CD19-Directed Chimeric Antigen Receptor Autologous T Cells (CART19) for Lupus

This is a single-center, single-arm, open-label phase 1/2 study of CART19 in children and young adults with refractory Systemic lupus erythematosus (SLE), including both patients diagnosed with lupus nephritis (LN) and patients with non-renal Systemic lupus erythematosus (SLE).

Phase 1 will evaluate the safety of CART19 in 6-12 patients with Systemic lupus erythematosus (SLE). There is no planned dose escalation, but a dose de-escalation will be made based on the incidence of Dose Limiting Toxicities. Phase 2 will evaluate the efficacy and further evaluate the safety of CART19 in this population.

Lupus disease activity is associated with increased numbers of activated naïve B cells and polyclonal expansion of antibody secreting cells, indicating a central role for B cells in the pathogenesis of SLE. While traditional anti-CD19 antibody therapies have been utilized with varying success in the treatment of Systemic lupus erythematosus (SLE), CD19 directed cellular therapies have emerged as an attractive therapeutic option that may lead to immunosuppression-free remission in this population given the ability of CD19 directed CAR T cells to more deeply deplete the B cell compartment. Previous clinical experience utilizing CD19 directed CAR T cells in patients diagnosed with Systemic lupus erythematosus (SLE) have exceeded any other Systemic lupus erythematosus (SLE) therapeutic available; although, those clinical trials have treated a limited number of subjects. During this trial the test article will be CART19 cells transduced with a lentiviral vector to express anti-CD19 scFv:41-BB:TCRζ, administered by IV injection.

Eligibility Criteria:
Inclusion Criteria:

1. Signed informed consent form must be obtained prior to any study procedure. Labs or other procedures obtained during routine clinical care may be used for eligibility if obtained within the protocol required window.
2. Patient age must be 12-29 years, inclusive, at time of enrollment.
3. Meeting ACR/EULAR Classification Criteria for SLE
4. ANA positive \> 1:80 and/or double-stranded DNA (dsDNA) positive
5. Active (refractory) disease, despite at least three months of conventional therapy, defined as follows:

   a. Lupus nephritis subjects must meet both the following criteria: i. ISN/RPS active nephritis Class III/IV +/- V lupus nephritis diagnosed by biopsy within past 12 months.

ii. Persistent and clinically significant: ≥2 measurements with urine protein on first morning sample with either of the following:

1. \> 1000mg/g creatinine
2. \> 500 mg/g creatinine associated with renal dysfunction or low albumin.
3. \> 500 mg/g creatinine in a patient with rising proteinuria after prior complete renal response b. Non-renal SLE subjects must meet either of the following criteria: i. SLEDAI-2K ≥ 8 and clinical SLEDAI-2K ≥ 6 ii. Inability to decrease prednisone ≤7.5mg/day or 0.15mg/kg/day, whichever is lower, due to active disease.

6. Patients must have had at least 3 months conventional therapy defined as:

1. Conventional induction immunosuppressive agent(s) (mycophenolate mofetil or cyclophosphamide), and
2. At least one additional therapy:

i. B-cell directed biologic therapy (e.g., rituximab, belimumab, ofatumumab, obinutuzumab) ii. Calcineurin inhibitor (e.g., tacrolimus, cyclosporine, voclosporin) iii. Other immunosuppressive medication for SLE (e.g., anifrolumab, abatacept, JAK inhibitor, others) 7. Adequate organ function status

1. Renal: eGFR must be ≥30 and subject cannot be receiving dialysis.
2. Hepatic: Transaminases \< 5x upper limit of normal and serum conjugated (Direct) bilirubin \<1.5x upper limit of normal unless attributable to SLE. If attributable to autoimmune disease, Child-Pugh score must be class A or class B. Child-Pugh score cannot be class C.
3. Cardiac: Shortening fraction \> 28%, left ventricular ejection fraction \>45%, and no evidence of severe pulmonary hypertension
4. Pulmonary: Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and \<Grade 3 hypoxia; DLCO ≥40% (corrected for anemia and/or VA volume) if PFTs are clinically appropriate as determined by the treating investigator.

   8. Subjects of reproductive potential must agree to use acceptable birth control methods.

Exclusion Criteria:

1. Active, untreated infections
2. HIV infection
3. Active Hepatitis B

   a. Patients must have negative hepatitis B surface antigen to be enrolled on this study.
4. Hepatitis C
5. Patients with severe neuropsychiatric lupus or neurologic manifestations of SLE (e.g. stroke, seizure, psychosis, demyelinating syndromes, organic brain syndrome, or lupus related headaches)
6. Monogenic lupus (known)
7. Previous autologous or allogenic stem cell transplant
8. Previous kidney transplant
9. History of seizure disorder 'Patients who are on anti-epileptic therapy.
10. Participation in a clinical trial in which the patient receives an investigational drug within a time period equal or less than 5.5 half-lives of the investigational agent prior to study enrollment.
11. Use of concurrent immunosuppression

    1. Given the potential risks of additive immunosuppression and potentially deleterious effects of steroids, DMARDs and other biologics on the CART product, these medications are standardly discontinued prior to any cellular therapy. Subjects should be on stable doses of DMARDs for at least two weeks prior to enrollment. Subjects who are unwilling or unable to discontinue disallowed immunosuppressive medications at the times of T cell collection and CART19 infusion will be excluded from the trial.
    2. Disallowed immunosuppression includes any therapy (drugs, biologics or other treatments) clearly given for the purpose of treating the underlying autoimmune disease. This will include any FDA-approved or experimental agents not currently available but that become available during the period of the trial. Anti-malarial drugs for the treatment of SLE are permitted. The use of physiologic replacement hydrocortisone (or equivalent) or inhaled steroids is permitted.
    3. Immunosuppression for SLE treatment at times other than cell collection or at the time of infusion are permitted.
12. Any comorbidity that in the opinion of the investigators would jeopardize the ability of the subject to tolerate therapy.
13. Pregnant patients. All participants of childbearing potential must have negative pregnancy test.
14. Lactating participants who want to continue breastfeeding.
15. Patients who are unwilling to consent to LTFU