Genetically Modified T-cells with Membrane Bound IL 15 for the Treatment of Adult Patients with Stage III or IV Melanoma

Inclusion Criteria

• Male or female patients age >= 18 at the time of signing informed consent form (ICF)
• 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 tumor infiltrating lymphocytes (TILs) and at least one separate lesion for RECIST response assessment
• 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 Food and Drug Administration (FDA)-approved targeted therapy
• Eastern Cooperative Oncology Group Performance (ECOG) Performance status 0-1
• Absolute neutrophil count (ANC) >= 1000/mm^3 (Within 7 days of tumor harvest and within 7 days of initiating lymphodepletion)
• Hemoglobin >=8.0 g/dL (transfusion allowed) (Within 7 days of tumor harvest and within 7 days of initiating lymphodepletion)
• Platelet count >= 75,000/mm^3 (Within 7 days of tumor harvest and within 7 days of initiating lymphodepletion)
• Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) and aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) =< 2.5 x the upper limit of normal (ULN) (Within 7 days of tumor harvest and within 7 days of initiating lymphodepletion)
• Patients with liver metastases may have liver function tests (LFT) =< 5.0 x ULN (Within 7 days of tumor harvest and within 7 days of initiating lymphodepletion)
• Calculated creatinine clearance (Cockcroft-Gault) >= 50.0 mL/min (Within 7 days of tumor harvest and within 7 days of initiating lymphodepletion)
• Total bilirubin =< 1.5 X ULN (Within 7 days of tumor harvest and within 7 days of initiating lymphodepletion)
• Negative serum pregnancy test (female patients of childbearing potential) (Within 7 days of tumor harvest and within 7 days of initiating lymphodepletion)
• Patients must have a 12-lead electrocardiogram (EKG) showing no active ischemia and Fridericia’s corrected QT interval (QTcF) less than 480 ms
• Patients must have echocardiogram showing no evidence of congestive heart failure (as defined by New York Heart Association Functional Classification III or IV) or left ventricular ejection fraction (LVEF) < 50%
• Women of child-bearing potential (WCBP), defined as a sexually mature woman who has not undergone a hysterectomy or tubal ligation or who has not been naturally postmenopausal for at least 24 consecutive months, must have a negative serum pregnancy test prior to treatment. All sexually active WCBP and all sexually active male patients must agree to use effective methods of birth control throughout the study. Approved methods of birth control are as follows: * Hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring) * Intrauterine device (IUD) * Tubal Ligation or hysterectomy * Subject/partner status post vasectomy * Implantable or injectable contraceptives * Condoms plus spermicide
• Patient (or legally authorized representative) has voluntarily agreed to participate in the study by providing signed and dated informed consent (ICF) in accordance with International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines and applicable local regulations
• Patient has agreed to abide by all protocol required procedures including study related assessments, and management by treating institution for the duration of the study and long-term follow-up (LTFU)
• Patients who have received bridging therapy between time of TIL harvest and initiation of lymphodepletion must meet all required clinical, laboratory and imaging criteria in order to qualify for therapy initiation
• Lesions amenable to radiotherapy or palliative radiotherapy (e.g.-bone metastases or metastases causing nerve impingement) should be treated > 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

• Patients with uncontrolled intercurrent medical illnesses, including active systemic infection, coagulation disorders or major cardiovascular, respiratory or immune diseases. Principal investigator (PI) or his/her designee shall make the final determination regarding appropriateness of enrollment
• Patients on chronic steroid therapy for primary immunodeficiency; however, prednisone or its equivalent is allowed at =< 10 mg/day
• Patients who are pregnant or breastfeeding
• Chemotherapy within 2 weeks prior to TIL harvest
• Treatment with small molecule targeted antineoplastics and chemotherapy within 2 weeks of initiation of lymphodepletion, or 5 half-lives, whichever is shorter
• The use of immune checkpoint inhibitors may not be used as bridging therapy
• Patients who have received live vaccines within 30 days prior to TIL harvest and initiation of lymphodepletion
• Patients with active infection requiring systemic therapy or causing fever (temperature > 38.1 degrees celcius [C]) or patients with unexplained fever (temperature > 38.1 degrees C) within 7 days prior to day of investigational product administration
• Patient has active infection with human immunodeficiency virus (HIV), hepatitis B virus, hepatitis C virus (HCV) requiring active antiviral therapy
• 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
• Positive herpes simplex virus (HSV)-1 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
• 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
• History of organ or hematopoietic stem cell transplant
• History of clinically significant autoimmune disease. The following are exceptions to the criterion: * Patients with vitiligo or alopecia * Patients with hypothyroidism, type 1 diabetes or adrenal insufficiency stable on hormone replacement therapy * Patients without active disease in the last 5 years may be included but only after consultation with the PI * Any other history or questionable history of autoimmune disease is to be considered after consultation with the PI
• History of active/untreated central nervous system metastases and/or leptomeningeal spread of melanoma. Treated stable brain metastases for at least 4 weeks are allowed
• Patients with significant clinical cardiac abnormalities: * Left ventricular ejection fraction (LVEF) < 50% * Congestive heart failure, defined by New York Heart Association Functional Classification III or IV * Unstable angina * Serious uncontrolled cardiac arrhythmia * A myocardial infarction within 6 months prior to study entry or a history of myocarditis
• Patients with a history of interstitial lung disease
• History of a concurrent second malignancy (diagnosed in the last 2 years). Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, localized thyroid cancer or in situ cervical cancer that has undergone potentially curative therapy
• Patients unable to provide informed consent and follow the study procedures (e.g., due to language problems, psychological disorders, dementia)
• Documented severe/life threatening sulfa allergy
• Chronic need for acetazolamide or other carbonic anhydrase inhibitor