Solid Tumor TIL Therapy Is Infiltrating Multiple Centers With Lympho-“sights” Set on Becoming Standard of Care

Tumor-infiltrating lymphocyte (TIL) therapy involves a multistep extraction and manufacturing process that exploits infused T cells to specifically target antigen derived from tumor-specific mutations.^1,2  Surgical resection of a metastatic lesion produces a tumor fragment consisting of malignant cells that are often rich with T cells (i.e., TILs). These T cells are logarithmically expanded ex vivo by coculture with the tumor and cytokines, particularly IL-2, forming the TIL infusion product. The product is then infused into the patient's blood following lymphodepleting chemotherapy with fludarabine and cyclophosphamide that allows for preferential homeostatic repopulation of the TIL.³  Post–TIL infusion IL-2 therapy is given to promote additional in vivo expansion.

Pioneered at the National Cancer Institute by Dr. Steven Rosenberg and colleagues,^2,4  TIL therapy has demonstrated efficacy in multiple single-center trials against malignant melanoma, though these mostly took place prior to the advent of immune checkpoint inhibitor therapy.⁵  Despite the remarkable success of immune checkpoint inhibitor therapy across multiple solid tumor types, notably melanoma, a large proportion of patients with metastatic solid tumors do not experience long-term disease-free survival.^6,7  Dr. Amod Sarnaik and colleagues report results of a groundbreaking phase II trial — to our knowledge the first testing centrally manufactured TILs, with intention to support U.S. Food and Drug Administration (FDA) approval in advanced melanoma.⁸ 

In this phase II trial, 78 patients underwent tumor resection, with 66 patients receiving intravenous infusion with the planned TIL therapy named lifileucel, consisting of between 1 billion and 150 billion expanded TILs. The protocol-specified lymphodepletion regimen consisted of cyclophosphamide (60 mg/kg) once daily for two days followed by fludarabine (25 mg/m²) once daily for five days, with lifileucel infusion to occur 24 hours from the last dose of fludarabine. Bolus IL-2 (600,000 IU/kg) was started three to 24 hours after lifileucel infusion and was administered every eight to 12 hours for up to six doses, with hold parameters based on vital signs. All patients had received prior anti–programmed death 1 pathway-blocking antibody therapy; 80 percent received prior anticytotoxic T-lymphocyte–associated protein 4–blocking antibody therapy, with 52 percent having previously received both concurrently. Of the 17 patients who were BRAF V600 mutation–positive, 88 percent had received BRAF +/–MEK inhibitors. Patients had high tumor burden at baseline (mean sum of target lesion diameters was 106 mm) and 42 percent of patients had liver and/or brain metastasis.

With a median follow-up of 18.7 months in patients receiving lifileucel, the objective response rate was 36 percent, and the disease control rate was 80 percent (3% complete responses, 33% partial responses, and 44% stable disease). Of all evaluable patients, 81 percent had a reduction in tumor burden. The median overall survival was 17.4 months, and the one-year duration of response was 69 percent. All patients experienced an adverse event, with the cytopenia being common and expected due to lymphodepleting chemotherapy. There were two fatal adverse events on the study: One patient died of abdominal tumor hemorrhage and another of acute respiratory failure assessed as unrelated to TIL.

In this article, the authors demonstrated for the first time that TIL can be centrally manufactured and cryopreserved, administered across multiple centers, and have efficacy in advanced melanoma progressed after immune checkpoint inhibitor therapy. Additional trials are planned by the sponsor and others to determine efficacy of TIL in other solid tumors, including cervical cancer and non–small-cell lung cancer.⁹  A recent single center trial report demonstrated the safety and efficacy of TIL followed by nivolumab therapy in patients with metastatic lung cancer.¹⁰  Following regulatory approvals, the oncology community will need to carefully consider ways to make this therapy broadly available and accessible to all patients. The FDA has granted lifileucel a regenerative medicine advanced therapy designation, orphan drug designation, and a fast track designation for advanced melanoma. Setbacks related to certification of each lifileucel product's potency, rather than efficacy, have delayed the sponsor from getting regulatory approvals to make TIL a standard of care. However, this trial demonstrates what is widely believed: In the future, TIL therapy will be a valuable tool in the armamentarium of standard-of-care cell therapy treatments for cancer.