Nivolumab and Tumor-Infiltrating Lymphocyte Regimen Elicits Activity in Metastatic NSCLC

Nivolumab followed by tumor-infiltrating lymphocyte therapy and maintenance nivolumab demonstrated a suitable safety profile and antitumor activity in patients with metastatic non–small cell lung cancer.

Nivolumab (Opdivo) followed by tumor-infiltrating lymphocyte (TIL) therapy and maintenance nivolumab demonstrated a suitable safety profile and antitumor activity in patients with metastatic non–small cell lung cancer (NSCLC), according to findings from a phase 1 study (NCT03215810) published in Nature Medicine.1

Across the study population, the severe toxicity rate was 12.5% (95% CI, 3%-29%), meeting the primary end point of the study, which required a less than or equal to rate of 17% of severe toxicity (95% CI, 3%-29%).

Additionally, initial tumor regression occurred in 11 of 16 patients at the first CT scan, which was performed 1 month after TIL therapy, with a median best change in sum of target lesion diameters of -35.5% (range, +20% to -100).

“We found that excisional tumor biopsy and nivolumab followed by administration of cyclophosphamide, fludarabine, [and] IL-2 with TIL infusion in pretreated metastatic lung cancer was feasible in an academic center setting and had manageable adverse effects (AEs),” wrote lead study author Benjamin C. Creelan, MD, a medical oncologist at Moffitt Cancer Center, and coauthors, in the study publication.

Adoptive cell therapy with TILs has shown activity in metastatic melanoma, but its activity in metastatic NSCLC had been previously unknown. Moreover, approved regimens, such as PD-1/PD-L1 inhibitors, in combination with chemoimmunotherapy, fail to elicit a durable response in most patients with metastatic NSCLC.

As such, investigators conducted an open-label, single-arm trial that evaluated TIL therapy and nivolumab in patients with advanced NSCLC.

In the study, after excisional biopsy of the patient’s metastasis, all patients were treated with at least 4 cycles of intravenous nivolumab at a dose of 240 mg every 2 weeks.

If clinical benefit was apparent after 2 sequential computed tomography scans, then nivolumab was continued until progression. If there was evidence of progression, defined by tumor enlargement or new lesions, cyclophosphamide and fludarabine lymphodepletion was administered followed by TIL infusion, IL-2, and 1 year of nivolumab.

Notably, at least 2 sequential CT scans were required to reduce the possibility of confounding error because of pseudoprogression.

The primary end point was safety, with secondary end points of objective response rate, duration of response, and T-cell persistence.

Among the 20 patients enrolled, 50% were current or former smokers. The median age was

54 years (range, 38-75), and the median PD-L1 proportion score was 6%. Forty percent of patients were PD-L1 negative and 30% had a PD-L1 score over 50%.

The median nonsynonymous tumor mutation burden by whole-exome sequencing was 1.5 mutations per megabase of DNA (range, 0.1-10.2). Four patients had EGFR mutations, including 2 classical exon 19 deletions, and 2 patients had anaplastic lymphoma kinase translocations.

Most patients had lung adenocarcinoma, and half of patients had not received prior systemic therapy. Most patients had bulky disease, with a mean sum of target lesion diameters of 8.5 cm prior to TIL treatment.

Additional results showed that 90% of patients were discharged within 1 day of the excisional biopsy for TIL collection. Treatment with nivolumab did not cause any previously unreported AEs.

Regarding the feasibility of TIL expansion and infusion, TILs were able to be expanded for 95% of patients to a median dose of 95 billion CD3+ cells (range, 4.3-175). Sixteen patients received lymphodepleting chemotherapy with cyclophosphamide and fludarabine followed by TIL infusion and IL-2 for 5 days. All patients received a full course of lymphodepleting chemotherapy without dose modification.

All treated patients started an infusion of IL-2, and the majority (56%) received all planned doses. Six patients remained as inpatients after completing cyclophosphamide, and the median length of inpatient stay was 12 days (range, 7-22). Patients with a smoking history appeared to have a longer inpatient recovery time.

In terms of safety, the adverse effects (AEs) largely resulted from the combination of lymphodepleting chemotherapy and IL-2. Common nonhematologic AEs included hypoalbuminemia, hypophosphatemia, nausea, hyponatremia, and diarrhea.

Two patients died before a response assessment, both of whom had deteriorated to an ECOG performance status of 3 and required supplemental oxygen before lymphodepletion.

After these patients, more stringent pre-lymphodepletion performance status criteria were added to the protocol.

Following lymphodepletion, patients recovered lymphoid and myeloid lineages, with a median neutrophil count recovery time of 7.5 days (range, 4.7-20.6).

Most treatment-emergent AEs resolved within 1 month after TIL treatment. After 6 months of maintenance nivolumab, 1 patient had severe thrombocytopenia, which resolved with tapered corticosteroids and nivolumab discontinuation.

Another patient had enlargement of her only target lesion and a biopsy showed fibrosis tissue.

She went on without disease-related symptoms on trial for 1.5 years, before developing progression with new lesions.

In terms of efficacy, radiographic response, including unconfirmed response, occurred in 6 of 13 evaluable patients. Three of these patients had confirmed responses (CRs), leading to continued treatment with nivolumab; 2 of these responses were ongoing 1.5 years later.

Additionally, 2 patients had an unconfirmed partial response because of subsequent new brain metastases. Another 2 patients remained in clinical remission with local ablative therapy of a new lesion that was performed between 6 and 17 months after TIL infusion.

Another 2 patients with an initial nivolumab benefit had biopsy-proven progression while on nivolumab and were treated with TILs.

The median overall survival was not reached in the intent-to-treat population or after TIL treatment.

Additional findings from an exploratory analysis demonstrated that T cells that recognized several types of cancer mutations were detected after TIL treatment and were enriched in responding patients. Moreover, neoantigen-reactive T-cell clonotypes increased and lasted in peripheral blood after treatment.

“Although infusion of mutation-reactive T cells seems to be important for a successful TIL response, the lineage differentiation status of T cells may be paramount,” concluded the authors.


  1. Creelan BC, Wang C, Teer JK, et al. Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial. Nat Med. 2021;27(8):1410-1418. Published online August 12, 2021. doi:10.1038/s41591-021-01462-y