Allogeneic CD6 Chimeric Antigen Receptor T Regulatory Cells (CD6-CAR Tregs) for the Treatment of Patients with Chronic Graft Versus Host Disease after Allogeneic Hematopoietic Cell Transplantation

Inclusion Criteria

• PATIENT (RECIPIENT) INCLUSION CRITERIA:
• All participants must have the ability to understand and the willingness to sign a written informed consent
• Participants must agree to allow the use of archival tissue from diagnostic biopsies. * If unavailable, exceptions may be granted with study PI approval Note: For research participants who do not speak English, a short form consent may be used with a City of Hope (COH) certified interpreter/translator to proceed with screening and leukapheresis, while the request for a translated full consent is processed
• Age >= 18 years
• Karnofsky performance status of >= 70%
• Received allogeneic hematopoietic stem cell transplantation (alloHCT) from matched unrelated or sibling/haploidentical donor as part of treatment of hematologic disorders * Of note, the first 3 subjects enrolled and treated on this study will be limited to those with matched sibling/related donors Note: The donor needs to consent for leukapheresis
• Clinical diagnosis of steroid-dependent or refractory, moderate to severe cGVHD * Steroid dependent cGVHD defined as having persistent signs and symptoms of cGVHD per institutional policy despite the use and tapering of prednisone for 2 months without complete resolution of signs and symptoms * Steroid refractory cGVHD is defined as (1) progression of GvHD while on prednisone at ≥1 mg/kg/day for 1 to 2 weeks; or (2) stable cGvHD on ≥ 0.5 mg/kg/day (or 1 mg/kg every other day) of prednisone for 1 to 2 months
• Estimated life expectancy > 90 days
• Stable dose of corticosteroids for >= 14 days prior to enrollment not exceeding 15mg/day of prednisone or equivalent with up to 4-7ng/mL sirolimus with therapeutic drug monitoring * Patients will be monitored weekly for the first 28 days of enrollment for thrombotic microangiopathies (TMA) by laboratory parameters lactate dehydrogenase (LDH), haptoglobin, nucleated red blood cell (RBC) counts and peripheral smear for schistocytes
• Failed 2 or more lines of therapy besides steroids, including at least 1 of the Food and Drug Administration (FDA) approved tyrosine kinase inhibitor (TKI) therapies for cGVHD
• Naive to anti-CD6 therapy post most recent alloHCT
• Absolute neutrophil count (ANC) >= 1,000/mm^3 (without myeloid growth factors within 1 week of study entry) (performed within 28 days prior to enrollment)
• Platelets >= 50,000/mm^3 (performed within 28 days prior to enrollment) NOTE: Platelet transfusions are not permitted within 14 days of platelet assessment
• Total bilirubin =< 2 mg/dL (exception permitted in patients with Gilbert’s syndrome), unless hepatic dysfunction is a manifestation of presumed cGVHD) (performed within 28 days prior to enrollment)
• Aspartate aminotransferase (AST) =< 3.0 x upper limit of normal (ULN) (performed within 28 days prior to enrollment)
• Alanine aminotransferase (ALT) =< 3.0 x ULN (performed within 28 days prior to enrollment)
• NOTE: Abnormal liver function tests (LFTs) (liver function panel) in the context of active cGVHD involving other organ systems may also be permitted if the treating physician documents the abnormal LFTs as being consistent with hepatic cGVHD and a liver biopsy will not be mandated in this situation
• Creatinine clearance of >= 30 mL/min per 24-hour urine test or the Cockcroft-Gault formula (performed within 28 days prior to enrollment)
• Seronegative for human immunodeficiency virus (HIV) antigen/antibody (Ag/Ab) combo, hepatitis C virus (HCV)*, active hepatitis B virus (HBV) (surface antigen negative), and syphilis (rapid plasma reagin [RPR]) (performed within 28 days prior to enrollment) * If positive, hepatitis C ribonucleic acid (RNA) quantitation must be performed OR * If seropositive for HIV, HCV or HBV, nucleic acid quantitation must be performed. Viral load must be undetectable
• Subjects must have negative QuantiFERON-tuberculosis (TB) Gold (QFTG) test (performed within 28 days prior to enrollment). Patients with positive QFTG test need clearance from infectious disease (ID) before enrollment
• Negative for coronavirus disease 2019 (COVID-19) within 72 hours of day 0 of protocol therapy (performed within 28 days prior to enrollment)
• Negative for cytomegalovirus (CMV) and HHV6 by polymerase chain reaction (PCR)-based assay (performed within 28 days prior to enrollment)
• Meets other institutional and federal requirements for infectious disease titer requirements
• Women of childbearing potential (WOCBP): negative urine or serum pregnancy test (performed within 28 days prior to enrollment) Note: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• Cardiac function (12 lead-electrocardiography [ECG]): corrected QT interval (QTc) must be =< 480 msec (performed within 28 days prior to enrollment)
• Left ventricular ejection fraction > 40% (performed within 28 days prior to enrollment)
• Not requiring supplemental oxygen or mechanical ventilation (unless requirement is caused by suspected CAR Treg expansion), oxygen saturation (and FiO2 requirements) 40% or higher on room air
• Oxygen saturation 92% or above at room air or carbon monoxide diffusing capability test (DLCO) of 80% of reference (performed within 28 days prior to enrollment) Note: The above criteria only applies to participants who are not experiencing lung GVHD bronchiolitis obliterans syndrome (BOS). For those with pulmonary cGVHD score of 0 or 1, baseline O2 saturation and DLCO must be score < 2 or oxygen saturation (SaO2) 90% and DLCO 70% of reference ranges. Reference ranges for DLCO are based on age/sex matched controls
• If pulmonary function tests (PFT) are not available, NIH symptom-based lung score shortness of breath (SOB) symptoms of 0 or 1
• NIH PFT-based lung score forced expiratory volume (FEV1) of < 1 (i.e., 60-79% or higher). Reference ranges for FEV1 are based on age/sex matched controls
• NOTE: Abnormal PFTs (i.e., > 1 lung score) in the context of active cGVHD involving other organ systems may also be permitted if the treating physician documents the abnormal PFTs as being consistent with lung cGVHD and a lung biopsy will not be mandated in this situation
• Agreement by females and males of childbearing potential* to use an effective method of birth control** or abstinence from sexual activity for the course of the study through at least 6 months after the last dose of protocol therapy. * Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only) ** Effective birth control defined as hormonal and/or barrier contraception)
• ALLOGENEIC DONOR CRITERIA FOR APHERESIS DONATION:
• CRITERIA TO PROCEED WITH LEUKAPHERESIS (DONOR): Donor has signed the leukapheresis informed consent
• CRITERIA TO PROCEED WITH LEUKAPHERESIS (DONOR): Donor must have met all eligibility criteria below
• CRITERIA TO PROCEED WITH LEUKAPHERESIS (DONOR): Donor must have appropriate venous access or be willing to undergo temporary line placement
• ADDITIONAL INCLUSION CRITERIA: The identified donor must be the original donor whose stem cells were used for the research participant’s alloSCT * Karnofsky Performance Status (KPS) >= 70 * Documented body weight * Age: >= 18 years * The donor is approved and has completed the donor evaluation per institutional guidelines (as indicated in DACT 122 – Administrative Protocol for Allogeneic Hematopoietic Progenitor Cell, Apheresis [HPC(A)] Collections). Additionally, donor will also be screened for the following infectious diseases: ** Epstein-Barr virus (EBV), ** Human herpes virus 6, 7, and 8 (HHV6, HHV7, HHV8) ** Parvovirus B19 *** Note: ID test results for EBV, HHV6, HHV7, HHV8 and Parvovirus B19 are not necessary to proceed with the apheresis procedure but do have to be resulted and negative before participant CAR Treg infusion

Exclusion Criteria

• PATIENT (RECIPIENT) EXCLUSION CRITERIA:
• Concurrent other investigational agents, including biologics
• Vaccines within 28 days prior to enrollment
• Donor lymphocyte infusion within 100 days of enrollment
• No known contraindications to steroids or tocilizumab
• Overlap syndrome
• Current active malignancy* (Exception: Basal or squamous cell carcinoma)
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
• Active uncontrolled infection requiring systemic antibiotics and/or anti-virals * Exceptions will be made for those on prophylactic or pre-emptive systemic anti-virals; however, if there is evidence of end organ damage due to viral reactivation, the infection should be clear before the subject can be eligible for screening
• Active autoimmune/inflammatory conditions requiring systemic therapy
• Clinically significant uncontrolled illness
• History of vascular disease (e.g., deep vein thrombosis, stroke)
• Unstable cardiac disease as defined by one of the following: * Cardiac events such as myocardial infarction (MI) within 6 months prior to enrollment * NYHA (New York Heart Association) heart failure class III-IV * Uncontrolled atrial fibrillation or hypertension
• Subjects with a pulmonary cGVHD score ≥ 2
• If pulmonary function tests (PFT) are not available, NIH symptom-based lung score SOB > 2
• NIH PFT-based lung score force expiratory volume (FEV1) > 1. Reference ranges are based on age/sex matched controls. Reference ranges for FEV1 are based on age/sex matched controls
• Subjects with liver cirrhosis
• Females only: Pregnant or breastfeeding
• Inability to comply with protocol therapy and follow up visits
• Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)