Clinical Trial Finder

Inclusion Criteria:

• - Diagnosis of histologically confirmed advanced or metastatic melanoma that has progressed after at least 12 weeks or a minimum of 2 doses of treatment with a standard of care PD1/PDL1 containing therapy (nivolumab, pembrolizumab, atezolizumab, or durvalumab) as their last treatment regimen.

• - Age: ≥18 years of age.

• - Have an Eastern Cooperative Oncology Group Performance Status <3 at screening.

• - For Arm 2: have an available allogeneic NK cell donor who meets the following criteria: - At least 18 years of age.

• - Able and willing to undergo leukapheresis.

• - In general good health, and medically able to tolerate leukapheresis required for harvesting the NK cells for this study.

• - Negative for hepatitis, HTLV, and HIV on donor viral screen.

• - Not pregnant.

• - Voluntary written consent to participate in this study.

• - All HLA-match/mismatch statuses will be included.

• - Adequate organ function as defined below: - Total bilirubin < 2 mg/dL.

• - AST(SGOT)/ALT(SGPT) < 3.0 x ULN.

• - Creatinine within normal institutional limits OR creatinine clearance > 40 mL/min/1.73 m^2 by Cockcroft-Gault Formula.

• - Oxygen saturation ≥ 90% on room air.

• - Ejection fraction ≥ 45% - Patients with a prior history of symptomatic CNS metastases must have received treatment and be neurologically stable for at least for 4 weeks and off anti-seizure medication and steroids for 7 days prior to initiation of LDC are eligible.

• - Able to be off corticosteroids and any other immune suppressive medications for at least 14 days prior to apheresis or lymphodepletion and continuing until 30 days after the infusion of the ML NK cells.

However, use of physiological dosing of corticosteroids (defined as ≤15mg prednisone or equivalent) is permitted if deemed medically necessary.

• - Women of childbearing potential must have a negative pregnancy test within 28 days prior to study registration.

Female and male patients (along with their female partners) must agree to use two forms of acceptable contraception, including one barrier method, during participation in the study and until 30 days after the last ML NK cells infusion.

• - Life expectancy >12 weeks.

• - Ability to understand and willingness to sign an IRB approved written informed consent document.

Exclusion Criteria:

• - Active autoimmune disorder requiring immunosuppression (physiologic steroids defined as ≤15mg prednisone or equivalent are acceptable).

• - Prior history of an immune-related Grade 3 or 4 AE attributed to prior cancer immunotherapy (other than endocrinopathy managed with either replacement therapy or asymptomatic elevation of serum amylase or lipase) that resulted in permanent discontinuation of the prior immunotherapeutic agent.

• - Patients with Grade ≤2 irAE who have not completely recovered from irAE (i.e. have residual toxicities >Grade 1) related to prior cancer immunotherapy (other than endocrinopathy management with replacement therapy or stable vitiligo).

Patients treated with corticosteroids for irAE must demonstrate absence of related signs or symptoms for ≥7 days following discontinuation of corticosteroids.

• - Leptomeningeal disease, carcinomatous meningitis, or symptomatic CNS metastases.

Patients with asymptomatic brain metastasis with no pending intervention needed, or patients with treated CNS disease and stable for at least 4 weeks and off anti-seizure medication and steroids for 7 days prior to initiation of LDC are eligible.

• - Known hypersensitivity to one or more of the study agents.

• - Comorbidities and any conditions, that in the opinion of the investigator, that put the subject at unacceptable risk for study therapy or prevent the participant from consenting or participating in the study.

• - Uncontrolled or untreated infections, including but not limited to HIV, Hepatitis B or C infection.

• - Uncontrolled angina, severe uncontrolled ventricular arrhythmias, or EKG suggestive of acute ischemia or active conduction system abnormalities.

• - New progressive pulmonary infiltrates on screening chest CT scan that have not been evaluated with bronchoscopy.

Infiltrates attributed to infection must be stable/ improving after 1 week of appropriate therapy (4 weeks for presumed or proven fungal infections).

• - Received any investigational drugs within the 14 days prior to the first dose of fludarabine.

(Wash-out period of at least 5 half-lives from the last dose of any investigational therapy prior to screening period or 14 days, whichever is longer).

• - Pregnant or breastfeeding.

• - Subjects are not acceptable candidates if they received prior tumor infiltrating lymphocytes (TIL) therapy (either in the setting of clinical trial or standard of care if TIL therapy is FDA approved in the future).

Arms

Experimental: Arm 1: Autologous: Memory-like natural killer cells + nivolumab + relatilimab

Subjects enrolled into arm 1 will receive autologous ML NK cells on Day 0. Relatlimab/nivolumab will be initiated at day 29 and continue every 28 days for 11 cycles, or until unacceptable toxicity, or progression, whichever is earlier.

Experimental: Arm 2: Allogeneic: Memory-like natural killer cells + nivolumab + relatilimab

Subjects with a haploidentical donor will enroll into arm 2, where ML NK cells sourced from the haploidentical allogenic donor will be activated. Subjects will receive the IV infusion of ML NK cells on Day 0. Relatlimab/nivolumab will be initiated at day 29 and continue every 28 days for 11 cycles, or until unacceptable toxicity, or progression, whichever is earlier.

No Intervention: Allogeneic Donors

Interventions

Biological: - Memory-like natural killer cells

Cell product processing is performed at the Siteman Cancer Center Biological Therapy Core Facility (BTCF).

Biological: - Relatilmab

Standard of care

Biological: - Nivolumab

Standard of care