Phase I, Open-Label, Study of Tumor Infiltrating Lymphocytes Engineered With Membrane Bound IL15 Plus Acetazolamide in Adult Patients With Metastatic Melanoma

The goal of this clinical research study is to find the recommended dose of OBX-115 in combination with acetazolamide that can be given to patients with metastatic melanoma previously treated with immune checkpoint inhibitors. The safety and tolerability of the study drug combination will also be studied.

Inclusion Criteria: 1. Male or female patients age ≥ 18 at the time of signing ICF 2. Patient has a pathologically confirmed diagnosis of metastatic melanoma that is unresectable stage III or stage IV and has lesion(s) amenable to resection for the generation of TILs and at least one separate lesion for RECIST v1.1 response assessment 3. Patient must be relapsed and/or refractory to immune checkpoint inhibitor (ICI) therapy including either anti PD-1 either with or without anti CTLA-4 blocking antibody and/or anti LAG-3 antibody. Patients should have received standard-of-care (SOC) therapy per standard clinical practice guidelines. Patients must not have had exposure to more than 3 prior lines of anti-PD-1 antibody-containing therapeutic regimens administered in the metastatic setting If the patient is BRAF V600 mutation-positive with rapidly progressing disease, the patient should have received available FDA-approved targeted therapy. 4. ECOG Performance status 0-1 5. Within 7 days of tumor harvest and within 7 days of initiating lymphodepletion, patients must meet the following laboratory criteria: • Absolute neutrophil count (ANC) ≥ 1000/mm3 • Hemoglobin ≥ 8.0 g/dL (transfusion allowed) • Platelet count ≥ 75,000/mm3 • ALT/SGPT and AST/SGOT ≤ 2.5 x the upper limit of normal (ULN) • Patients with liver metastases may have liver function tests (LFT) ≤ 5.0 x ULN • Calculated creatinine clearance (Cockcroft-Gault) ≥ 50.0 mL/min • Total bilirubin ≤ 1.5 X ULN • Negative serum pregnancy test (female patients of childbearing potential) 6. Patients must have a 12-lead electrocardiogram (EKG) showing no active ischemia and Fridericia's corrected QT interval (QTcF) less than 480 ms 7. Patients must have echocardiogram showing no evidence of congestive heart failure (as defined by New York Heart Association Functional Classification III or IV) or LVEF \ 4 weeks prior to enrollment and subjects must be fully recovered from the effects of radiation. However, palliative radiation is permitted if subjects recover from all side effects to ≤ Grade 1 toxicities (based on CTCAE, v.5) and is \> 2 weeks prior to starting lymphodepletion. Exclusion Criteria: 1. Patients with uncontrolled intercurrent medical illnesses, including active systemic infection, coagulation disorders or major cardiovascular, respiratory or immune diseases. PI or his/her designee shall make the final determination regarding appropriateness of enrollment 2. Patients on chronic steroid therapy for primary immunodeficiency; however, prednisone or its equivalent is allowed at ≤ 10 mg/day 3. Patients who are pregnant or breastfeeding 4. Chemotherapy within 2 weeks prior to TIL harvest 5. Treatment with small molecule targeted antineoplastics and chemotherapy within 2 weeks of initiation of lymphodepletion, or 5 half-lives, whichever is shorter 6. The use of immune checkpoint inhibitors as bridging therapy is not allowed. 7. Patients who have received live vaccines within 30 days prior to TIL harvest and initiation of lymphodepletion 8. Patients with active infection requiring systemic therapy or causing fever (temperature \> 38.1oC) or patients with unexplained fever (temperature \> 38.1oC) within 7 days prior to day of investigational product administration 9. Patient has active infection with human immunodeficiency virus (HIV), hepatitis B virus, hepatitis C virus (HCV) requiring active antiviral therapy. 10. Cytomegalovirus (CMV) IgM antibody titer or PCR assay; and Epstein-Barr virus (EBV) IgM or PCR assay indicating active infection. Tumor harvest may take place even with positive results as long as consult with infectious disease physician is planned and the infection can be appropriately treated, if needed, prior to initiation of lymphodepletion. 11. Positive herpes simplex virus (HSV)-1 serology or PCR assay • Patients who are HSV PCR assay positive will need to receive appropriate treatment and become PCR assay negative prior to starting the lymphodepletion Tumor harvest may take place even with positive results as long as consult with infectious disease physician is planned and the infection can be appropriately treated, if needed, prior to initiation of lymphodepletion. 12. Persistent prior therapy-related toxicities greater than Grade 2 according to Common Toxicity Criteria for Adverse Events (CTCAE) v5.0, except for peripheral neuropathy, alopecia, or vitiligo prior to enrollment. Patients with prior immune mediated hypophysitis or adrenal insufficiency or hypothyroidism are eligible for treatment as long as they are on stable, physiologic doses of hormone repletion. 13. History of organ or hematopoietic stem cell transplant 14. History of clinically significant autoimmune disease The following are exceptions to the criterion: 1. Patients with vitiligo or alopecia. 2. Patients with hypothyroidism, type 1 diabetes or adrenal insufficiency stable on hormone replacement therapy. 3. Patients without active disease in the last 5 years may be included but only after consultation with the PI. 4. Any other history or questionable history of autoimmune disease is to be considered after consultation with the PI 15\. History of central nervous system metastases and/or leptomeningeal spread of melanoma. 16\. Patients with significant clinical cardiac abnormalities: • Left ventricular ejection fraction (LVEF) \