A Study of Anti-CD19 Chimeric Antigen Receptor T-Cell ( CAR-T) Therapy in Subjects with Non-relapsing and Progressive Forms of Multiple Sclerosis

Inclusion Criteria:

1. Patient is ≥ 18 years old, and ≤65 years of age, at time of screening visit.

2. Diagnosis of MS according to the 2017 McDonald Criteria.

3. Progressive MS by 2014 Lublin MS phenotypic criteria.

4. Presence of varicella-zoster virus (VZV) antibodies, or completion of at least onedose of the varicella zoster glycoprotein E (gE) Shingrix vaccine at least fourweeks prior to treatment.

5. Presence of anti EBV antibodies.

6. Organ and Marrow Function

• Absolute neutrophil count (ANC) ≥ 2000/uL.

• Platelet count ≥ 150,000/uL.

• Absolute lymphocyte count ≥ 1000/uL.

• Serum immunoglobulin G (IgG) ≥ 500mg/dL.

• Hemoglobin ≥ 9 g/dL.

• Adequate renal, hepatic, pulmonary and cardiac function defined as:

• Creatinine ≤ 2mg/dL or creatinine clearance (as estimated by CockcroftGault Equation) ≥ 60 mL/min.

• Serum alanine transaminase (ALT)/aspartate aminotransferase (AST) ≤ 3upper limit of normal (ULN).

• Total bilirubin ≤ 1.5 mg/dl, except in subjects with Gilbert's syndrome

• Cardiac ejection fraction ≥ 40%, no evidence of physiologicallysignificant pericardial effusion as determined by an ECHO, and noclinically significant ECG findings.

• Baseline oxygen saturation > 94% on room air.

7. Testing for

• Hepatitis B core antibody (HBc Ab)

• Hepatitis C antibody (HCV Ab)

• Hepatitis B surface antigen (Hep B surf. AG)

• HIV 1&2 Ab

• Syphilis Screen

• Human T-cell lymphotropic virus (HTLV) Ab I & II

• Nucleic acid test multiplex (NAT MPX) for HIV, HCV, HBV

• Herpes Simplex Virus 1 & 2 IgG panel

• Varicella-Zoster (VZ) IgG

• Cytomegalovirus (CMV) Total Ab Must be seronegative for HIV-1 RNA polymerase chain reaction (PCR); HIV 1 and HIV 2Ab (antibody); HTLV-1 and HTLV-2 Ab; PCR+ or negative surface antigen for hepatitisB; negative for the Treponema pallidum antibody Syphilis screen; and negative forHIV-1 and hepatitis C by nucleic acid testing (NAT) within 40 days of apheresisprocedures.

8. Females of childbearing potential have a negative serum or urine pregnancy testbecause of the potentially dangerous/unknown effects on the fetus. Females who haveundergone hysterectomy or who have been postmenopausal for at least 2 years are notconsidered to be of childbearing potential.

9. Contraception: Subjects of child-bearing or child-fathering potential must bewilling to practice highly effective birth control from the time of enrollment onthis study and for the entire study period which is 12 months after receiving theCAR T cell infusion.

10. Ability to understand and the willingness to sign a written informed consentdocument. Patients must have signed informed consent to participate in the trial.

11. Adequate vital sign criterion with acceptable numerical ranges of:

• Systolic Blood Pressure (mmHg) ≥ 100 and ≤ 150

• Diastolic Blood pressure (mmHg) ≥ 60 and ≤ 90

• To ensure subject safety and stability, any subject who is noted to have a BP > 150/90 mm Hg should be stable on anti-hypertensive medications with repeated BP ≤150/90 for at least one month prior to enrollment in the study

• Heart Rate ≥ 60 and ≤ 100 bpm

• Oral Temperature ≤ 37.7 C/afebrile

• Respiratory rate ≥ 12 and ≤ 20bpm

Exclusion Criteria:

1. History of neuromyelitis optica spectrum disorder (NMOSD) or MOG antibody associateddisease (MOGAD).

2. Prior treatment with any investigational agent within 3 months, or 5 half-lives,whichever is longer. Agents authorized by the FDA for prevention or treatment ofsevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are not consideredinvestigational.

3. Initiation of any DMT between the completion of apheresis and start oflymphodepletion (LD) chemotherapy. The use of methylprednisolone for bridgingtherapy between apheresis and start of LD chemotherapy will be allowed.

4. History of CNS or spinal cord tumor, metabolic or infectious cause of myelopathy,genetically inherited progressive CNS disorder, sarcoidosis or non-MS progressiveneurologic condition affecting ability to perform study assessments.

5. History of cytopenia consistent with the diagnosis of myelodysplastic syndrome (MDS).

6. History of sickle cell anemia or other hemoglobinopathy.

7. Coagulation abnormalities defined by: international normalized ratio (INR) > 1.5,prothrombin time (PT) > 14 seconds, partial thromboplastin time (PTT) > 45 secondsto the exclusion criteria. Patients with positive antiphospholipid antibodies,including anti-cardiolipin, or lupus anticoagulant.

8. Presence of fungal, bacterial, viral, or other infection that is not controlled and/or requiring hospitalization or treatment with IV antimicrobials within 4 weeks ofscreening. Simple urinary tract infection (UTI) and uncomplicated bacterialpharyngitis are permitted if responding to active treatment.

9. Psychiatric disorder(s) or psychosocial circumstance(s) which in the opinion of theStanford Transplant team caring for this potential patient would place the patientat an unacceptable risk.

10. Presence or history of liver cirrhosis.

11. History of malignancy other than non-melanoma skin cancer or carcinoma in situ (e.g.cervix, bladder, breast) unless disease free for at least 3 years

12. Active infection with HIV, hepatitis B (HBsAg positive) or hepatitis C virus (anti-HCV positive) as the immunosuppression contained in this study may poseunacceptable risk. A prior history of hepatitis B or hepatitis C is permittedproviding the viral load is undetectable per quantitative PCR and/or nucleic acidtesting. Hepatitis B surface antibody following hepatitis B immunization is notconsidered to be evidence of past infection.

13. Central nervous system (CNS) disorder such as cerebrovascular ischemia/hemorrhage,dementia, cerebellar disease unrelated to MS that in the judgment of theinvestigator may impair the ability to evaluate neurotoxicity.

14. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina,or other clinically significant cardiac disease (uncontrolled congestive heartfailure) within 4 months of enrollment. Subjects with stable cardiac diseasefulfilling inclusion criteria are allowed.

15. Subjects receiving anticoagulation therapy or subjects with concomitant use ofantiplatelet agents.

16. History of Crohn's, rheumatoid arthritis, systemic lupus that required continuedsystemic immunosuppression/systemic disease modifying agents within the 2 yearsprior to trial enrollment.

17. A primary immune deficiency disease

18. In the investigator's judgment, the subject is unlikely to completeprotocol-required study visits or procedures, including follow-up visits, or complywith the study requirements for participation.

19. History of severe immediate hypersensitivity reaction to any of the agents used inthis study. This includes contraindications or life-threatening allergies,hypersensitivity, or intolerance to KYV-101 or its excipients, including dimethylsulfoxide; Bendamustine; or tocilizumab.

20. Any medical condition that in the judgement of the investigator is likely tointerfere with assessment of safety or efficacy of study treatment.

21. Prior treatment with total lymphoid irradiation or mitoxantrone exceeding 36 mg/m2cumulative dose

22. Prior treatment with autologous hematopoietic stem cell transplantation, or priorhistory of cellular immunotherapy (eg. CAR T) or gene therapy directed at anytarget.

23. Prior treatment with anti-CD20+ monoclonal antibody therapy within 9 months of trialinitiation. A 30-day washout will be required for prior treatment with glatirameracetate, interferon-beta, and fumarates. A 60-day washout will be required forsphingosine-i-phosphate modulators and natalizumab. Excluded will be patients whoreceived prior treatment with mitoxantrone regardless of prior cumulative dose.

24. Prior history of solid organ transplantation

25. Impaired cardiac function or clinically significant cardiac disease including:

• a. Unstable angina or myocardial infarction or coronary artery bypass graft (CABG) within 6 months prior to apheresis.

• b. New York Heart Association (NYHA) stage III or IV congestive heart failure.

• c. History of clinically significant cardiac arrhythmia (eg, ventriculartachycardia), complete left bundle branch block, high-grade atrioventricular (AV) block.

• d. History of severe nonischemic cardiomyopathy.

• e. Left ventricular ejection fraction (LVEF) <45% as assessed by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan (performed ≤8 weeks ofapheresis).

• f. Active, current cardiac manifestations of systemic lupus erythematosus (SLE)including pericarditis, pericardial effusion, and myocarditis.

26. Prior history of splenectomy

27. History of moderate or worse than moderate asthma or chronic obstructive pulmonarydisease (COPD)

28. Corrected QT interval (QTc) >450msec in males or >470msecs in females

29. Subjects with valvular heart disease (regurgitation, stenosis or atresia

30. Moderate or worse renal impairment using criteria

• Stage 1: Kidney damage with normal or increased GFR (>90 mL/min/1.73 m^2).

• Stage 2: Mild reduction in GFR (60-89 mL/min/1.73 m^2).

• Stage 3a: Moderate reduction in GFR (45-59 mL/min/1.73 m^2).

• Stage 3b: Moderate reduction in GFR (30-44 mL/min/1.73 m^2).

• Stage 4: Severe reduction in GFR (15-29 mL/min/1.73 m^2).

• Stage 5: Kidney failure (GFR < 15 mL/min/1.73 m^2 or dialysis)

31. Previously received Mavenclad, yet drug washout is ≤9 months.

32. History of a seizure disorder even if the seizure disorder is well controlled withanti-epileptics

33. Prior history of treatment with cellular immunotherapy (e.g. CAR T) gene therapyproduct directed as any target.