This phase I trial tests the effect of Circadian-Optimized Light Therapy (COLT) in conjunction with standard of care tumor-infiltrating lymphocytes (TIL) therapy in treating patients with melanoma that may have spread from where it first started to nearby tissue, lymph nodes or distant parts of the body (advanced). Circadian rhythm is the body's natural 24 hour clock which helps keep the body operating on a healthy wake-sleep cycle. Exposure to morning light has been shown to have a positive impact. Patients with advanced cancers often experience circadian disruption, including exposure to hospital-related light, treatment side effects, and inflammation. TIL are made by collecting and growing specialized T cells (a type of white blood cell) from a patient's tumor and given back to the patient to help stimulate the immune system in different ways to stop tumor cells from growing. However, disruptions in the circadian rhythm may impact the effectiveness of TIL therapy. COLT is a home-based digital intervention that delivers circadian-effective morning light using the Circadian OS iPad application. Daily light exposure may help prevent circadian disruption and improve immune and inflammatory responses. Adding COLT sessions to standard of care therapy with TIL may be safe and tolerable in patients with advanced melanoma.

PRIMARY OBJECTIVE:

I. Evaluate the feasibility of COLT with TIL therapy.

SECONDARY OBJECTIVES:

I. Evaluate the safety of COLT with TIL therapy. II. Evaluate the acceptability of COLT intervention to patients. III. Evaluate the effect of COLT on patient-reported quality of life metrics.

EXPLORATORY OBJECTIVES:

I. Evaluate changes that occur in patient circadian clocks with COLT during TIL therapy using actigraphy and circadian clock gene analysis.

II. Evaluate the alterations and time course that occur in tumor immune cell subsets and phenotype with COLT during TIL therapy.

III. Evaluate the toxicities related to TIL therapy (i.e., cytopenia, interleukin 2 [IL-2] toxicity) that occur with COLT during TIL therapy.

OUTLINE:

Starting on day -14, patients receive access to the Circadian OS application and within the first hour of waking up undergo light therapy sessions over 1 hour daily between 8:00 and 10:00 am for up to 28 days after TIL in the absence of disease progression or unacceptable toxicity. Patients also receive standard of care TIL infusion on day 0. Patients may optionally continue COLT for up to 90 days post TIL infusion. Patients also wear wrist actigraphy continuously to monitor sleep-wake cycles, light exposure, and circadian rhythms during TIL therapy. Additionally, patients undergo blood sample collection throughout the study.

After completion of study intervention, patients are followed up at 30 days.

Inclusion Criteria:

• Documented informed consent of the participant and/or legally authorized representative
• Age: ≥ 18 years
• Ability to read and understand English for questionnaires
• Progression on or after immune checkpoint inhibitor therapy
• Deemed eligible and consented for standard-of-care TIL therapy (lifileucel/Amtagvi)
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (typically required for TIL therapy; confirm with clinical standards of practice [SOP])

Exclusion Criteria:

• Explicit Munich Chronotype Questionnaire (MCTQ) cutoffs (< 2:00, > 5:00)
• Use of melatonin or pharmacologic sleep aids (e.g., zolpidem, trazodone, benzodiazepines) within 14 days prior to enrollment
• Night shift work within the past 30 days or expected during the intervention
• Travel across ≥ 2 time zones within the past 14 days
• Diagnosed or suspected untreated moderate to severe obstructive sleep apnea
• History of mania, hypomania, bipolar disorder, migraine (with or without photophobia), or active seizure disorder
• Active psychosis, suicidal ideation, or recent psychiatric hospitalization (< 3 months)
• Ocular conditions exacerbated by bright light exposure
• Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
• Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)