This prospective, single-center pilot study is being performed to find out whether Zr-89 crefmirlimab berdoxam "CD8 PET/CT" scans can improve the effectiveness of the tumor-infiltrating lymphocyte (TIL) therapy called lifileucel ("Study Treatment") in treating metastatic melanoma.

Participants must first provide consent to the companion protocol (UPCC 19426, PICSTAT CD8 PET) before being eligible to consent to this protocol.

Inclusion Criteria:

• Must have a confirmed diagnosis of unresectable or metastatic melanoma (Stage IV)

• Participants must have progressed following ≥ 1 prior systemic therapy for Stage IV or unresectable Stage III disease including a PD- 1 blocking antibody; and if BRAF V600 mutation-positive, a BRAF inhibitor or BRAF inhibitor in combination with MEK inhibitor.

• At least two resectable previously non-irradiated lesions (or aggregate of lesions resected) of a minimum 1.5 cm in diameter post- resection to generate TIL; surgical removal with minimal morbidity (defined as any procedure for which expected hospitalization is ≤ 3 days)

• Lesions in the spleen should not be selected as resectable lesions, because they are not well evaluated by CD8 PET/CT imaging due to high background signal in that organ

• In addition to the two resectable lesions, at least one measurable target lesion, as defined by RECIST v1.1

  1. Lesions in previously irradiated areas (or other local therapy) should not be selected as target lesions, unless treatment was ≥ 3 months prior to Screening, and there has been demonstrated disease progression in that particular lesion
  2. If a lesion is partially resected to generate TIL, and remains visible on the Baseline scan after surgery, then the partially resected lesion can be used for RECIST v1.1 response assessment, but only as a non- target lesion

• Participants must be ≥ 18 years of age at the time of consent.

• Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 .

• Participants must have signed informed consent for the PICSTAT companion CD8 PET imaging protocol.

• Participants are eligible for treatment with AMTAGVI per the recommendation of the treating oncologist.

• Participant (or legally authorized representative) is capable of giving signed informed consent form (ICF) which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

• Participants of childbearing potential or their partners of childbearing potential must be willing to take the appropriate precaution to avoid pregnancy or fathering a child for the duration of the protocol and practice an approved, highly effective method of birth control during treatment and for 12 months after receiving the last protocol-related therapy

• Palliative radiation therapy is permitted so long as it does not involve lesions being selected for TIL, or as target or non-target lesions. Washout is not required if all related toxicities have resolved to ≤ Grade 1 as per CTCAE v 6.0.

Exclusion Criteria:

• Participants who have received an organ allograft or prior cell transfer therapy within the past 20 years that included a non-myeloablative or myeloablative chemotherapy regimen.

• Participant has melanoma of uveal/ocular origin.

• Participants who have a history of hypersensitivity to any component or excipient of lifileucel (AMTAGVI) or other study drugs: a. Hypersensitivity to PET tracer b. LD chemo regimen (cyclophosphamide, mesna, and fludarabine) c. Proleukin®, aldesleukin, IL-2 d. Antibiotics (ABX) of the aminoglycoside group (i.e., streptomycin, gentamicin); (These participants may be eligible if current hypersensitivity has been excluded.) e. Any component of the lifileucel infusion product formulation including dimethyl sulfoxide (DMSO), human serum albumin (HSA), IL-2, and dextran-40.

• Participant has symptomatic untreated brain metastases. Participants with brain metastases may be considered for study participation with the following considerations and only after discussion with the Investigator:

  1. Participants with asymptomatic brain metastases who do not clinically require treatment may be considered for study participation.
  2. A participant with historically treated brain metastases (i.e., treatment was completed >28 days prior to consenting for study participation) may be considered for study participation if the participant is clinically stable for ≥ 2 weeks, there are no new or worsening brain lesions via screening CT or MRI, and the participant does not require ongoing corticosteroid treatment (>10 mg/day prednisone or equivalent).
  3. If there are progressive or new brain metastases on the screening CT or MRI, the participant should first receive treatment for them prior to restarting or continuing screening. A participant with recently treated brain metastases (i.e., treatment of brain metastases was completed ≤ 28 days prior to consenting for study participation) may be considered for study participation if the participant is asymptomatic, clinically stable for ≥ 2 weeks, and does not require corticosteroids (>10 mg/day prednisone or equivalent) by the end of the screening period. Repeat brain imaging is not required after treatment.

• Participant requires systemic steroid therapy > 10 mg/day of prednisone or another steroid equivalent dose.

Participants receiving steroids as replacement therapy for adrenocortical insufficiency at ≤ 10 mg/day of prednisone or another steroid equivalent dose may be eligible

• Participant has evidence of any active viral, bacterial, or fungal infection requiring ongoing systemic treatment or identified during screening
• Participants who are pregnant or breastfeeding.
• Participants who have active medical illness(es) that would pose increased risk for study participation, including: active uncontrolled infections requiring systemic ABX, coagulation disorders, or other active major medical illnesses of the cardiovascular, respiratory, or immune systems.
• Participants who have received or will receive a live or attenuated vaccination within 28 days prior to the start of LD chemo regimen.

6 months

Access to the IPD will be by written request with a clear description of what data is required and what the data will be used for. There will be no website to publicize sharing of this data, but serious requests will be handled rapidly.