Lymphodepletion Chemotherapy, CD40L-Augmented Tumor Infiltrating Lymphocytes, and Interleukin-2 for the Treatment of Advanced, Unresectable, and Metastatic Melanoma

Inclusion Criteria

• Participants must have histologically confirmed, unresectable (stage III/IV) or metastatic melanoma as follows: * Cutaneous, non-acral, melanoma (including melanoma of unknown primary) * Cutaneous acral melanoma * Mucosal melanoma * Ocular melanoma (including uveal, iris, conjunctival melanoma)
• Participants must have failed, be refractory to, or unable to tolerate at least one line of standard of care in the opinion of the Investigator. For participants with cutaneous non-acral melanoma, standard of care therapy includes a PD-1/L1 or combination therapy with anti-PD1 and anti-CTLA4 or combination therapy of anti-PD1 and anti-LAG3 or if BRAF V600 activating mutation positive, a BRAF ± MEK inhibitor. Participants are allowed to be enrolled in this trial if they failed one line of any of those standards of care therapy regimens. * Note: if treatment failure occurs during adjuvant therapy or within 6 months of adjuvant therapy completion, this will count as a failure of the applicable regimen as noted above
• Any systemic therapy, including anti-cancer monoclonal antibodies, must have been completed at least 4 weeks from the start of lymphodepleting therapy, and any prior therapy-related AEs must have resolved to grade =< 1 except for alopecia and vitiligo. Neuropathy must have resolved to grade =< 2. BRAF/MEK targeted therapy as a bridging therapy will be allowed for patients who already received BRAF/MEK targeted therapy for melanoma management and demonstrated disease progression on those agents before enrollment to this study. If the patient was not previously intolerant – in order to prevent potential disease hyper-progression due to abrupt stoppage of targeted therapy during manufacturing period, bridging therapy will be allowed with continuation of BRAF/MEK targeted therapies and should be stopped at least 2 weeks (+/- 10 days) from the start of lymphodepleting therapy. Other bridging therapy options will include but not be limited to chemotherapy (preferably 1 cycle, more than 1 is allowed), and/or radiation therapy and should be completed at least 2 weeks from the start of lymphodepleting therapy
• Participants must be between the ages of 18 and 75 years old. Additionally, participants who are >= 50 years of age must undergo a cardiology evaluation including a cardiac stress test or coronary computed tomography after which they must be deemed to be low/acceptable risk. This cardiac evaluation may be omitted for patients who underwent testing within 6 months and have no interval change in cardiopulmonary clinical status. Additionally, participants between the ages of 71-75 must meet all other inclusion criteria and have express written permission provided by the clinical principal investigator (PI)
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Absolute neutrophil count ≥ 1,500/mcL (non-growth factor supported)
• Platelet count >= 100,000/mcL
• Hemoglobin >= 8.0 g/dL
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase [SGPT]) =< 3 times the institutional upper limit of normal (ULN); =< 5 times ULN if patient has liver metastasis
• Cockcroft-Gault estimated glomerular filtration rate (GFR) (creatinine) >= 50 mL/min
• Total bilirubin =< 2.0 mg/dL (except in patients with Gilbert's Syndrome where the bilirubin must be =< 3 mg/dL)
• Seronegative for human immunodeficiency virus (HIV) antibody, hepatitis B surface antigen, and hepatitis C (HCV) antibody (if HCV antibody positive, must be tested for HCV ribonucleic acid [RNA], which must be negative to be eligible)
• Participants with brain metastases are eligible provided that the brain metastases have been successfully treated with stereotactic radiosurgery or resection and clinically stable for at least 4 weeks
• Participants must be willing and able to undergo an apheresis procedure
• Women of child-bearing potential must have a negative pregnancy test
• The effects of CD40L-augmented TIL on the developing human fetus are unknown. For this reason and because TIL agents, as well as other therapeutic agents used in this trial including IL-2 are known to be teratogenic, both males and females of child-bearing potential must be willing to practice birth control starting with screening through 1 year after the last study drug is administered for females or 6 months for males. * Contraception requirement ** To prevent pregnancy, patients who are able to conceive or father children must use a highly effective contraception method during sexual activity starting with screening through 1 year after the last study drug is administered for females or 6 months for males. ** Based on their mechanisms of action, the non-myeloablative lymphodepleting (NMA-LD) chemotherapy, aldesleukin (IL-2), can cause fetal harm when administered to a pregnant woman. Effects of CD40L-augmented on fetal development are unknown. * Definition of non-reproductive potential ** For this trial, male patients will be considered to be of non-reproductive potential if they have azoospermia (whether due to having had a vasectomy or due to an underlying medical condition). ** Female patients will be considered of non-reproductive potential if they are either: *** Postmenopausal (defined as at least 12 months with no menses without an alternative medical cause; in women < 45 years of age, a high follicle stimulating hormone [FSH] level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. In the absence of 12 months of amenorrhea, a single FSH measurement is insufficient); *** Or have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy, or bilateral tubal ligation/occlusion, at least 6 weeks prior to screening. *** Or has a congenital or acquired condition that prevents childbearing. * Definition of highly effective contraception ** The following are examples of acceptable contraception methods to prevent pregnancy. This list may not be comprehensive for all regions, so the investigator must discuss sexual activity and contraception usage with the patient. *** Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive injection *** Intrauterine device (IUD) *** Intrauterine hormone releasing system (IUS) *** Bilateral tubal occlusion *** Vasectomized partner
• Should a woman become pregnant or suspect she is pregnant while she or her partner are participating in this study, she should inform her treating physician immediately
• Ability to understand and the willingness to sign a written informed consent document
• Participants should have at least one surgically accessible lesion for tumor harvest for preparation of TIL, and at least one RECIST version (v)1.1 measurable lesion after tumor harvest to follow for response assessment

Exclusion Criteria

• Participants, regardless of age, who have a current or past medical history of ischemic heart disease, or clinically significant atrial or ventricular rhythm abnormality are excluded unless they undergo a cardiac stress test and cardiology clearance examination and are determined to be low or acceptable risk. * Note: Participants with any clinically significant cardiac wall movement abnormality are excluded
• Participants with either a primary immunodeficiency disorder (i.e., severe combined immunodeficiency syndrome) or acquired immunodeficiency disorders (such as HIV/AIDS)
• Pregnant women are excluded from this study because the agents used in this study have teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with CD40L-augmented TIL or the other agents in the study, breastfeeding should be discontinued if the mother is enrolled in the study
• Participants taking systemic steroid therapy (other than replacement therapy or prednisone equivalent of =< 10mg daily) or therapy with any immunosuppressive medications such as mycophenolate mofetil (MMF). Participants who require more than 10mg of prednisone or equivalent other steroid therapy should taper their steroid therapy to 10 mg prednisone 1 week prior to planned first interventional drug therapy (lymphodepleting therapy). Participants who are on baseline replacement therapy or prednisone equivalent of =< 10mg daily and require stress doses of steroid therapy will be allowed to receive stress dose steroids during the trial interventions. Participants who require dapsone for pneumocystis pneumonia (PCP) prophylaxis during TIL therapy are eligible
• Participants who have a history of severe immediate hypersensitivity reaction to the study agents including cyclophosphamide, fludarabine, or IL-2 or any of their constituents
• Participants with a left ventricular ejection fraction (LVEF) =< 45% or New York Heart Association (NYHA) functional classification > 1
• Forced expiratory volume (FEV1) =< 60% of predicted value and diffusing capacity of the lungs for carbon monoxide (DLCO) (corrected) < 60% of predicted value. Participants who underwent pulmonary function testing within 6 months of screening may omit pulmonary function tests (PFTs) if they demonstrate stable cardiopulmonary status
• Participants who, in the opinion of the investigator, have a medical condition that would subject the patient to prohibitive risk by participation in this study, or who may be unable to safely complete the apheresis, tumor harvest, lymphodepletion regimen, TIL infusion, or aldesleukin administration
• Participants with active infections requiring antibiotics
• Participants with autoimmune disease currently requiring systemic treatment with immunosuppressive doses of corticosteroids (> 10 mg of prednisone-equivalent daily dosing), immunosuppressive biologic agents, or disease modifying antirheumatic drug agents (DMARDs). * Note: Participants with autoimmune thyroiditis on replacement thyroid medication are eligible. Participant who are on steroids due to immune-related adverse events may taper their steroid therapy to 10 mg prednisone1 week before receiving first interventional drug therapy (lymphodepleting therapy). Participants who are on baseline replacement therapy or prednisone equivalent of =< 10mg daily and require stress doses of steroid therapy will be allowed to receive stress dose steroids during the trial interventions
• Participants requiring chronic anti-coagulant therapy that cannot either be discontinued or changed to an anti-coagulant such as a low molecular weight heparin, which has a relatively short half-life, if clinically indicated during the period of thrombocytopenia resulting from the lymphodepletion regimen
• Has evidence of impeding perforation, obstruction or bleeding (requiring transfusion) due to the tumor
• Patients who received prior live cell therapy are excluded, unless express written permission is provided by the clinical PI
• Patients between the ages 71-75 are excluded, unless they meet all other inclusion criteria and express written permission is provided by the clinical PI