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A phase I clinical trial of malignant pleural mesothelioma treated with locally delivered autologous anti-FAP-targeted CAR T-cells

Date

30 Sep 2019

Session

Poster Display session 3

Presenters

Alessandra Curioni

Citation

Annals of Oncology (2019) 30 (suppl_5): v475-v532. 10.1093/annonc/mdz253

Authors

A. Curioni1, C. Britschgi2, S. Hiltbrunner3, L. Bankel4, P. Gulati5, W. Weder6, I. Opitz6, O. Lauk7, C. Caviezel7, A. Knuth8, C. Münz9, C. Renner10, R.A. Stahel11, U. Petrausch12

Author affiliations

  • 1 Hematology And Oncology, University Hospital Zürich, 8091 - Zurich/CH
  • 2 Department Of Hematology And Oncology, University Hospital Zürich, 8091 - Zurich/CH
  • 3 Hematology And Oncology Department, UZH - Universitat Zurich Schlieren (WAA), 8952 - Schlieren/CH
  • 4 Medical Oncology, University Hospital Zürich, 8091 - Zurich/CH
  • 5 Pharmaceutical Sciences, F. Hoffmann-La Roche AG, 4070 - Basel/CH
  • 6 Thoracic Surgery Department, University Hospital Zürich, 8091 - Zurich/CH
  • 7 Thoracic Surgery, University Hospital Zurich, 8091 - Zurich/CH
  • 8 Hematology, Medical Oncology, Bmt, Hamad Medical Corporation (HMC)-National Center for Cancer Care and Research (Al Amal Hospital), Doha/QA
  • 9 Institute Of Experimental Immunology, University of Zurich, 8057 - Zurich/CH
  • 10 Hem & Onc, Klinik Im Park Oncology Center, 8038 - Zurich/CH
  • 11 Medical Oncology And Hematology, University Hospital Zürich, 8091 - Zurich/CH
  • 12 Oncology, OnkoZentrum Zürich, 8038 - Zurich/CH
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Resources

Background

Malignant pleural mesothelioma (MPM) is a cancer with a worldwide increasing incidence due to the use of asbestos. MPM is incurable despite the use of multimodality treatment. Tumor spread confined to the thoracic cavity is a hallmark of MPM, providing a rational for local treatment. We developed a chimeric antigen receptor (CAR) targeting FAP (fibroblast activating protein), a cell-surface antigen that we have shown to be highly expressed in epithelial cancers.

Methods

Using a Δ-CD28-costimulated CAR, we initiated a phase I clinical trial (NCT01722149) to determine the safety and persistence of intra-pleural administered anti-FAP-CAR T cells in the periphery. A single dose of 1x 106 re-directed T cells was administered through a pleural catheter. Patients were monitored on an intensive care unit for 48h. Clinical evaluations of on-target and off-tumor toxicity were assessed for 3 months. Laboratory analyses included cytokines, CRP and the detection of CAR-T cells in the pleural effusion and blood over time. Radiological evaluation with PET-CT scans was performed as standard of care.

Results

Three patients with metastatic MPM were treated (all patients received at least two cycles of chemotherapy previous to CAR T-cell administration). No CAR T-cell-related toxicities were observed. Intense monitoring for cytokine release syndrome showed significant changes on a subset of cytokines. CAR T-cells were detected in the peripheral blood after treatment. Activity of the patient’s redirected T cells was confirmed in vitro. Furthermore, one patient received an anti-PD1 checkpoint blockade antibody 8 months after CAR T-cell instillation with no toxicity. With a median follow-up of 18 months, 2 out of 3 patients are alive.

Conclusions

In this phase I clinical trial, intra-pleural administration of anti-FAP CAR T-cells was well tolerated without any evidence of treatment related toxicity. Persistence of CAR T-cells was documented in the periphery.

Clinical trial identification

NCT01722149.

Editorial acknowledgement

Legal entity responsible for the study

Unviersity Hospital Zurich.

Funding

Swiss Cancer League.

Disclosure

A. Curioni: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: F. Hoffmann-La Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck Sharp and Dohme; Advisory / Consultancy: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer ; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Takeda . C. Britschgi: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Takeda. W. Weder: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Medtronic. R.A. Stahel: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy: AbbVie; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Officer / Board of Directors: F. Hoffmann-La Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Merck Sharp and Dohme; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Officer / Board of Directors: Takeda; Research grant / Funding (institution): Genentech. All other authors have declared no conflicts of interest.

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