Re-directed T cells for the treatment of fibroblast activation protein (FAP)-positive malignant pleural mesothelioma (FAPME-1)

Our plain-English summary of Re-directed T cells for the treatment of fibroblast activation protein (FAP)-positive malignant pleural mesothelioma (FAPME-1), by U. Petrausch, P.C. Schuberth, C. Hagedorn, et al (BMC Cancer, 2012).

The study

• Authors: U. Petrausch, P.C. Schuberth, C. Hagedorn, A. Soltermann, S. Tomaszek, R. Stahel, W. Weder, C. Renner
• Journal: BMC Cancer
• Published: 2012;12:615
• Cited by: 75 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Asbestos 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/design: This is a phase I trial for patients with malignant pleural mesothelioma with pleural effusion testing the safety of a fixed single dose of 1x106 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.

Discussion: Adoptive 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 Registration: ClinicalTrials.gov (NCT01722149).

In plain English

This article was a study protocol. It described a planned phase I trial (FAPME-1, registered as NCT01722149) at University Hospital Zurich and reported no treatment results. The trial was designed to test the safety of a single injection of genetically re-programmed immune cells into the pleural effusion (fluid around the lung) of patients with malignant pleural mesothelioma who could not have surgery. CD8 positive T cells taken from each patient's blood were to be given a chimeric antigen receptor that recognizes fibroblast activation protein (FAP). Three patients were to be treated after three cycles of palliative chemotherapy. The number would expand to six if a treatment-related severe or serious adverse event occurred. The protocol would be judged safe if no dose limiting toxicity occurred in the first 3 patients, or not more than 1 in 6 patients. The authors reported that their own laboratory work showed FAP in all mesothelioma subtypes, illustrated in epithelioid and sarcomatoid tumors. Injecting the cells into the chest fluid rather than a vein was intended to limit side effects elsewhere in the body. The authors stated that the protocol was not intended to prove that the treatment works. Asbestos appeared only as background.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Study protocol for a planned phase I (safety) trial using one fixed dose, with no dose escalation. The protocol would be judged safe if no dose limiting toxicity occurred in the first 3 patients, or not more than 1 in 6 patients.
• Who was studied: Planned: 3 patients (expandable to 6) aged 18 to 75 years, with histologically or cytologically confirmed malignant pleural mesothelioma with pleural effusion, not operable at screening, treated after 3 cycles of palliative chemotherapy, at University Hospital Zurich, Switzerland.
• Exposure: No asbestos exposure was studied. The intervention was the patient's own CD8 positive T cells, given a chimeric antigen receptor recognizing FAP by retroviral transfer, injected once into the pleural effusion. The dose is printed as 1x106, which appears to mean 1x10 to the power of 6 (one million) cells.
• Main results:
  • The authors reported FAP expression in all subtypes of malignant pleural mesothelioma in their own immunofluorescence analysis. The figure shows epithelioid and sarcomatoid tumors. No patient outcomes were reported.
• The authors' conclusion: The authors presented the trial as a design to test the safety of FAP-specific re-directed T cells, already evaluated in preclinical work, given into the pleural space of patients with malignant pleural mesothelioma.
• Limitations the authors state:
  • The authors stated that the protocol was not designed to show whether the treatment is effective.
  • Only descriptive statistics were planned.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Fibroblast, Pleural Mesothelioma, Latency, Median Overall Survival, Palliative Care, Chemotherapy, Pleural Effusion.

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