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Cancer Immunology, Immunotherapy (2018) 67:1221–1230
https://doi.org/10.1007/s00262-018-2174-4
ORIGINAL ARTICLE
Establishment of adoptive cell therapy with tumor infiltrating
lymphocytes for non-small cell lung cancer patients
Ronny Ben‑Avi
1
· Ronit Farhi
2
· Alon Ben‑Nun
1
· Marina Gorodner
2
· Eyal Greenberg
2
· Gal Markel
2,3
·
Jacob Schachter
2
· Orit Itzhaki
2
· Michal J. Besser
2,3
Received: 29 August 2017 / Accepted: 15 May 2018 / Published online: 29 May 2018
© Springer-Verlag GmbH Germany, part of Springer Nature 2018
Abstract
Adoptive cell therapy (ACT) of tumor infiltration lymphocytes (TIL) yields promising clinical results in metastatic mela-
noma patients, who failed standard treatments. Due to the fact that metastatic lung cancer has proven to be susceptible to
immunotherapy and possesses a high mutation burden, which makes it responsive to T cell attack, we explored the feasibility
of TIL ACT in non-small cell lung cancer (NSCLC) patients. Multiple TIL cultures were isolated from tumor specimens of
five NSCLC patients undergoing thoracic surgery. We were able to successfully establish TIL cultures by various methods
from all patients within an average of 14 days. Fifteen lung TIL cultures were further expanded to treatment levels under
good manufacturing practice conditions and functionally and phenotypically characterized. Lung TIL expanded equally
well as 103 melanoma TIL obtained from melanoma patients previously treated at our center, and had a similar phenotype
regarding PD1, CD28, and 4-1BB expressions, but contained a higher percent of CD4 T cells. Lung carcinoma cell lines
were established from three patients of which two possessed TIL cultures with specific in vitro anti-tumor reactivity. Here,
we report the successful pre-clinical production of TIL for immunotherapy in the lung cancer setting, which may provide a
new treatment modality for patients with metastatic NSCLC. The initiation of a clinical trial is planned for the near future.
Keywords Non-small cell lung cancer · Tumor infiltrating lymphocytes · Adoptive cell therapy · Immunotherapy
Abbreviations
ACT Adoptive cell therapy
CM Complete medium
REP Rapid expansion procedure
TIL Tumor infiltrating lymphocytes
TRC Tissue remnant culture
Introduction
Lung cancer is the leading cause of cancer death worldwide.
Age and smoking are the primary risk factors of lung can-
cer. For NSCLC, treatment based on surgical removal in the
early stages of the disease results in better survival. Yet the
overall 5-year survival rate is only 15% [1]. Patients with
advanced disease that are less prone to benefit from surgical
intervention or systemic treatments such as platinum-based
chemotherapy and novel biological treatments [2] continue
to challenge physicians in daily clinical practice.
Lately, a number of monoclonal antibodies specific to the
PD-1 (nivolumab and pembrolizumab) or its ligand PD-L1
(atezolizumab) were approved for immunotherapy-based
treatments for lung cancer [3, 4]. Nivolumab, a human IgG4
PD-1 receptor blocking antibody with no ADCC activity,
was FDA approved in 2015 for second-line chemotherapy
treatment of resistant squamous NSCLC. A single-arm,
phase II trial evaluating the activity and safety of nivolumab
in advanced, refractory NSCLC demonstrated a 14.5%
objective response rate (17 of 117 patients), as measured by
Electronic supplementary material The online version of this
article (https ://doi.org/10.1007/s0026 2-018-2174-4) contains
supplementary material, which is available to authorized users.
* Orit Itzhaki
orit.itzhaki@sheba.health.gov.il
* Michal J. Besser
michal.besser@sheba.health.gov.il
1
Department of Thoracic Surgery, Sheba Medical Center,
52621 Ramat Gan, Israel
2
Ella Lemelbaum Institute for Immuno-Oncology, Sheba
Medical Center, 52621 Ramat Gan, Israel
3
Department of Clinical Microbiology and Immunology,
Sackler School of Medicine, Tel Aviv University, Tel Aviv,
Israel
@Phil_Robichaud
@deepthiw
@JoseServera