TILs Therapy Shows Promise in the Management of Anti-PD-1-Resistant Metastatic NSCLC

A cell therapy with autologous tumour-infiltrating lymphocytes (TILs), followed by maintenance nivolumab, was safe and clinically active upon initial progression on nivolumab monotherapy in patients with metastatic non-small cell lung cancer (NSCLC). The findings from a single-arm, open-label, phase I study are published by Dr. Benjamin C. Creelan of the Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute in Tampa, FL, US and colleagues on 12 August 2021 in the Nature Medicine. Among the authors, Dr. Benjamin C. Creelan, Dr. Chao Wang, Dr. Eric B. Haura and Prof. Scott J. Antonia contributed equally.

The authors wrote in the study background that adoptive cell therapy using TILs has shown activity in melanoma, but it has not been previously evaluated in patients with metastatic NSCLC. They conducted the phase I study and administered TILs with nivolumab in 20 patients with metastatic NSCLC following initial progression on nivolumab monotherapy. 

The study primary endpoint was safety. The secondary endpoints included objective response rate, duration of response and T cell persistence. Autologous TILs were expanded ex vivo from minced tumours cultured with interleukin-2. Patients received cyclophosphamide and fludarabine lymphodepletion, TILs infusion and interleukin-2, followed by maintenance nivolumab.

The study team reported that the endpoint of safety was met according to the prespecified criteria of ≤17% rate of severe toxicity (95% confidence interval 3–29%).

Among 13 evaluable patients, 3 had confirmed responses and 11 had reduction in tumour burden, with a median best change of 35%. Two patients achieved complete responses that were ongoing 1.5 years later.

In exploratory analyses, the researchers found T cells recognising multiple types of cancer mutations that were detected after TILs treatment and were enriched in responding patients. Neoantigen-reactive T cell clonotypes increased and persisted in peripheral blood after treatment.

The authors concluded that the treatment with TILs may constitute a new treatment strategy in patients with metastatic NSCLC.

In an accompanied article, Prof. Stanley R. Riddell of the Fred Hutchinson Cancer Research Center, University of Washington in Seattle, WA, US and colleagues wrote that epithelial cancers are driven by somatic mutations and aberrantly expressed genes. Immune checkpoint blockade can improve T cell function resulting in tumour regression. This phase I study shows promising antitumour activity of TILs in patients with metastatic NSCLC.

This work was supported by a Catalyst Award Clinical Trial grant through the Stand Up to Cancer Foundation, Barbara Bauer Prelude to a Cure Foundation grant, ER Squibb for nivolumab supply, Iovance Biotherapeutics as a research grant, Clinigen for aldesleukin supply, the US National Cancer Institute Support Grant and 2018 Young Investigator award from the Adaptive Biotechnologies.


Creelan BC, Wang C, Teer JK, et al. Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial. Nature Medicine 2021; 27:1410-1418. DOI: https://doi.org/10.1038/s41591-021-01462-y

Veatch JR, Simon S & Riddell SR. Tumor-infiltrating lymphocytes make inroads in non–small-cell lung cancer. Nature Medicine 2021; 27:1339-1341. DOI: https://doi.org/10.1038/s41591-021-01445-z