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

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) \<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

17\. Patients with a history of interstitial lung disease

18\. 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.

19\. Patients unable to provide informed consent and follow the study procedures (e.g., due to language problems, psychological disorders, dementia).

20\. Documented severe/life threatening sulfa allergy.

21\. Chronic need for acetazolamide or other carbonic anhydrase inhibitors

What this study is about