Two Metastatic Lung Cancer Patients Are Disease-Free for 1.5 Years after TILs

Megan Brooks

August 24, 2021

Adoptive cell therapy using tumor-infiltrating lymphocytes (TILs) led to complete and long-lasting responses in 2 of 16 patients with metastatic non-small cell lung cancer (NSCLC) who fully underwent the therapy in a phase 1 study.

The results are "very impressive with two complete responses that are ongoing 1.5 years later, so it's durable and that's encouraging," Fred Hirsch, MD, PhD, director of the Center of Excellence for Thoracic Oncology at Mount Sinai's Tisch Cancer Institute in New York City, told Medscape Medical News.

Hirsch, who wasn't involved in the research, also noted that this study is in immunotherapy-resistant metastatic lung cancer — "a situation where we actually don't know exactly how best to treat it today."

The study was published online August 12 in Nature Medicine.

A form of immunotherapy, TILs have been studied extensively in melanoma, as reported by Medscape Medical News, but this is the first test of the TIL therapy in metastatic NSCLC.

The single-arm, open-label phase 1 trial involved 20 patients who had TILs collected, including 16 who eventually received TILs. Median age was 54 years; all patients had metastatic NSCLC and disease progression after nivolumab monotherapy.

TILs cultured from an individual patient's tumor were expanded ex vivo from minced tumors cultured with interleukin-2 (IL-2). Via this method, "billions of activated T cells can be produced and infused back into a patient," explain the authors.

The full treatment regimen comprised cyclophosphamide and fludarabine lymphodepletion, TIL infusion and IL-2, followed by maintenance nivolumab.

"We found that infusion of TILs in combination with lymphodepletion and IL-2 had manageable toxicity and mediated tumor regressions in several patients, including complete responses," report Benjamin Creelan, MD, of the Moffitt Cancer Center & Research Institute, Tampa, Florida, and colleagues.

The endpoint of safety was met according to the prespecified criteria of a rate of severe toxicity of 17% or less.

Among 13 evaluable patients, 3 had confirmed responses and 11 had reduction in tumor burden. Two patients achieved complete responses that were ongoing 1.5 years following TIL treatment.

One durable complete response occurred in a PD-L1-negative, never-smoker, who had a low tumor mutation burden and who was refractory to nivolumab.

"This may be particularly encouraging for the large subset of never-smoker patients, for whom immune-checkpoint inhibitors have historically had limited efficacy," the investigators say.

This complete responder had "features where you wouldn't expect to see a response for immunotherapy," Hirsch told Medscape Medical News.

"Low tumor mutation burden, negative PDL-1, and never-smoker are three factors which indicate some kind of resistance to immunotherapy and despite that, there was a complete response with this specific therapy. That is fascinating," he said.

In exploratory analyses, T cells recognizing multiple types of cancer mutations were detected after TIL treatment and were enriched in patients who responded to treatment. 

The researchers say these early data indicate that TILs can mediate effective responses in tumor subtypes that are not sensitive to traditional immune-checkpoint-targeted therapy.

"Therefore, therapy with TILs may extend the scope and impact of immunotherapy into wider populations," they write.

"Yeoman's Effort" Paving the Way Forward

Also weighing in on the study, Philip Greenberg, MD, professor and head of immunology, Fred Hutchinson Cancer Center, Seattle, Washington said, "In some respects, it's quite promising and in other respects, actually more limited than you would hope for."

"I think it's a great demonstration that there is activity here and there's a world of things that can be done to improve the activity and no doubt that will be done. After this trial, I'm sure we will see next-generation trials," said Greenberg.

He said key issues going forward are how cells are selected and manufactured: "That's going to be a critical piece for making it better."

"There is now a world of data that says T cells that recognize mutations in cancers can be effective in solid tumors," Greenberg said.

"Sustaining that response is still a huge obstacle for achieving the kinds of therapeutic benefits we'd like to be achieved. And having that response be broad enough, particularly in the setting where most of the mutations are just passenger mutations, not driver oncogenes, is going to require a way of generating a large poly-specific population of cells that can persist for a long time," he further commented.

All in all, this study was a "yeoman's effort" and the researchers "deserve a lot of credit for pushing it forward," Greenberg said.

The study was supported in part by grants from Stand Up to Cancer Foundation, the Barbara Bauer Prelude to a Cure Foundation, Iovance Biotherapeutics, and a Young Investigator award from Adaptive Biotechnologies. Nivolumab was supplied by Bristol-Myers Squibb. Aldesleukin (IL-2) was supplied by Clinigen Group.  A complete list of author disclosures is available with the original article. Hirsch and Greenberg have disclosed no relevant financial relationships.

Nat Med. Published online August 12, 2021. Abstract

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