Re-directed T cells for the treatment of fibroblast activation protein FAP-positive malignant pleural mesothelioma FAPME-1Reportar como inadecuado




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BMC Cancer

, 12:615

Infection, immunity and cancer vaccines

Abstract

BackgroundAsbestos is the main cause of MPM in industrialized countries. Even since asbestos is banned in most developed countries, the peak wave of MPM incidence is anticipated for the next years due to the long latency of asbestos induced MPM. MPM patients not eligible for surgical procedures like decortication or pleuro-pneumectomie have a median survival of 12 months with palliative chemotherapy. Therefore, new therapeutic approaches are of crucial need in this clinical situation.

Methods-designThis is a phase I trial for patients with malignant pleural mesothelioma with pleural effusion testing the safety of a fixed single dose of 1x10 adoptively transferred FAP-specific re-directed T cells given directly in the pleural effusion. Lymphocytes will be taken 21 days before transfer from peripheral blood. CD8 positive T cells will be isolated and re-programmed by retroviral transfer of a chimeric antigen receptor recognizing FAP which serves as target structure in MPM. At day 0 of the protocol, re-directed T cells will be injected in the pleural effusion and patients will be monitored for 48h under intermediate care conditions. AE, SAE, SADR and SUSAR will be monitored for 35 days and evaluated by an independent safety board to define any dose limiting toxicity DLT. No further patient can be treated before the previous patient passed day 14 after T cell transfer. The protocol will be judged as save when no DLT occurred in the first 3 patients, or 1 DLT in 6 patients. Secondary objectives are feasibility and immune monitoring.

DiscussionAdoptive T cell transfer is a new and rapidly expanding branch of immunotherapies focusing on cancer treatment. Recently, objective responses could be observed in patients with chronic lymphatic leukemia treated with adoptively transferred CD19-specific re-directed T cells. The choice of the target antigen determines the possible on-target off-tissue toxicity of such approaches. There are reports of severe toxicity in patients who received T cells intravenously due to unexpected expression of the target antigen on-target in other tissues than the tumor off-tissue. To minimize the risk of on-target off-tissue toxicity and to maximize the on-target anti-tumor effect we propose a clinical protocol with loco-regional administration of re-directed T cells. FAP-specific T cells will be directly injected in the pleural effusion of patients with MPM.

Trial registrationClinicalTrials.gov NCT01722149

AbbreviationsAEAdverse Event

ARDSAcute Respiratory Distress Syndrome

CARChimeric antigen receptor

CDCluster of Differentiation

DLTDose limiting toxicity DLT

ELISAEnzyme Linked Immunoabsorbent Assay

ECOGEastern Cooperative Oncology Group Performance Status

FAPFibroblast activation protein

IFNInterferon

ILInterleukin

ICUIntermediate Care Unit

mABmonoclonal Antibody

MPMMalignant pleural mesothelioma

SADRSuspected adverse drug reaction

SAESerious Adverse Event

SUSARSuspected Unexpected Serious Adverse Reaction

TAATumor associated antigen

TGFTumor growth factor

TNFTumor necrosis factor

TpPTransplantation product.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2407-12-615 contains supplementary material, which is available to authorized users.

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Autor: Ulf Petrausch - Petra C Schuberth - Christian Hagedorn - Alex Soltermann - Sandra Tomaszek - Rolf Stahel - Walter Weder -

Fuente: https://link.springer.com/







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