Inclusion Criteria:
1. Be 18 years or older of age on the day of signing informed consent.
2. Have had historical or current histologically confirmed isocitrate dehydrogenase 1(IDH1) wild-type glioblastoma and variants as defined by the World Health Organization
3. Patient must have a T1 weighted 3D MRI with Gadolinium enhancement within 14 days prior to lymphodepletion at Day -5
4. Patient must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
5. Radiologically confirmed recurrent glioblastoma at first or second recurrence have contrast enhancing measurable disease with a bidimensional diameter greater than or equal to 10 mm x 10 mm according to RANO and be eligible to undergo tumor resection.
6. Patients must be a candidate to undergo non-emergent surgical resection of the primary target lesion.
7. Multifocal GBM is permissible in the study if there is contiguous T2FLAIR hyperintensity between enhancing lesions on T1 post gadolinium sequences and if in the opinion of the PI surgical resection of the multifocal disease is achievable.
• NOTE: Multicentric disease with no demonstrated ventricle communication at the time of screening is excluded.
8. The patient must either be on no steroids or on a stable dose of dexamethasone or equivalent no greater than \> 2 mg a day for at least 5 days prior to lymphodepletion.
9. Karnofsky performance status (KPS) ≥ 60
10. Have washout periods for prior therapies defined as at five half-lives or (4 weeks) prior to the administration of lymphodepletion whichever is shorter
11. Demonstrate at screening adequate organ function by laboratory values as follows:
* Absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L
* Platelet count ≥ 100 x 10\^9/L (patient needs to have a minimum of 70 x10\^9/L to undergo resection)
* Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L
* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \<2 .5 the upper limit of normal (ULN)
* Calculated creatinine clearance ≥ 45.0 mL/minute as estimated by Cockcroft-Gault formula
* Total bilirubin ≤ 1.5 x ULN, unless due to Gilbert's syndrome
* Total albumin ≥ 3.0 g/dL (30 g/L)
* Prothrombin Time (PT) ≤1.5 x ULN unless patient is receiving anticoagulant therapy if PT or PTT is within therapeutic range of intended use of anticoagulants
* activated Partial Thromboplastin Time (aPTT) ≤ 1.5 x ULN unless patient is receiving anticoagulant therapy if PT or PTT is within therapeutic range of intended use of anticoagulants.
* Adequate coagulation function defined as INR ≤ 1.5 x ULN, unless the patient is receiving anticoagulant therapy with PT or a PTT/PTT is within therapeutic range.
12. Patients must agree to use a highly effective method of contraception if procreative potential exists from the start of the study until one year after the completion of lymphodepletion for females and 4 months after completion of lymphodepletion for males.
* A Female of Childbearing Potential (FCBP) is defined as: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months).
Exclusion Criteria:
Exclusion Criteria:
1. Midline shift greater than 0.5 cm or pending herniation.
2. Patients who were previously treated with Bevacizumab. The use of Bevacizumab for edema or radiation necrosis treatments may be allowed with prior approval from the medical monitor
3. Anticipated Extent of Resection by volumetric analysis is less than 70%
4. Patients with greater than two recurrences of GBM are excluded
5. Patients with any contraindications to MRIs
6. Treatment with other investigational agents, check point inhibitors and prior immunotherapy such as Vaccine therapy, dendritic cells vaccine within 4 weeks prior to lymphodepletion.
7. Prior radiation therapy within 12 weeks of screening MRI unless there is unequivocal histological confirmation of tumor progression.
8. Patients with known disease in the posterior fossa, gliomatous meningitis, extracranial disease or multicentric enhancing disease. Multicentric disease is defined as discrete sites of contrast enhancing disease without contiguous T2/FLAIR abnormality.
• NOTE: Satellite lesions that are associated with a contiguous area of T2/FLAIR abnormality as the main lesion(s) may be included.
9. Patients with concurrent use of tumor treating fields (TTF) or laser interstitial thermal therapy (LITT) is excluded. Prior use of TTF or LITT is allowed prior to signing the ICF
10. Patients with current Carmustine wafers. (Patients that agree to remove the Carmustine wafers at the time of tumor resection during the study are allowed in the study)
11. Patents who are receiving systemic steroid therapy \> 2 mg of dexamethasone or equivalent total dose per day or any other form of immunosuppressive therapy within 5 days of lymphodepletion.
• Patients that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Patients requiring physiological doses of steroids (i.e., adrenal insufficiency or hypopituitarism) not to exceed equivalent of dexamethasone 2 mg will not be excluded from the study.
12. Patients with history of anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome
13. Active autoimmune disease other than controlled connective tissue disorder or those who are not on active therapy.
14. Any other organ dysfunction (CTCAE Version 5.0 Grade 3 or greater) that will interfere with the administration of the lymphodepletion regimen, rhIL-2, CYNK-001 or the surgical resection as outlined.
15. Known hypersensitivity to cyclophosphamide, fludarabine, Mesna or rhIL-2.
16. Have active or clinically significant cardiac disease including:
* History or presence of serious uncontrolled cardiac arrhythmias.
* Clinically significant resting bradycardia.
* Left ventricular ejection fraction (LVEF) by echocardiogram (ECHO) \<50% or multiple gated acquisition scan (MUGA) \<45%.
* Any of the following within 6 months prior to the start of the study treatments: myocardial infarction (MI), severe/unstable angina, congestive heart failure (CHF), transient ischemic attack (TIA).
17. Patients with an SaO2 ≤ 92% on room air.
• Pulmonary Function Tests may be performed during screening for patients with SaO2 ≤ 92% on room air and based on the clinical judgment of the treating physician, patients with an FEV1 ≥ 50% of predicted and DLCO (corrected) of ≥ 40% of predicted may be enrolled.
18. Has any form of primary immunodeficiency, such as severe combined immunodeficiency disease or acquired immune deficiency syndrome (AIDS).
• Patients with history of human immunodeficiency virus (HIV) infection must have undetectable HIV ribonucleic acid (RNA).
19. Known active infection with hepatitis B, hepatitis C or other viral infections requiring systemic therapy.
20. Has a QTc prolongation to \> 450 millisecond (ms) in males and \> 470 ms in females.
21. Is Pregnant or breastfeeding.
22. Received a live vaccine within 30 days prior to lymphodepletion (Day -5).
23. Any other clinically significant medical disease or condition that, in the Principal Investigator's opinion, may interfere with protocol adherence or the patient's ability to provide informed consent.
