CAR-T cell responses in patients present multiphasic kinetics with distribution, expansion, contraction, and persistence phases. The characteristics and duration of each phase depend on the tumor type, the infused product, and patient-specific characteristics. We present a mathematical model that describes the multiphasic CAR-T cell dynamics resulting from the interplay between CAR-T and tumor cells, considering patient and product heterogeneities. The CAR-T cell population is divided into functional (distributed and effector), memory, and exhausted CAR-T cell phenotypes. The model is able to describe the diversity of CAR-T cell dynamical behaviors in different patients and hematological cancers as well as their therapy outcomes. Our results indicate that the joint assessment of the area under the concentration-time curve in the first 28 days and the corresponding fraction of non-exhausted CAR-T cells may be considered a potential marker to classify therapy responses. Overall, the analysis of different CAR-T cell phenotypes can be a key aspect for a better understanding of the whole CAR-T cell dynamics.

Monitoring of kinetics and exhaustion markers of circulating CAR-T cells as early predictive factors in patients with B-cell malignancies

“…At this time after infusion, CAR-T cells may have an elevated activity after rapid expansion and elimination of tumor cells and may have therefore acquired a more activated, cytotoxic, and exhausted phenotype. Altogether these data indicate that, at the time of peak expansion, CAR-T cells have been through an antigen-driven differentiation leading to a reduced CD4/CD8 ratio, an increased effector memory phenotype and the acquisition of an activated and exhausted phenotype (30,(34)(35)(36). It is important to remark that, although there are several studies about the phenotypic characterization of CAR-T cell in the leukapheresis and infusion products (6,13,25,37), scarce information is available about the phenotypic characterization of CAR-T cells at the time of peak expansion as the current study shows.…”

Mechanisms of Resistance to CAR-T cell Immunotherapy: Insights from a Mathematical Model

“…Based on our previous work [25], the expansion function κ(t) displays a high expansion level that may be sustained for a certain period, forming a plateau, before finally decreasing to a baseline level. This is formally described by…”

“…Here, f (C T , T ) is a modified Hill function inspired by [43,25]. For the cytotoxicity function, we propose a smooth step function g(x) ∈ [g 0 , 1] that modulates CAR-T cell cytotoxicity as an antigendriven mechanism.…”

“…The model has successfully captured the experimentally observed CAR-T kinetics, in which CAR T-cells rapidly expand upon injection and reach their peak within the first 2 weeks. Then, the effector CAR-T cells rapidly decrease during the contraction phase until the total population is predominantly formed by the long-lasting memory cells, defining the persistence phase [25]. Most of the patients in the Relapse− cohort have a large memory pool, a marked persistence phase, and it is possible to observe a significant amount of CAR-T effector cells even if below the detection threshold (Figure 2, top panel).…”

“…In a preclinical model for hematological cancers, Barros et al [24] modeled the dynamics of two CAR-T cell populations (effector and memory), highlighting the importance of the memory pool formation for the response to therapy. Subsequently, Paixão et al [25] extended this model to the clinical scenario, resulting in a model that describe the patient-specific multiphasic dynamics of CAR-T cell kinetics through the differentiation of functional, memory, and exhausted phenotypes, as well as the dynamics of cancer cells. Singh et al [26] used a multiscale PK/PD model to study the relationship between CAR-affinity, antigen abundance, tumor cell depletion, and CAR T-cell expansion in mouse models.…”