In a phase I clinical trial, tumor-infiltrating lymphocyte therapy combined with the anti–PD-1 drug nivolumab was considered safe and tolerable—and exhibited preliminary signs of efficacy—in patients with stage IV or recurrent non–small cell lung cancer.

Tumor-infiltrating lymphocyte (TIL) therapy in combination with the anti–PD-1 drug nivolumab (Opdivo; Bristol-Myers Squibb) could help patients with stage IV or recurrent non–small cell lung cancer (NSCLC) reach remission. The safety of the combination, along with early hints of efficacy, were revealed by a phase I trial reported at the American Association for Cancer Research Virtual Annual Meeting I: April 27–28, 2020.

To create a TIL therapy, T cells are extracted from a patient's excised tumor, cultured, and selected for specific recognition of tumor cells based on interferon production or 41BB expression. The cultures are then pooled and T-cell populations are expanded and infused back into the patient; thus, unlike chimeric antigen receptor T-cell therapy, no genome editing is required.

“There's a diverse spectrum of responses” to the TIL therapy, said Ben Creelan, MD, MS, of the Moffitt Cancer Center in Tampa, FL, who presented the preliminary findings. Six of 12 evaluable patients responded to the therapy: Two exhibited complete responses that have lasted longer than a year, one experienced a durable partial response, two had partial responses followed by progression, and one had an unconfirmed partial response.

The data were regarded as promising—and somewhat surprising—given that most patients had low PD-L1 expression and low tumor mutational burden (TMB), both often considered predictors of poor response to therapies targeting the PD-1 axis. Notably, three of the six responders—including one of the patients who had a durable complete response—had received prior therapies and did not have high PD-L1 expression or high TMB. “This is a patient population that is hardly expected to respond to nivolumab, so two partial responses and one durable complete response is really phenomenal,” said study discussant Gal Markel, MD, PhD, of the Sackler School of Medicine at Tel Aviv University in Israel.

Creelan's group previously found evidence that adding PD-1–axis blockade to TILs from lung tumors improved the cells’ proliferative capacity and autologous tumor reactivity, so they incorporated nivolumab into the therapeutic regimen even in patients unlikely to benefit from anti–PD-1 monotherapy.

Interpretation of the TILs’ potential benefit is limited by the small number of patients and the lack of a control arm. Further hampering the interpretation of the results, three of the six responders had not previously received any therapy. One of these patients had high PD-L1 expression and another had high TMB, so they might have benefited from nivolumab monotherapy.

To control for the fact that some patients may have been responsive to nivolumab even without the TILs, trial investigators gave patients four doses of nivolumab and performed CT scans to demonstrate a lack of benefit from anti–PD-1 monotherapy prior to TIL therapy.

The side effects of the treatment—including cytopenia, lymphopenia, fever, nausea, and diarrhea—were considered manageable. Thus, in addition to showing early signs of efficacy, the trial met its primary endpoint of safety and tolerability.

“In my view this study provides a very good proof-of-concept of clinical activity of TIL therapy in lung cancer in the advanced setting,” Markel said. –Nicole Haloupek