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 hasprogressed after at least 12 weeks or a minimum of 2 doses of treatment with astandard of care PD1/PDL1 containing therapy (nivolumab, pembrolizumab,atezolizumab, or durvalumab).

• Age: ≥18 years of age

• Have an Eastern Cooperative Oncology Group Performance Status (ECOG) ≤ 2 atscreening Form Arm 1 only: Patients must meet the eligibility criteria to undergoapheresis to obtain autlogous NK cells.

• For Arm 2 only: Patient must have an available allogeneic NK cell donor who meetsthe eligibility criteria.

• 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 > 40mL/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 receivedtreatment and be neurologically stable for at least for 4 weeks and off anti-seizuremedication and steroids for 7 days prior to initiation of LDC.

• Able to be off corticosteroids and any other immune suppressive medications for atleast 14 days prior to apheresis or lymphodepletion and continuing until 30 daysafter the infusion of the ML NK cells. However, use of physiological dosing ofcorticosteroids (defined as ≤15mg prednisone or equivalent) is permitted if deemedmedically necessary.

• Women of childbearing potential must have a negative pregnancy test within 28 daysprior to study registration. Female and male patients (along with their femalepartners) must agree to use two forms of acceptable contraception, including onebarrier method, throughout participation in the study and for at least 5 monthsafter the last dose of relatlimab.

• Life expectancy >12 weeks

• Ability to understand and willingness to sign an IRB approved written informedconsent document

Exclusion Criteria:

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

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

• Patients with Grade ≤2 irAE who have not completely recovered from irAE (i.e. haveresidual toxicities >Grade 1) related to prior cancer immunotherapy (other thanendocrinopathy management with replacement therapy or stable vitiligo). Patientstreated with corticosteroids for irAE must demonstrate absence of related signs orsymptoms 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, orpatients with treated CNS disease and stable for at least 4 weeks and offanti-seizure medication and steroids for 7 days prior to initiation of LDC areeligible.

• Has previously received and progressed on prior nivolumab and relatlimab therapy.

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

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

• Uncontrolled and active systemic infections, including but not limited to HIV,Hepatitis B or C infection.

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

• New progressive pulmonary infiltrates concerning for new or uncontrolled infectiousprocess. Infiltrates attributed to infection must be stable/ improving after 1 weekof appropriate therapy (4 weeks for presumed or proven fungal infections).

• Received any investigational or off-label drugs, or cytotoxic chemotherapy withinthe 14 days or five half-lives (whichever is greater) prior to apheresis.

• Pregnant or breastfeeding.

• Subjects are not acceptable candidates if they received prior tumor infiltratinglymphocytes (TIL) therapy (either in the setting of clinical trial or standard ofcare if TIL therapy is FDA approved in the future), or an organ allograft.

• Has a known additional malignancy that is progressing or required active treatmentwithin the past 2 years. Note: participants with basal cell carcinoma of the skin,squamous cell carcinoma of the skin, or carcinoma in situ (eg. Breast carcinoma,cervical cancer in situ) that has undergone potentially curative therapy are notexcluded.

• Received a live or attenuated vaccine within 28 days prior to the beginning of thelymphodepletion therapy.

Eligibility Criteria for Haploidentical Donors (For Arm 2 only)

• Donor must be at least 18 years of age.

• Donor must be willing, in general good health, and medically able to tolerateleukapheresis required for harvesting the NK cells for this study.

• Donor must be negative for hepatitis, HTLV, and HIV on donor viral screen.

• Donor may not be pregnant and/or breastfeeding. Women of childbearing potential musthave a negative pregnancy test within 30 days prior to apheresis.

• Donor must be able to understand and willing to sign an IRB-approved writteninformed consent document.

• Only haploidentical donors will be included.

• Donor must meet the requirements of institutional donor guidelines, including therequirements of Foundation for the Accreditation of Hematopoietic Cell Therapy (FACT) criteria.

Eligibility Criteria for Autologous Patients (For Arm 1 only)

• Patient must be willing and medically able to tolerate leukapheresis required forharvesting the NK cells for this study.

• Patient must be negative for hepatitis, HTLV, and HIV on the viral screen.

• Patient may not be treated with any cytotoxic treatment within 2 weeks prior toleukapheresis.