Phase I/II Study of AD-PluReceptor Plus Tafasitamab-cxix and Lymphodepleting Chemotherapy in Patients With Autoimmune Disorders

The goal of Safety Lead-In is to confirm the safety of tafasitamab when given to patients with SSc, SLE, and LN.

The goal of Phase 1 is to find the recommended dose of AD-PluReceptor-NK cells in combination with tafasitamab and lymphodepleting chemotherapy that can be given to patients with the disease.

The goal of Phase 2 is to learn if the dose of AD-PluReceptor-NK cells found in Phase 1 in combination with tafasitamab and lymphodepleting chemotherapy can help to control the disease.

Primary Objectives:

To determine the safety, tolerability and optimal cell dose of AD-PluReceptor plus Tafasitamab cxix and lymphodepleting chemotherapy in patients with systemic sclerosis and systemic lupus erythematosus (including lupus nephritis).

Secondary Objectives:

To assess the overall response rate.

To evaluate the persistence and kinetics of infused allogeneic donor AD-PluReceptor cells in the recipient.

To conduct comprehensive immune reconstitution studies.

To evaluate the number of patients not requiring any systemic immunosuppressive therapy for their autoimmune disease at 1 year post infusion.

Eligibility Criteria:
Inclusion Criteria:

Systemic Sclerosis Specific Inclusion Criteria

A. Diagnosis of SSc defined as follows:

i) Fulfilling 2013 American College of Rheumatology (ACR)and European League Against Rheumatism classification (EULAR) criteria for SSc.46 ii) Antinuclear Antibody (ANA) by immunofluorescence positive at titer ≥ 1:80 at screening or prior to screening.

B. SSc disease activity i) Diffuse SSc meeting the following criteria:

(1) Disease duration ≤ 5 years (from onset of first non-Raynaud manifestation) AND (2) mRSS ≥ 15 at screening (Appendix 1) ii) Participants diagnosed with diffuse or limited cutaneous SSc AND progressive ILD on HRCT and ≤ 5 years duration (from onset of first non-Raynaud manifestation) defined by either (1) or (2)

1. Progressive ILD as defined by Raghu et al47 (≥ 2 of the following):

   1. worsening respiratory symptoms
   2. physiological evidence of disease progression (≥ 1 of the following):

   (i) Absolute decline in FVC ≥ 5% predicted within 1 year of follow-up (ii) Absolute decline in DLCO (corrected for Hb) ≥ 10% predicted within 1 year of follow-up radiological evidence of disease progression (iii) Increased extent or severity of traction bronchiectasis and bronchiolectasis.

   (iv) New ground-glass opacity with traction bronchiectasis (v) New fine reticulation (vi) Increased extent or increased coarseness of reticular abnormality. (vii) New or increased honeycombing (viii) Increased lobar volume loss
2. FVC \< 80% predicted and moderate to severe ILD, as assessed by a radiologist. C. Inadequate response to at least 2 of the following treatments used for at least 3 months: mycophenolate, cyclophosphamide, rituximab, and/or tocilizumab.

SLE Specific Inclusion Criteria

1. A clinical diagnosis of SLE, based on the 2019 EULAR/ ACR classification criteria for adult SLE.
2. Positive ANA titer ≥1:80 or positive anti-dsDNA antibody at screening.
3. For LN subjects only: Active, biopsy-proven lupus nephritis (kidney biopsy should have been done within 6 months of study enrollment) class III or IV, with or without the presence of Class V, using the 2018 Revised International Society of Nephrology/Renal Pathology Society criteria48.
4. Diagnosed with active SLE. Subjects with either LN or without LN will be eligible if they meet the following criteria:

   1. For LN subjects: urine protein-to-creatinine ratio (UPCR) ≥1 mg/mg on 2 first morning void urine samples during screening despite prior or current treatment with standard of care therapy for at least 12 weeks, including corticosteroids, MMF/mycophenolic acid (MPA), CY, calcineurin inhibitors, belimumab, and/or rituximab. Patients should have failed at least 2 standard of care immunosuppressive therapies tried for 3 months,
   2. For non-renal SLE subjects: SLEDAI-2K ≥8 and clinical SLEDAI-2K ≥6 (excluding headache, alopecia, mucosal ulcers, fever, and organic brain syndrome) during screening despite prior or current treatment with standard of care therapy, including corticosteroids, rituximab or other B cell depleting agents, CY, MMF/MPA, azathioprine, methotrexate, 6-mercaptopurine, sirolimus, tacrolimus, thalidomide, leflunomide, mizorbine, anifrolumab, and/or belimumab. Patients should have failed at least 2 standard of care immunosuppressive therapies tired for 3 months.
5. If a subject is currently receiving:

   1. Standard immunosuppressive therapy (including MMF/MPA, CY, azathioprine, antimalarial therapy, methotrexate, 6-mercaptopurine, sirolimus, tacrolimus, thalidomide, leflunomide, or mizorbine), the therapy must have been initiated at least 12 weeks prior to screening and on a stable dose for at least 8 weeks prior to screening, except for dose reduction due to safety or tolerability.
   2. A renin-angiotensin-aldosterone inhibitor, (including direct renin inhibitors, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and mineralocorticoid receptor blockers), the subject must be on a stable dose for at least 8 weeks prior to screening.A sodium-glucose cotransporter-2 (SGLT2) inhibitor, the subject must be on a stable dose for at least 8 weeks prior to screening.
   3. Regarding oral corticosteroid, doses \<0.5 mg/kg prednisone equivalent at the time of infusion are required.
6. Adequate renal function, defined as:

   1. For LN subjects: Estimated glomerular filtration rate of ≥45 mL/min/1.73m2 using the chronic kidney disease-epidemiology equation.
   2. For non-renal SLE subjects: Estimated glomerular filtration rate of ≥60 mL/min/1.73m2 using the chronic kidney disease-epidemiology equation

Exclusion Criteria SSc specific exclusion criteria

1. SSc related pulmonary arterial hypertension (PAH) requiring active treatment.
2. Rapidly progressive SSc related lower GI (small and large intestines) involvement (requiring parenteral nutrition); active gastric antral vascular ectasia.
3. Prior scleroderma renal crisis.
4. Uncontrolled or rapidly progressive ILD (FVC \< 50; DLCO \< 50%); oxygen saturation (SaO2) \< 92% (room air at rest); or who have required mechanical breathing assistance (ventilator) within 1 year of signing informed consent.

SLE specific Exclusion Criteria

Subjects are excluded from the study if any of the following criteria apply:

1. Treatment with rituximab or other B cell-depleting agent within 26 weeks prior to screening, or within 12 weeks if there are laboratory results indicating presence of CD19+ B cells.
2. Treatment with voclosporin or other calcineurin inhibitor within 8 weeks prior to screening.
3. Treatment with anifrolumab, belimumab, or other biologic agent within 12 weeks prior to screening.
4. For LN subjects only: Evidence of severe chronicity on kidney biopsy, defined as a modified National Institute of Health chronicity index score of 3+ for any of the following individual biopsy features: total glomerulosclerosis score, fibrous crescents, tubular atrophy, or interstitial fibrosis.
5. A diagnosis of antiphospholipid antibody syndrome by the 2006 Revised Sapporo International Consensus Criteria at the time of screening49
6. The presence of biopsy-proven kidney disease other than active lupus nephritis
7. Moderate-to-severe chronic pulmonary disease, including asthma requiring or refractory to medium or high-dose inhaled corticosteroids combined with other longer-acting medications, In subjects who have had pulmonary function tests: Spirometry results of forced expiratory volume (FEV1)/forced vital capacity \<0.7 and FEV1 \<80% predicted after bronchodilators, or diffusing capacity of the lungs for carbon monoxide results \<60% predicted.
8. Active, severe cardiac manifestations of SLE, including constrictive pericarditis, hemodynamically significant pericardial effusions, and myocarditis at the time of screening.

Inclusion Criteria: For both SLE and SSc

1. Able to provide informed consent.
2. Age ≥18 to ≤65 years.
3. All subjects should be up to date on age-appropriate recommended vaccinations, including against COVID-19/SARS-CoV-2, as per Centers for Disease Control and Prevention (CDC) or institutional guidelines for immune-compromised individuals Vaccination requirement. .
4. Adequate organ function i) Peripheral blood absolute neutrophil count (ANC) ≥ 1 × 109/L, unless the neutropenia is deemed to be caused by the underlying autoimmune disease.

   iii) Hemoglobin ≥ 8 g/dl , unless the anemia is deemed to be caused by the underlying autoimmune disease.

   iv) Platelet count ≥ 50 × 109/L without platelet transfusion support, unless the thrombocytopenia is deemed to be caused by the underlying autoimmune disease. No clinically significant active bleeding.

   vi) Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) ≤ 1.5 × upper limit of normal (ULN) and total bilirubin \< 1.5 × ULN (or direct bilirubin \< 1.5× ULN with documented Gilbert's syndrome).

   viii) Oxygen saturation (SaO2) ≥ 92% on room air. ix) Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) ≥ 45% as assessed by echocardiogram (ECHO) or multigated acquisition (MUGA) scan.
5. Recovery to ≤ Grade 1 or baseline of any non-hematological toxicities due to prior therapy.
6. Negative pregnancy test in WOCBP.
7. All participants who are able to have children must practice effective birth control while on study and up to 3 months post completion of therapy. Acceptable forms of birth control for female patients include hormonal birth control, intrauterine device, diaphragm with spermicide, condom with spermicide, or abstinence, for the length of the study. If the participant is a female and becomes pregnant or suspects pregnancy, she must immediately notify her doctor. If the participant becomes pregnant during this study, she will be taken off this study. Men who are able to have children must use effective birth control while on the study. If the male participant fathers a child or suspects that he has fathered a child while on the study, he must immediately notify his doctor. Participant is willing and able to adhere to the study visit schedule and other protocol requirements and willing to sign informed consent.

Exclusion Criteria for both SLE and SSc

Subjects are excluded from the study if any of the following medical conditions apply:

1. Other systemic autoimmune diseases (e.g., multiple sclerosis, psoriasis, inflammatory bowel disease, etc.) are excluded. Participants with type I autoimmune diabetes mellitus, thyroid autoimmune disease, Celiac disease, or secondary Sjögren's syndrome are not excluded.
2. Uncontrolled medical, psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol, as judged by the Investigator; or unwillingness or inability to follow the procedures required in the protocol.
3. Active, clinically significant central nervous system pathology
4. Prior history of malignancies or lymphoproliferative disease, following are allowed: Basal or squamous cell carcinoma of the skin, Carcinoma in situ of the cervix or breast. History of malignancy that has been treated with a curative intent and is in remission \> 2 years may be allowed after discussion with PI.
5. Active hepatitis B, active hepatitis C, active syphilis, any human immunodeficiency virus (HIV), human lymphocytic T-cell virus type 1 and/or type 2 (HTLV-1 and/or HTLV-2
6. Uncontrolled or active systemic fungal, bacterial, viral, or other infection despite appropriate anti-infective treatment at screening or within 72 hours before LD chemotherapy, or 5 days before AD-PluReceptor administration.
7. History of any one of the following cardiovascular conditions within the 6 months prior to screening: Class III or IV heart failure as defined by the New York Heart Association, myocardial infarction, unstable angina, or other clinically significant cardiac disease.
8. Prior CAR T cell therapy, genetically modified T cell therapy, concurrent immunosuppressive drugs, e.g., mycophenolate mofetil, systemic steroids, tocilizumab. Immunosuppressive medications are allowed if not being used for management of SLE, LN or SSc.
9. History of anaphylactic or severe systemic reaction to FLU, CY, or any of their metabolites.
10. Active infection requiring medical intervention at screening.
11. Current symptoms of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal (on TPN), pulmonary, psychiatric, cardiac, neurological, or cerebral disease, including severe and uncontrolled infections, such as sepsis and opportunistic infections.
12. Concomitant medical conditions that, in the opinion of the investigator, might place the subject at unacceptable risk for participation in this study, interfere with the assessment of the effects or safety of the investigational product or with the study procedures.
13. Autoimmune disorder other than SLE or SSc requiring immunosuppressive therapies