Study of Autologous, Metabolically Optimized, CD137+ Tumor-Infiltrating Lymphocytes Followed by Consolidative Oral Cyclophosphamide, Bevacizumab, and Pembrolizumab

Inclusion Criteria: 5.1.1 STEP 1: RESECTION OF TUMOR \& INITIATION OF TIL EXPANSION Patients must fulfill all of the following criteria to be eligible for the study at the time of tumor resection and initiation of TIL expansion. 1. Provision of signed and dated informed consent form. 2. Stated willingness to comply with all study procedures and availability for the duration of the study. 3. Female, aged 18 to 80 years. 4. Patients must have recurrent epithelial ovarian cancer, all subtypes will be eligible. 5. Measurable disease for target lesion(s) per RECIST prior to resection. If only one measurable lesion prior to surgery, residual disease measurable lesion must be present after resection on baseline imaging. 6. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 to 1 and life expectancy of \> 6 months. 7. Patients must have progressed on at least one prior standard of care treatment regimen for metastatic disease, may include platinum sensitive and resistant patients. Platinum sensitive disease as defined by recurrence of disease more than 6 months following a complete response to initial treatment and platinum recurrent as defined by recurrence less than 6 months after a complete response to initial treatment. If patients are 2nd line platinum sensitive, they must have progressed \< 1 year of last platinum therapy. Also, for 2nd line platinum sensitive patients that are candidates for PARP maintenance, they must have had a frontline PARP maintenance or attempt at PARP maintenance with unacceptable toxicity/intolerance. For 3rd line or more platinum sensitive patients, all platinum free intervals (PFI) are acceptable. a. The allowance of platinum sensitive patients is based on the high response rate and durability (Sensitive: ORR-60% DOR-11.5 mos, vs Resistant: ORR 43.3, DOR 5.5 mos) seen in the study that gave rationale for the consolidative regimen of oral cyclophosphamide, bevacizumab, pembrolizumab (Zsiros et al, 2021). As well, higher responses are observed to targeted therapies in platinum sensitive patients (mirvetuximab Plat Sens: ORR 51% vs Plat resistant: 32%), similar to platinum combination response rates and PFS. By introducing an immunotherapeutic-targeted regimen in platinum sensitive patients, it further extends the platinum free interval (PFI) increasing later platinum response potential, especially those in the 6-12 mos PFI. 8. A negative pregnancy test (urine or serum) must be documented at screening for women of childbearing potential. 9. A MUGA/ECHO scan (ejection fraction \> 45% is required) ≤ 6 months prior to lymphodepletion. New York Heart Association functional classification Class \<1 are required. 10. Patients who have a history of ischemic heart disease, angina, or clinically significant atrial and/or ventricular arrhythmias must undergo a cardiac stress test, patients with abnormal cardiac stress test, may be considered for study if they have adequate ejection fraction (\>45%) and cardiology clearance with approval of Primary Investigator. 11. Screening Pulmonary function tests should be performed for select patients (see below) with postbronchodilator values: Forced expiratory volume in 1s, (FEV1)/forced vital capacity\>70%' or FEV1\>50% of predicted normal is recommended. 1. History of cigarette smoking of ≥ 20 pack-years 2. Cessation of smoking withing past 2 years or still smoking 3. History of pneumonitis (including related to prior cancer treatment), COPD, or asthma 4. Significant signs of respiratory dysfunction on exam (wheezing, rales, chronic cough) 5. History of pleural drainage in the past 3 months i. For patients with pleural effusions, if parameters are not met, consideration of drainage prior repeat PFT is reasonable, in this scenario, if reaccumulated on baseline CT after tumor procurement, consider drainage again prior to lymphodepletion. 12. Adequate renal function, including creatinine ≤ 1.5 mg/dL and CrCl \>40L/min, ideally \>60L/min. If creatinine is 1.6-2 mg/dL, then will need CrCl\>60L/min to be considered. 13. Adequate hepatic function total bilirubin ≤ 2.0 mg/dL, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dL, AST and ALT of less than 3 X institutional upper limit of normal (ULN), patients with liver metastasis may have up to 5xULN. 14. Adequate hematologic function, hemoglobin (hgb) of 8 gm/dL or more, and platelets of 75,000 per mm3 or more for surgical resection. A packed red blood cell transfusion is acceptable, though must remain stable above 8mg/dL on repeat evaluation remains stable on or after 7 days. 15. Patients must have a positive screening EBV antibody titer on screening test. 16. Participants may have had prior bevacizumab, cyclophosphamide, and/or pembrolizumab. 5.1.2 STEP 2: CHEMOTHERAPY/CELL INFUSION INCLUSION CRITERIA To be eligible for chemotherapy/cell infusion, patients must fulfil the following criteria: 1. Patients must have adequate TILs expanded, (\>1x109 cells). 2. Women of childbearing potential (WOCBP) must practice birth control while on regimen and for 3 months after receiving the preparative regimen. 3. Unless surgically sterile by bilateral tubal ligation or vasectomy of partner(s), the patient agrees to continue to use a method of contraception throughout the study and for 90 days after your last treatment such as: barrier (i.e. condom, diaphragm), hormonal, IUD, or sponge plus spermicide. 4. For women who have menstruated within the past 12 months and have not had a surgical procedure to accomplish sterilization, pregnancy testing (serum) will be performed within 7 days prior to treatment. 5. Clinical performance status of ECOG 0 to 1 at the time of chemotherapy infusion. 6. Absolute neutrophil count greater than or equal to 1000/mm3. 7. Platelet count greater than or equal to 100,000/mm3. 17\. Adequate renal function, including creatinine ≤ 1.5 mg/dL and CrCl \>40L/min, ideally \>60L/min. If creatinine is 1.6-2 mg/dL, then will need CrCl\>60L/min to be considered. a. Fludarabine dose should be reduced (20 mg/m2 in patients with CrCl 40-59 mL/min) 8.Adequate hepatic function total bilirubin ≤ 2.0 mg/dL, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dL, AST and ALT of less than 3 X institutional upper limit of normal (ULN), patients with liver metastasis may have up to 5xULN. 9.Adequate hematologic function, platelet count greater than or equal to 100,000/mm3. Hemoglobin (hgb) of 8 gm/dL or more, a packed red blood cell transfusion is acceptable, though must remain stable above 8mg/dL on repeat evaluation remains stable on or after 7 days. 10.Prothrombin time (PT) and partial thromboplastin time (PTT) within 1.5 times the institutional upper limit of normal. 11.Urinalysis within 14 days demonstrating no evidence of a urinary tract infection. Exclusion Criteria: 5.2.1 STEP 1: RESECTION OF TUMOR \& INITIATION OF TIL EXPANSION Patients who meet the following criteria will be excluded from study participation: 1. Patients with active systemic infections requiring intravenous antibiotics, coagulation disorders, or other major medical illnesses of the cardiovascular, respiratory, or immune system. 2. Frontline platinum refractory patients (progression on or \<90 days from last platinum dose) 3. Patients that have completed an adoptive cellular therapy regimen which included a non-myeloablative lymphodepletion strategy. Prior Bi-specific T-cell engagers are allowed if done without lymphodepletion and no grade 3 CRS/ICANs events were experienced. 4. Patients testing positive for HIV titer, hepatitis B surface antigen, human T-cell leukemia-lymphoma virus (HTLV) I or II antibody, or both rapid plasma regain (RPR) and fluorescent treponemal antibody (FTA). Patients with hepatitis C antibody must have a negative (undetectable) viral load by polymerase chain reaction (PCR). 5. Patients who are pregnant or nursing. 6. Patients needing chronic immunosuppressive systemic steroids (\>10mg/day prednisone or equivalent). 7. Patients with autoimmune diseases that require immunosuppressive medications. 8. Presence of a significant psychiatric disease, which in the opinion of the principal investigator or his designee, would prevent adequate informed consent or render immunotherapy unsafe or contraindicated. 9. Patients with active untreated central nervous system metastases. Patients will be allowed with historically treated brain metastasis (treatment completed \>28 days prior to consenting to study) and they undergo MRI at screening that reveals no new or worsening brain lesions and does not require ongoing corticosteroid treatment (\>10mg/day prednisone or equivalent). Patients with leptomeningeal disease are excluded regardless of prior brain treatment response. 10. Patients with a separate primary malignancy within the past 3 years (except those that did not require more than excisional curative treatment for early stage, or have been curatively treated, and in the judgement of the investigator does not pose a significant risk of recurrence, including but not limited to non-melanoma skin cancer, ductal/lobular carcinoma in situ of the breast, or superficial bladder cancer). 11. Patients with recent clinical evidence of malignant bowel obstruction (small intestine or colon) in the past 60 days unless was unrelated to malignancy and surgically corrected (ex. - hernia) \>28 days prior to signing consents. 12. Participants with any form of primary immunodeficiency (ex. Severe combined immunodeficiency disease or AIDS). 13. Patient with history of hypersensitivity to any component of the study intervention (cyclophosphamide, mesna, fludarabine, IL-2). Or to the components of the TIL product including dimethyl sulfoxide (DMSO), human serum albumin, IL-2. Patients will be allowed if they have hypersensitivity to any of the supportive medications as long as there is acceptable alternative, per primary investigator. 14. Patients with an inability to comprehend and give informed consent.