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1.
Cytotherapy ; 24(2): 193-204, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34711500

RESUMEN

Immune effector cell (IEC) therapies have revolutionized our approach to relapsed B-cell malignancies, and interest in the investigational use of IECs is rapidly expanding into other diseases. Current challenges in the analysis of IEC therapies include small sample sizes, limited access to clinical trials and a paucity of predictive biomarkers of efficacy and toxicity associated with IEC therapies. Retrospective and prospective multi-center cell therapy trials can assist in overcoming these barriers through harmonization of clinical endpoints and correlative assays for immune monitoring, allowing additional cross-trial analysis to identify biomarkers of failure and success. The Consortium for Pediatric Cellular Immunotherapy (CPCI) offers a unique platform to address the aforementioned challenges by delivering cutting-edge cell and gene therapies for children through multi-center clinical trials. Here the authors discuss some of the important pre-analytic variables, such as biospecimen collection and initial processing procedures, that affect biomarker assays commonly used in IEC trials across participating CPCI sites. The authors review the recent literature and provide data to support recommendations for alignment and standardization of practices that can affect flow cytometry assays measuring immune effector function as well as interpretation of cytokine/chemokine data. The authors also identify critical gaps that often make parallel comparisons between trials difficult or impossible.


Asunto(s)
Inmunoterapia , Recurrencia Local de Neoplasia , Tratamiento Basado en Trasplante de Células y Tejidos , Niño , Humanos , Estudios Prospectivos , Estudios Retrospectivos
2.
Ann Neurol ; 86(1): 42-54, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31074527

RESUMEN

OBJECTIVE: To test whether systemic cytokine release is associated with central nervous system inflammatory responses and glial injury in immune effector cell-associated neurotoxicity syndrome (ICANS) after chimeric antigen receptor (CAR)-T cell therapy in children and young adults. METHODS: We performed a prospective cohort study of clinical manifestations as well as imaging, pathology, CSF, and blood biomarkers on 43 subjects ages 1 to 25 who received CD19-directed CAR/T cells for acute lymphoblastic leukemia (ALL). RESULTS: Neurotoxicity occurred in 19 of 43 (44%) subjects. Nine subjects (21%) had CTCAE grade 3 or 4 neurological symptoms, with no neurotoxicity-related deaths. Reversible delirium, headache, decreased level of consciousness, tremor, and seizures were most commonly observed. Cornell Assessment of Pediatric Delirium (CAPD) scores ≥9 had 94% sensitivity and 33% specificity for grade ≥3 neurotoxicity, and 91% sensitivity and 72% specificity for grade ≥2 neurotoxicity. Neurotoxicity correlated with severity of cytokine release syndrome, abnormal past brain magnetic resonance imaging (MRI), and higher peak CAR-T cell numbers in blood, but not cerebrospinal fluid (CSF). CSF levels of S100 calcium-binding protein B and glial fibrillary acidic protein increased during neurotoxicity, indicating astrocyte injury. There were concomitant increases in CSF white blood cells, protein, interferon-γ (IFNγ), interleukin (IL)-6, IL-10, and granzyme B (GzB), with concurrent elevation of serum IFNγ IL-10, GzB, granulocyte macrophage colony-stimulating factor, macrophage inflammatory protein 1 alpha, and tumor necrosis factor alpha, but not IL-6. We did not find direct evidence of endothelial activation. INTERPRETATION: Our data are most consistent with ICANS as a syndrome of systemic inflammation, which affects the brain through compromise of the neurovascular unit and astrocyte injury. ANN NEUROL 2019.


Asunto(s)
Antígenos CD19/efectos adversos , Inmunoterapia Adoptiva/efectos adversos , Neuroglía/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico por imagen , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Adulto , Antígenos CD19/administración & dosificación , Antígenos CD19/inmunología , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Inmunoterapia Adoptiva/tendencias , Lactante , Masculino , Neuroglía/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Estudios Prospectivos , Adulto Joven
3.
J Clin Oncol ; : JCO2302229, 2024 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-39255444

RESUMEN

PURPOSE: B7-H3 is an immunoregulatory protein overexpressed by many pediatric solid tumors with limited expression on critical organs, making it an attractive immunotherapy target. We present a first-in-human phase I clinical trial systemically administered B7-H3 chimeric antigen receptor (CAR) T cells for young patients with relapsed or refractory solid tumors. PATIENTS AND METHODS: Patients were enrolled onto a phase I trial to examine the safety of B7-H3-specific CARs at various dose levels (DLs) using a standard 3 + 3 dose escalation design. RESULTS: Sixteen patients (range, 11-24 years; median, 18.5 years) were enrolled, and nine were treated at DL1 (0.5 × 106 CAR T cells/kg; n = 3) or DL2 (1 × 106 CAR T cells/kg; n = 6). There were no first infusion dose-limiting toxicities. Maximum first-infusion circulating CAR T cells detected in the peripheral blood were 4.98 cells/µL (range, 0-4.98 cells/µL) with detection of CAR T cells colocalizing with tumor cells at the site of metastatic disease in one patient. Patients were eligible for subsequent infusions. An objective partial response by PERCIST criteria was observed 28 days after a second CAR T cell infusion in a patient who did not have an objective response after the first infusion. The second infusion demonstrated marked enhancement of CAR T cell expansion to 1,590 cells/µL and was accompanied by cytokine release syndrome and dose-limiting transaminitis. Detailed peripheral blood cytokine profiling revealed elevated IL-21 levels preinfusion 2 compared with infusion 1. CONCLUSION: B7-H3 CAR T cells are tolerable and demonstrate limited antitumor activity without acute on-target, off-tumor toxicity. High levels of CAR T cell expansion may be necessary to achieve objective responses, but undefined host and tumor microenvironment factors appear to be critical (ClinicalTrials.gov identifier: NCT04483778).

4.
J Clin Invest ; 134(9)2024 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-38502193

RESUMEN

Chimeric antigen receptor (CAR) designs that incorporate pharmacologic control are desirable; however, designs suitable for clinical translation are needed. We designed a fully human, rapamycin-regulated drug product for targeting CD33+ tumors called dimerizaing agent-regulated immunoreceptor complex (DARIC33). T cell products demonstrated target-specific and rapamycin-dependent cytokine release, transcriptional responses, cytotoxicity, and in vivo antileukemic activity in the presence of as little as 1 nM rapamycin. Rapamycin withdrawal paused DARIC33-stimulated T cell effector functions, which were restored following reexposure to rapamycin, demonstrating reversible effector function control. While rapamycin-regulated DARIC33 T cells were highly sensitive to target antigen, CD34+ stem cell colony-forming capacity was not impacted. We benchmarked DARIC33 potency relative to CD19 CAR T cells to estimate a T cell dose for clinical testing. In addition, we integrated in vitro and preclinical in vivo drug concentration thresholds for off-on state transitions, as well as murine and human rapamycin pharmacokinetics, to estimate a clinically applicable rapamycin dosing schedule. A phase I DARIC33 trial has been initiated (PLAT-08, NCT05105152), with initial evidence of rapamycin-regulated T cell activation and antitumor impact. Our findings provide evidence that the DARIC platform exhibits sensitive regulation and potency needed for clinical application to other important immunotherapy targets.


Asunto(s)
Leucemia Mieloide Aguda , Lectina 3 Similar a Ig de Unión al Ácido Siálico , Sirolimus , Linfocitos T , Animales , Femenino , Humanos , Masculino , Ratones , Inmunoterapia Adoptiva , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Receptores Quiméricos de Antígenos/inmunología , Lectina 3 Similar a Ig de Unión al Ácido Siálico/inmunología , Lectina 3 Similar a Ig de Unión al Ácido Siálico/metabolismo , Sirolimus/farmacología , Sirolimus/administración & dosificación , Linfocitos T/inmunología , Linfocitos T/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
5.
Blood Adv ; 7(6): 1001-1010, 2023 03 28.
Artículo en Inglés | MEDLINE | ID: mdl-36006611

RESUMEN

There is a need for biomarkers to predict and measure the severity of immune effector cell-associated neurotoxicity syndrome (ICANS). Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) are well-validated biomarkers of astroglial and neuronal injury, respectively. We hypothesized that pretreatment GFAP and NfL levels can predict the risk of subsequent ICANS and that increases in GFAP and NfL levels during treatment reflect ICANS severity. We measured cerebrospinal fluid GFAP (cGFAP) and NfL (cNfL) along with serum NfL (sNfL) levels at pretreatment and day 7 to 10 after chimeric antigen receptor (CAR) T-cell infusion in 3 pediatric cohorts treated with CD19- or CD19/CD22-directed CAR T cells. cGFAP and cNfL levels increased during grade ≥1 ICANS in patients treated with CD19-directed CAR T cells but not in those who received CD19/CD22-directed CAR T cells. The sNfL levels did not increase during ICANS. Prelymphodepletion cGFAP, cNfL, and sNfL levels were not predictive of subsequent ICANS. Elevated baseline cGFAP levels were associated with a history of transplantation. Patients with prior central nervous system (CNS) radiation had higher cNfL levels, and elevated baseline sNfL levels were associated with a history of peripheral neuropathy. Thus, cGFAP and cNfL may be useful biomarkers for measuring the severity of CNS injury during ICANS in children. Elevated baseline levels of cGFAP, cNfL, and sNfL likely reflect the cumulative injury to the central and peripheral nervous systems from prior treatment. However, levels of any of the 3 biomarkers before CAR T-cell infusion did not predict the risk of ICANS.


Asunto(s)
Síndromes de Neurotoxicidad , Linfocitos T , Humanos , Niño , Proteína Ácida Fibrilar de la Glía , Filamentos Intermedios , Síndromes de Neurotoxicidad/diagnóstico , Síndromes de Neurotoxicidad/etiología , Proteínas Adaptadoras Transductoras de Señales , Antígenos CD19
6.
Cancer Discov ; 13(1): 114-131, 2023 01 09.
Artículo en Inglés | MEDLINE | ID: mdl-36259971

RESUMEN

Diffuse intrinsic pontine glioma (DIPG) remains a fatal brainstem tumor demanding innovative therapies. As B7-H3 (CD276) is expressed on central nervous system (CNS) tumors, we designed B7-H3-specific chimeric antigen receptor (CAR) T cells, confirmed their preclinical efficacy, and opened BrainChild-03 (NCT04185038), a first-in-human phase I trial administering repeated locoregional B7-H3 CAR T cells to children with recurrent/refractory CNS tumors and DIPG. Here, we report the results of the first three evaluable patients with DIPG (including two who enrolled after progression), who received 40 infusions with no dose-limiting toxicities. One patient had sustained clinical and radiographic improvement through 12 months on study. Patients exhibited correlative evidence of local immune activation and persistent cerebrospinal fluid (CSF) B7-H3 CAR T cells. Targeted mass spectrometry of CSF biospecimens revealed modulation of B7-H3 and critical immune analytes (CD14, CD163, CSF-1, CXCL13, and VCAM-1). Our data suggest the feasibility of repeated intracranial B7-H3 CAR T-cell dosing and that intracranial delivery may induce local immune activation. SIGNIFICANCE: This is the first report of repeatedly dosed intracranial B7-H3 CAR T cells for patients with DIPG and includes preliminary tolerability, the detection of CAR T cells in the CSF, CSF cytokine elevations supporting locoregional immune activation, and the feasibility of serial mass spectrometry from both serum and CSF. This article is highlighted in the In This Issue feature, p. 1.


Asunto(s)
Neoplasias del Tronco Encefálico , Glioma Pontino Intrínseco Difuso , Humanos , Antígenos B7 , Neoplasias del Tronco Encefálico/terapia , Linfocitos T
7.
Cancer Immunol Res ; 10(7): 856-870, 2022 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-35580141

RESUMEN

T cells modified to express a chimeric antigen receptor (CAR) targeting CD19 can induce potent and sustained responses in children with relapsed/refractory acute lymphoblastic leukemia (ALL). The durability of remission is related to the length of time the CAR T cells persist. Efforts to understand differences in persistence have focused on the CAR construct, in particular the costimulatory signaling module of the chimeric receptor. We previously reported a robust intent-to-treat product manufacturing success rate and remission induction rate in children and young adults with recurrent/refractory B-ALL using the SCRI-CAR19v1 product, a second-generation CD19-specific CAR with 4-1BB costimulation coexpressed with the EGFRt cell-surface tag (NCT02028455). Following completion of the phase I study, two changes to CAR T-cell manufacturing were introduced: switching the T-cell activation reagent and omitting midculture EGFRt immunomagnetic selection. We tested the modified manufacturing process and resulting product, designated SCRI-CAR19v2, in a cohort of 21 subjects on the phase II arm of the trial. Here, we describe the unanticipated enhancement in product performance resulting in prolonged persistence and B-cell aplasia and improved leukemia-free survival with SCRI-CAR19v2 as compared with SCRI-CAR19v1.


Asunto(s)
Linfoma de Células B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores Quiméricos de Antígenos , Antígenos CD19 , Niño , Ensayos Clínicos Fase I como Asunto , Humanos , Inmunoterapia Adoptiva/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos de Linfocitos T/genética , Receptores Quiméricos de Antígenos/genética , Recurrencia , Linfocitos T , Adulto Joven
8.
Nat Med ; 27(9): 1544-1552, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34253928

RESUMEN

Locoregional delivery of chimeric antigen receptor (CAR) T cells has resulted in objective responses in adults with glioblastoma, but the feasibility and tolerability of this approach is yet to be evaluated for pediatric central nervous system (CNS) tumors. Here we show that engineering of a medium-length CAR spacer enhances the therapeutic efficacy of human erb-b2 receptor tyrosine kinase 2 (HER2)-specific CAR T cells in an orthotopic xenograft medulloblastoma model. We translated these findings into BrainChild-01 ( NCT03500991 ), an ongoing phase 1 clinical trial at Seattle Children's evaluating repetitive locoregional dosing of these HER2-specific CAR T cells to children and young adults with recurrent/refractory CNS tumors, including diffuse midline glioma. Primary objectives are assessing feasibility, safety and tolerability; secondary objectives include assessing CAR T cell distribution and disease response. In the outpatient setting, patients receive infusions via CNS catheter into either the tumor cavity or the ventricular system. The initial three patients experienced no dose-limiting toxicity and exhibited clinical, as well as correlative laboratory, evidence of local CNS immune activation, including high concentrations of CXCL10 and CCL2 in the cerebrospinal fluid. This interim report supports the feasibility of generating HER2-specific CAR T cells for repeated dosing regimens and suggests that their repeated intra-CNS delivery might be well tolerated and activate a localized immune response in pediatric and young adult patients.


Asunto(s)
Glioblastoma/terapia , Inmunoterapia Adoptiva/efectos adversos , Receptor ErbB-2/genética , Receptores Quiméricos de Antígenos/genética , Antígenos CD19/inmunología , Quimiocina CCL2/genética , Quimiocina CXCL10/genética , Femenino , Glioblastoma/líquido cefalorraquídeo , Glioblastoma/genética , Glioblastoma/inmunología , Humanos , Inmunidad/genética , Inmunidad/inmunología , Estimación de Kaplan-Meier , Masculino , Recurrencia Local de Neoplasia/líquido cefalorraquídeo , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/terapia , Receptor ErbB-2/antagonistas & inhibidores , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/uso terapéutico , Receptores Quiméricos de Antígenos/inmunología , Linfocitos T/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto
9.
J Clin Invest ; 129(5): 2123-2132, 2019 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-30860496

RESUMEN

BACKGROUND: Chimeric antigen receptor (CAR) T cells can induce remission in highly refractory leukemia and lymphoma subjects, yet the parameters for achieving sustained relapse-free survival are not fully delineated. METHODS: We analyzed 43 pediatric and young adult subjects participating in a Phase I trial of defined composition CD19CAR T cells (NCT02028455). CAR T cell phenotype, function and expansion, as well as starting material T cell repertoire, were analyzed in relation to therapeutic outcome (defined as achieving complete remission within 63 days) and duration of leukemia free survival and B cell aplasia. RESULTS: These analyses reveal that initial therapeutic failures (n = 5) were associated with attenuated CAR T cell expansion and/or rapid attrition of functional CAR effector cells following adoptive transfer. The CAR T products were similar in phenotype and function when compared to products resulting in sustained remissions. However, the initial apheresed peripheral blood T cells could be distinguished by an increased frequency of LAG-3+/TNF-αlow CD8 T cells and, following adoptive transfer, the rapid expression of exhaustion markers. For the 38 subjects who achieved an initial sustained MRD-neg remission, remission durability correlated with therapeutic products having increased frequencies of TNF-α-secreting CAR CD8+ T cells, and was dependent on a sufficiently high CD19+ antigen load at time of infusion to trigger CAR T cell proliferation. CONCLUSION: These parameters have the potential to prospectively identify patients at risk for therapeutic failure and support the development of approaches to boost CAR T cell activation and proliferation in patients with low levels of CD19 antigen. TRIAL REGISTRATION: ClinicalTrials.gov NCT02028455. FUNDING: Partial funding for this study was provided by Stand Up to Cancer & St. Baldrick's Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113), RO1 CA136551-05, Alex Lemonade Stand Phase I/II Infrastructure Grant, Conquer Cancer Foundation Career Development Award, Washington State Life Sciences Discovery Fund, Ben Towne Foundation, William Lawrence & Blanche Hughes Foundation, and Juno Therapeutics, Inc., a Celgene Company.


Asunto(s)
Antígenos CD19/metabolismo , Linfocitos T CD8-positivos/citología , Regulación Leucémica de la Expresión Génica , Inmunoterapia Adoptiva , Leucemia/terapia , Adolescente , Adulto , Antígenos CD/metabolismo , Proliferación Celular , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Trasplante de Células Madre Hematopoyéticas , Receptor 2 Celular del Virus de la Hepatitis A/metabolismo , Humanos , Inmunofenotipificación , Lactante , Células K562 , Estimación de Kaplan-Meier , Leucemia/inmunología , Activación de Linfocitos , Masculino , Fenotipo , Receptor de Muerte Celular Programada 1/metabolismo , Receptores Quiméricos de Antígenos/metabolismo , Recurrencia , Inducción de Remisión , Factor de Necrosis Tumoral alfa/metabolismo , Adulto Joven , Proteína del Gen 3 de Activación de Linfocitos
10.
J Neuroimmunol ; 291: 1-10, 2016 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-26857488

RESUMEN

Japanese macaque encephalomyelitis (JME) is an inflammatory demyelinating disease that occurs spontaneously in a colony of Japanese macaques (JM) at the Oregon National Primate Research Center. Animals with JME display clinical signs resembling multiple sclerosis (MS), and magnetic resonance imaging reveals multiple T2-weighted hyperintensities and gadolinium-enhancing lesions in the central nervous system (CNS). Here we undertook studies to determine if JME possesses features of an immune-mediated disease in the CNS. Comparable to MS, the CNS of animals with JME contain active lesions positive for IL-17, CD4+ T cells with Th1 and Th17 phenotypes, CD8+ T cells, and positive CSF findings.


Asunto(s)
Sistema Nervioso Central/patología , Encefalomielitis/embriología , Encefalomielitis/patología , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Animales , Antígenos CD/metabolismo , Linfocitos B/metabolismo , Linfocitos B/patología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Linfocitos/metabolismo , Linfocitos/patología , Macaca , Macrófagos/metabolismo , Macrófagos/patología , Imagen por Resonancia Magnética , Proteínas de Microfilamentos/metabolismo , Microglía/metabolismo , Microglía/patología , Proteína Básica de Mielina/metabolismo , Proteínas del Tejido Nervioso/metabolismo
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