Memory-Like Natural Killer Cells With Nivolumab and Relatlimab in Advanced or Metastatic Melanoma After Progression on Checkpoint Inhibitors

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).