Multiple Sclerosis (MS) Clinical Trials

⁃ Individuals must meet all of the following criteria to be included in the trial:

• Have read, understood and signed/dated the informed consent form.

• Age ≥18 years at the time of screening.

• Diagnosis of multiple sclerosis fulfilling the 2017 McDonald criteria.

• Progressive or worsening MS according to 2014 Lublin MS phenotypic criteria

• Disease activity despite treatment:

∙ Definition for RRMS/SPMS:

∙ 1 or more relapses or an EDSS deterioration in the previous year (1 point or more if EDSS is between 3 and 5.5; 0.5 point or more if EDSS 6-6.5) or MRI activity (presence of at least 2 new/enlarging T2 lesions or T1CE lesions) despite on/previous treatment with an escalation therapy drug (i.e. natalizumab, ofatumumab, ocrelizumab, alemtuzumab or mitoxantrone) for at least 6 months.

‣ Definition for PPMS:

∙ EDSS deterioration in the previous year (1 point or more if EDSS between 3 and 5.5; 0.5 point or more if EDSS 6-6.5) or MRI activity (presence of at least 2 new/enlarging T2 lesions or T1CE lesions) despite on/previous treatment with ocrelizumab (treatment duration ≥ 6 months).

‣ Evidence of intrathecal IgG production through oligoclonal bands (OCBs) present in the cerebrospinal fluid in PPMS or SPMS.

• Fully vaccinated against Hepatitis B.

• Presence of varicella-zoster virus (VZV) antibodies, or completion of at least one dose of varicella zoster glycoprotein E Shingrix vaccine at least 4 weeks prior to treatment.

• Presence of anti EBV antibodies

• Organ function / lab parameters as follows

∙ Absolute Neutrophil count \> 2000/uL

‣ Platelets \> 150,000/uL

‣ Absolute Lymphocyte count \> 1000/uL

‣ Serum IgG \> 500 mg/dl

‣ Hemoglobin \> 9g/dl

⁃ Adequate renal, hepatic, pulmonary and cardiac function defined as

• Creatinine ,\< 2mg/dl or creatinine clearance \> to 60ml/min

∙ ALT/AST \< 3x ULN

∙ Total bilirubin \< 1,5 mg/dl, except for subjects with Gilbert syndrome.

∙ Cardiac ejection fraction \> 40%, no evidence of significant pericardial effusion (echography) or clinically significant ECG findings

∙ Baseline oxygen saturation \> 94% on air room

⁃ Negative test for Hepatitis B core antibody and Hepatitis C core antibody, CMV, VZ, Herpes simplex virus 1 and 2 ab

⁃ Negative test for Myelin-Oligodendrocyte-Glycoprotein (MOG) and Aquaporin-4 (AQP-4) autoantibodies

⁃ Women of childbearing potential (WOCBP) must be able and willing to use at least one highly effective method of contraception from the time of consent until 12 months after the administration of MB-CART2019.1. WOCBP must refrain from donating eggs during the same period. A woman is considered of childbearing potential, i.e., fertile, following menarche and until having been postmenopausal for at least 12 months or unless otherwise permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. For the definition and a list of highly effective methods of contraception, see Appendix 1 Contraception Guidelines.

⁃ Men whose sexual partners are WOCBP must be able and willing to use at least one highly effective method of contraception (used by themselves or their female partners; see Appendix 1 Contraception Guidelines) from the time of consent until 12 months after the administration of MB-CART2019.1.

⁃ Willingness and ability to comply with all trial procedures.

⁃ Adequate vital signs.