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 ≤55 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 one
   dose of the varicella zoster glycoprotein E (gE) Shingrix vaccine at least four weeks
   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 Cockcroft Gault
         Equation) ≥ 60 mL/min.

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

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

         - Cardiac ejection fraction ≥ 40%, no evidence of physiologically significant
         pericardial effusion as determined by an ECHO, and no clinically 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 2 Ab
   (antibody); HTLV-1 and HTLV-2 Ab; PCR+ or negative surface antigen for hepatitis B;
   negative for the Treponema pallidum antibody Syphilis screen; and negative for HIV-1
   and hepatitis C by nucleic acid testing (NAT) within 40 days of apheresis procedures.

   8. Females of childbearing potential have a negative serum or urine pregnancy test
   because of the potentially dangerous/unknown effects on the fetus. Females who have
   undergone hysterectomy or who have been postmenopausal for at least 2 years are not
   considered to be of childbearing potential.

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

10. Ability to understand and the willingness to sign a written informed consent document.
   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 associated
   disease (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 of
   severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are not considered
   investigational.

   3. Initiation of any DMT between the completion of apheresis and start of lymphodepletion
   (LD) chemotherapy. The use of methylprednisolone for bridging therapy 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 progressive
   neurologic 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 seconds to
   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 of
   screening. Simple urinary tract infection (UTI) and uncomplicated bacterial
   pharyngitis are permitted if responding to active treatment.

   9. Psychiatric disorder(s) or psychosocial circumstance(s) which in the opinion of the
   Stanford Transplant team caring for this potential patient would place the patient at
   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 pose unacceptable risk.
   A prior history of hepatitis B or hepatitis C is permitted providing the viral load is
   undetectable per quantitative PCR and/or nucleic acid testing. Hepatitis B surface
   antibody following hepatitis B immunization is not considered 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 the investigator
   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 heart failure)
   within 4 months of enrollment. Subjects with stable cardiac disease fulfilling
   inclusion criteria are allowed.

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

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

17. A primary immune deficiency disease

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

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

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

21. Prior treatment with total lymphoid irradiation or mitoxantrone exceeding 36 mg/m2
   cumulative dose

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

23. Prior treatment with anti-CD20+ monoclonal antibody therapy within 9 months of trial
   initiation. A 30-day washout will be required for prior treatment with glatiramer
   acetate, interferon-beta, and fumarates. A 60-day washout will be required for
   sphingosine-i-phosphate modulators and natalizumab. Excluded will be patients who
   received 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, ventricular
      tachycardia), 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 of apheresis).

      - 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 pulmonary
   disease (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.