RESUMEN
PURPOSE: Gemtuzumab ozogamicin (GO) is indicated for treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML). The QT interval, pharmacokinetics (PK), and immunogenicity following the fractionated GO dosing regimen have not been previously assessed. This phase IV study was designed to obtain this information in patients with R/R AML. METHODS: Patients aged ≥ 18 years with R/R AML received the fractionated dosing regimen of GO 3 mg/m2 on Days 1, 4, and 7 of each cycle, up to 2 cycles. The primary endpoint was mean change from baseline in QT interval corrected for heart rate (QTc). RESULTS: Fifty patients received ≥ 1 dose of GO during Cycle 1. The upper limit of the 2-sided 90% confidence interval for least squares mean differences in QTc using Fridericia's formula (QTcF) was < 10 ms for all time points during Cycle 1. No patients had a post-baseline QTcF > 480 ms or a change from baseline > 60 ms. Treatment-emergent adverse events (TEAEs) occurred in 98% of patients; 54% were grade 3-4. The most common grade 3-4 TEAEs were febrile neutropenia (36%) and thrombocytopenia (18%). The PK profiles of both conjugated and unconjugated calicheamicin mirror that of total hP67.6 antibody. The incidence of antidrug antibodies (ADAs) and neutralizing antibodies was 12% and 2%, respectively. CONCLUSION: Fractionated GO dosing regimen (3 mg/m2/dose) is not predicted to pose a clinically significant safety risk for QT interval prolongation in patients with R/R AML. TEAEs are consistent with GO's known safety profile, and ADA presence appears unassociated with potential safety issues. TRIAL REGISTRY: Clinicaltrials.gov ID: NCT03727750 (November 1, 2018).
Asunto(s)
Leucemia Mieloide Aguda , Humanos , Gemtuzumab/efectos adversos , Gemtuzumab/farmacocinética , Lectina 3 Similar a Ig de Unión al Ácido Siálico/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Calicheamicinas , Aminoglicósidos/efectos adversosRESUMEN
BACKGROUND: Based on the results from the ALFA-0701 study, gemtuzumab ozogamicin (GO) has been approved by the European Medicine Agency and by the Italian Drug Agency for the first line treatment of de novo acute-myeloid leukemia (AML). In this analysis, we assessed the cost-effectiveness of GO in combination with daunorubicin and cytarabine (DA), vs DA alone, adopting the perspective of the Italian National Health Service. METHODS: For this analysis, a cohort state transition model was developed. The model was designed to capture health states and events that occur throughout the entire disease course and that impact costs and outcomes. The ALFA-0701 study was the main source of clinical data for this analysis. In the model, patients had the same baseline characteristics and experienced the same clinical improvements as in the ALFA-0701 study. Economic data (resource consumption and unit costs) were adapted to reflect expenditure for the Italian National Health Service. Utilities per health state and disutilities due to adverse events were based on the literature and on the general population for those functionally cured. A lifetime horizon was adopted, with both costs and outcome being discounted of 3.0%, annually. Deterministic and probabilistic sensitivity analyses were conducted to assess the robustness of results. RESULTS: In the base case (lifetime horizon; primary source of data: study ALFA-0701; perspective: Italian National Health Service; discount rate on costs and outcomes: 3.0%), GO + DA was more effective DA both in terms of life-year (LY) survival (6.42 LY vs 5.75 LY, respectively) and quality-of-life adjusted survival (4.69 QALY vs 4.19 QALY, respectively). The overall costs were almost similar in the two groups (slightly lower with GO + DA than with DA; 162,424 and 162,708, respectively). The use of GO increased the costs of drug therapy but saved costs of relapse and costs associated with transplantation (HSCT). CONCLUSIONS: If results of the ALFA-0701 study are applied to the Italian healthcare environment, then gemtuzumab ozogamicin, in combination with daunorubicin and cytarabine, would clinical outcomes and reduce lifetime costs, compared with daunorubicin and cytarabine alone for the first line treatment of de novo AML. TRIAL REGISTRATION: Not applicable.
Asunto(s)
Análisis de Costo-Efectividad , Leucemia Mieloide Aguda , Humanos , Gemtuzumab/uso terapéutico , Medicina Estatal , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/etiología , Daunorrubicina/uso terapéutico , Citarabina/uso terapéutico , Italia , Resultado del Tratamiento , Lectina 3 Similar a Ig de Unión al Ácido Siálico/uso terapéuticoRESUMEN
Many therapeutic bispecific T-cell engagers (BiTEs) are in clinical trials. A modular and efficient process to create BiTEs would accelerate their development and clinical applicability. In this study, we present the design, production, and functional activity of a novel bispecific format utilizing synthetic orthogonal heterodimers to form a multichain modular design. Further addition of an immunoglobulin hinge region allowed a stable covalent linkage between the heterodimers. As proof-of-concept, we utilized CD33 and CD3 binding scFvs to engage leukemia cells and T-cells respectively. We provide evidence that this novel bispecific T-cell engager (termed IgGlue-BiTE) could bind both CD3+ and CD33+ cells and facilitates robust T-cell mediated cytotoxicity on AML cells in vitro. In a mouse model of minimal residual disease, we showed that the novel IgGlue-BiTE greatly extended survival, and mice of this treatment group were free of leukemia in the bone marrow. These findings suggest that the IgGlue-BiTE allows for robust simultaneous engagement with both antigens of interest in a manner conducive to T cell cytotoxicity against AML. These results suggest a compelling modular system for bispecific antibodies, as the CD3- and CD33-binding domains can be readily swapped with domains binding to other cancer- or immune cell-specific antigens.
Asunto(s)
Anticuerpos Biespecíficos , Leucemia Mieloide Aguda , Animales , Ratones , Linfocitos T/metabolismo , Lectina 3 Similar a Ig de Unión al Ácido Siálico/metabolismo , Lectina 3 Similar a Ig de Unión al Ácido Siálico/uso terapéutico , Anticuerpos Biespecíficos/farmacología , Anticuerpos Biespecíficos/uso terapéutico , Leucemia Mieloide Aguda/metabolismo , Complejo CD3RESUMEN
INTRODUCTION: Acute Myeloid Leukaemia (AML) is the most common blood cancer in adults. Although 2 out of 3 AML patients go into total remission after chemotherapies and targeted therapies, the disease recurs in 60%-65% of younger adult patients within 3 years after diagnosis with a dramatically decreased survival rate. Therapeutic oligonucleotides are promising treatments under development for AML as they can be designed to silence oncogenes with high specificity and flexibility. However, there are not many well validated approaches for safely and efficiently delivering oligonucleotide drugs. This issue could be resolved by utilizing a new generation of delivery vehicles such as extracellular vesicles (EVs). METHODS: In this study, we harness red blood cell-derived EVs (RBCEVs) and engineer them via exogenous drug loading and surface functionalization to develop an efficient drug delivery system for AML. Particularly, EVs are designed to target CD33, a common surface marker with elevated expression in AML cells via the conjugation of a CD33-binding monoclonal antibody onto the EV surface. RESULTS: The conjugation of RBCEVs with the CD33-binding antibody significantly increases the uptake of RBCEVs by CD33-positive AML cells, but not by CD33-negative cells. We also load CD33-targeting RBCEVs with antisense oligonucleotides (ASOs) targeting FLT3-ITD or miR-125b, 2 common oncogenes in AML, and demonstrate that the engineered EVs improve leukaemia suppression in in vitro and in vivo models of AML. CONCLUSION: Targeted RBCEVs represent an innovative, efficient, and versatile delivery platform for therapeutic ASOs and can expedite the clinical translation of oligonucleotide drugs for AML treatments by overcoming current obstacles in oligonucleotide delivery.
Asunto(s)
Vesículas Extracelulares , Leucemia Mieloide Aguda , MicroARNs , Adulto , Anticuerpos Monoclonales/uso terapéutico , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , MicroARNs/genética , Oligonucleótidos Antisentido/uso terapéutico , Lectina 3 Similar a Ig de Unión al Ácido Siálico/uso terapéutico , Tirosina Quinasa 3 Similar a fms/uso terapéuticoRESUMEN
CD33 is a transmembrane protein that is found on cells of myeloid lineage. It is also intensely expressed on acute myeloid leukemia (AML) progenitor cells but not on normal stem cells. It internalizes on binding and dimerization, making it a specific and ideal target for AML therapeutics and drug delivery. Several targeted therapies have been tested and many are still currently in development. Gemtuzumab ozogamicin was the first and only CD33-directed antibody-drug conjugate to be US Food and Drug Administration approved for AML. Other targeted agents have not achieved such success. Promising new strategies include cellular therapy mechanisms and linker molecules. This is an exciting target that requires a considerable amount of precision to yield clinical benefit.
Asunto(s)
Gemtuzumab/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Lectina 3 Similar a Ig de Unión al Ácido Siálico/uso terapéutico , Ensayos Clínicos como Asunto , Relación Dosis-Respuesta a Droga , Gemtuzumab/administración & dosificación , Gemtuzumab/efectos adversos , Gemtuzumab/inmunología , Inmunoterapia Adoptiva/métodos , Receptores Quiméricos de Antígenos/uso terapéutico , Lectina 3 Similar a Ig de Unión al Ácido Siálico/administración & dosificación , Lectina 3 Similar a Ig de Unión al Ácido Siálico/efectos adversos , Lectina 3 Similar a Ig de Unión al Ácido Siálico/inmunología , Células MadreRESUMEN
Acute myeloid leukemia (AML) is a kind of a malignant hematologic tumor caused by uncontrolled repopulation of myeloid hematopoietic stem cells (HSCs). Current therapeutic effects for AML patients are unsatisfactory. In particular, relapsed and refractory AML still have a poor prognosis. T cells modified by chimeric antigen receptor (CAR) was an immunotherapeutic strategy for malignancies, which has a broad developing prospect. Most AML cells overexpress the myeloid antigen CD33. Therefore, CD33-specific CAR-T cells with different co-stimulators (CD28, 4-1BB, or both, referred to as CD33 28z.CAR-T cells, CD33 BBz.CAR-T cells, or CD33 28BBz.CAR-T cells, respectively) were developed to evaluate their efficacy against AML. The effectiveness of three types of CD33 CAR-T cells against AML was verified by specific killing effect to AML cells and prolonged survival of a xenograft mouse model. In terms of CAR-T cell efficacy, especially when transfused into human bodies, the persistence of T cells is also an important index, as it is closely associated with the long-term effect of CAR-T cells. Therefore, the characteristics of three types of CD33 CAR-T cells related to the persistence of T cells were examined. It was found that during expansion, CD33 BBz.CAR-T cells had an increased central memory compartment, while CD33 28z.CAR-T cells were predominantly effector memory T cells. In addition, CD33 28z.CAR-T cells were more inclined to become exhausted. The study suggests that incorporation of 4-1BB in CARs may endow T cells with long-lasting survival ability, thus improving the long-term anti-leukemia effect of CAR-T cells, especially when transfused to the human body.
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Inmunoterapia Adoptiva , Leucemia/terapia , Receptores Quiméricos de Antígenos/inmunología , Lectina 3 Similar a Ig de Unión al Ácido Siálico/inmunología , Animales , Línea Celular Tumoral , Citotoxicidad Inmunológica , Humanos , Leucemia/genética , Leucemia/inmunología , Ratones , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/uso terapéutico , Lectina 3 Similar a Ig de Unión al Ácido Siálico/antagonistas & inhibidores , Lectina 3 Similar a Ig de Unión al Ácido Siálico/uso terapéutico , Linfocitos T/inmunología , Linfocitos T/trasplante , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
In vivo persistence of chimeric antigen receptor (CAR)-modified T cells correlates with therapeutic efficacy, yet CAR-specific factors that support persistence are not well resolved. Using a CD33-specific CAR in an acute myeloid leukemia (AML) model, we show how CAR expression alters T cell differentiation in a ligand independent manner. Ex vivo expanded CAR-T cells demonstrated decreased naïve and stem memory populations and increased effector subsets relative to vector-transduced control cells. This was associated with reduced in vivo persistence. Decreased persistence was not due to specificity or tumor presence, but to pre-transfer tonic signaling through the CAR CD3ζ ITAMs. We identified activation of the PI3K pathway in CD33 CAR-T cells as responsible. Treatment with a PI3K inhibitor modulated the differentiation program of CAR-T cells, preserved a less differentiated state without affecting T cell expansion, and improved in vivo persistence and reduced tumor burden. These results resolve mechanisms by which tonic signaling of CAR-T cells modulates their fate, and identifies a novel pharmacologic approach to enhance the durability of CAR-T cells for immunotherapy.
Asunto(s)
Inmunoterapia Adoptiva/métodos , Leucemia Mieloide Aguda/terapia , Fosfatidilinositol 3-Quinasas/metabolismo , Receptores Quiméricos de Antígenos/uso terapéutico , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Humanos , Activación de Linfocitos/efectos de los fármacos , Inhibidores de las Quinasa Fosfoinosítidos-3 , Lectina 3 Similar a Ig de Unión al Ácido Siálico/farmacología , Lectina 3 Similar a Ig de Unión al Ácido Siálico/uso terapéutico , Linfocitos T , Carga Tumoral/efectos de los fármacosRESUMEN
After being pulled from the market 7 years ago, gemtuzumab ozogamicin has been reapproved by the FDA, this time for adults newly diagnosed with acute myeloid leukemia, as well as patients 2 years of age and older with relapsed/refractory disease. The CD33-targeting antibody-drug conjugate can be given as a single agent or in combination with chemotherapy.
Asunto(s)
Aminoglicósidos/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Inmunoconjugados/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Lectina 3 Similar a Ig de Unión al Ácido Siálico/uso terapéutico , Adulto , Anciano , Aminoglicósidos/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Supervivencia sin Enfermedad , Aprobación de Drogas , Femenino , Gemtuzumab , Humanos , Inmunoconjugados/efectos adversos , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Lectina 3 Similar a Ig de Unión al Ácido Siálico/antagonistas & inhibidores , Lectina 3 Similar a Ig de Unión al Ácido Siálico/inmunologíaRESUMEN
Attaching a cytotoxic "payload" to an antibody to form an antibody-drug conjugate (ADC) provides a mechanism for selective delivery of the cytotoxic agent to cancer cells via the specific binding of the antibody to cancer-selective cell surface molecules. The first ADC to receive marketing authorization was gemtuzumab ozogamicin, which comprises an anti-CD33 antibody conjugated to a highly potent DNA-targeting antibiotic, calicheamicin, approved in 2000 for treating acute myeloid leukemia. It was withdrawn from the US market in 2010 following an unsuccessful confirmatory trial. The development of two classes of highly potent microtubule-disrupting agents, maytansinoids and auristatins, as payloads for ADCs resulted in approval of brentuximab vedotin in 2011 for treating Hodgkin lymphoma and anaplastic large cell lymphoma, and approval of ado-trastuzumab emtansine in 2013 for treating HER2-positive breast cancer. Their success stimulated much research into the ADC approach, with >60 ADCs currently in clinical evaluation, mostly targeting solid tumors. Five ADCs have advanced into pivotal clinical trials for treating various solid tumors-platinum-resistant ovarian cancer, mesothelioma, triple-negative breast cancer, glioblastoma, and small cell lung cancer. The level of target expression is a key parameter in predicting the likelihood of patient benefit for all these ADCs, as well as for the approved compound, ado-trastuzumab emtansine. The development of a patient selection strategy linked to target expression on the tumor is thus critically important for identifying the population appropriate for receiving treatment.