RESUMO
Chimeric antigen receptor (CAR) T-cell therapy is potentially an effective targeted immunotherapy for glioblastoma, yet there is presently little known about the efficacy of CAR T-cell treatment when combined with the widely used anti-inflammatory and immunosuppressant glucocorticoid, dexamethasone. Here we present a mathematical model-based analysis of three patient-derived glioblastoma cell lines treated in vitro with CAR T-cells and dexamethasone. Advanced in vitro experimental cell killing assay technologies allow for highly resolved temporal dynamics of tumor cells treated with CAR T-cells and dexamethasone, making this a valuable model system for studying the rich dynamics of nonlinear biological processes with translational applications. We model the system as a nonautonomous, two-species predator-prey interaction of tumor cells and CAR T-cells, with explicit time-dependence in the clearance rate of dexamethasone. Using time as a bifurcation parameter, we show that (1) dexamethasone destabilizes coexistence equilibria between CAR T-cells and tumor cells in a dose-dependent manner and (2) as dexamethasone is cleared from the system, a stable coexistence equilibrium returns in the form of a Hopf bifurcation. With the model fit to experimental data, we demonstrate that high concentrations of dexamethasone antagonizes CAR T-cell efficacy by exhausting, or reducing the activity of CAR T-cells, and by promoting tumor cell growth. Finally, we identify a critical threshold in the ratio of CAR T-cell death to CAR T-cell proliferation rates that predicts eventual treatment success or failure that may be used to guide the dose and timing of CAR T-cell therapy in the presence of dexamethasone in patients.
Assuntos
Dexametasona , Glioblastoma/metabolismo , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos/efeitos dos fármacos , Adulto , Linhagem Celular Tumoral , Dexametasona/administração & dosagem , Dexametasona/farmacologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Chimeric antigen receptor (CAR) therapy is a promising immunotherapeutic strategy for treating multiple refractory blood cancers, but further advances are required for solid tumor CAR therapy. One challenge is identifying a safe and effective tumor antigen. Here, we devise a strategy for targeting hepatocellular carcinoma (HCC, one of the deadliest malignancies). We report that T and NK cells transduced with a CAR that recognizes the surface marker, CD147, also known as Basigin, can effectively kill various malignant HCC cell lines in vitro, and HCC tumors in xenograft and patient-derived xenograft mouse models. To minimize any on-target/off-tumor toxicity, we use logic-gated (log) GPC3-synNotch-inducible CD147-CAR to target HCC. LogCD147-CAR selectively kills dual antigen (GPC3+CD147+), but not single antigen (GPC3-CD147+) positive HCC cells and does not cause severe on-target/off-tumor toxicity in a human CD147 transgenic mouse model. In conclusion, these findings support the therapeutic potential of CD147-CAR-modified immune cells for HCC patients.
Assuntos
Basigina/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Imunoterapia Adotiva/métodos , Neoplasias Hepáticas/tratamento farmacológico , Receptores de Antígenos Quiméricos/efeitos dos fármacos , Animais , Basigina/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Células Hep G2 , Humanos , Células Matadoras Naturais , Fígado/patologia , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Aim: Although numerous pro-inflammatory cytokines promote signaling via intracellular pathways involving Janus kinases, it remains unclear if ruxolitinib, a Janus kinase1/2 inhibitor, provides control of cytokine-release syndrome (CRS) without toxicity against therapeutic T cells. Materials & methods: We report successful clinical experience using ruxolitinib as adjuvant therapy to treat steroid-refractory CRS, which was related to CD22/CD19 chimeric antigen receptor-modified T cell sequential infusion, in a patient with Philadelphia chromosome-like acute lymphoblastic leukemia. Results: His symptoms improved rapidly after first dose of ruxolitinib; this was associated with reduced levels of circulating pro-inflammatory indicators. He eventually achieved minimal residual disease negative remission. Discussion: This is the first case in which ruxolitinib was used to treat steroid-refractory CRS; furthermore, this intervention had no apparent impact on the antileukemic actions of the chimeric antigen receptor-modified T cells. Our results suggest that adjuvant ruxolitinib therapy may be an alternative therapeutic approach for the management of CRS.
Assuntos
Síndrome da Liberação de Citocina/tratamento farmacológico , Imunoterapia/métodos , Nitrilas/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Adulto , Terapia Combinada , Síndrome da Liberação de Citocina/imunologia , Glucocorticoides/uso terapêutico , Humanos , Masculino , Receptores de Antígenos Quiméricos/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Resultado do TratamentoRESUMO
Monotherapy with immune checkpoint inhibitors, specifically those targeting programmed death 1 (PD-1), has revolutionized the treatment of metastatic melanoma: approximately 40% of patients achieve a partial or complete response, many of which are durable. However, a subset of patients who initially respond to therapy will progress, leaving the majority of patients in need of an effective second-line approach. While some standard therapies exist, there has been robust interest in utilizing targeted immunotherapy combinations in this population to overcome primary or acquired resistance. Other approaches include treatment with anti-PD-1 agents beyond progression; targeting oligometastatic disease with surgery, radiation, and/or intratumor injections; and the use of other approved systemic therapies. This review summarizes the current available treatment strategies for patients with advanced melanoma when PD-1-directed therapy is not enough.