Donor Immune Cells in Combination with Low-Dose Aldesleukin for the Treatment of Steroid-Refractory Chronic Graft Versus Host Disease

Inclusion Criteria

• Recipients of 7-8/8 human leukocyte antigen (HLA)-matched (HLA-A, -B, -C, -DRB1) allogeneic hematopoietic stem cell transplantation or recipients of haploidentical allogeneic hematopoietic stem cell transplantation
• Age >= 2 years, including pediatric and adult participants. In our institutional experience and according to published reports, the incidence of cGVHD in children aged less than 2 years is rare. Daily SC injections of low-dose IL-2 were well-tolerated in our previous study (Dana-Farber Cancer Institute [DFCI] 14-452; NCT02318082) in patients as young as 2 years old with no upper age limit. Low-dose IL-2 is now prescribed as part of standard-of-care for both pediatric and adult patients with cGVHD
• Participants must have steroid-refractory cGVHD that is still active despite at least 4 weeks of treatment with low-dose subcutaneous (SC) aldesleukin. Low-dose is defined as 1 x 10^6 IU/m^2 based on previous dose escalation trial * Steroid-refractory cGVHD is defined as having persistent signs and symptoms of cGVHD despite the use of prednisone at >= 0.25 mg/kg/day (or 0.5 mg/kg every other day) for at least 4 weeks (or equivalent dosing of alternate glucocorticoids) without complete resolution of signs and symptoms. Participants with either moderate or severe chronic GVHD requiring systemic therapy are eligible * Participants must demonstrate tolerance of SC low-dose aldesleukin after at least 4 weeks of treatment
• Stable dose of glucocorticoids for 2 weeks prior to enrollment
• No addition or subtraction of other immunosuppressive medications (e.g. mycophenolate mofetil, ruxolitinib) for 4 weeks prior to enrollment. The dose of immunosuppressive medications may be adjusted based on the therapeutic range of that drug
• Total bilirubin =< 2.0 mg/dl - exception permitted in participants with Gilbert's Syndrome (within 30 days of eligibility review) * For participants with abnormal liver function tests (LFTs) as the sole manifestation of cGVHD, documented GVHD on liver biopsy will be required prior to enrollment. Abnormal LFTs 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
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2 x institutional upper limit of normal (ULN), unless hepatic dysfunction is presumed to be a manifestation of cGVHD (within 30 days of eligibility review) * For participants with abnormal LFTs as the sole manifestation of cGVHD, documented GVHD on liver biopsy will be required prior to enrollment. Abnormal LFTs 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
• Forced expiratory volume in 1 second (FEV1) >= 50% or hemoglobin corrected diffusion capacity of the lung for carbon monoxide (DLCO[Hb]) >= 40% of predicted unless pulmonary dysfunction is deemed to be due to chronic GVHD (within 30 days of eligibility review)
• Creatinine clearance >= 60 mL/min/1.73 m^2 (within 30 days of eligibility review)
• Absolute neutrophil count (ANC) >= 1000/mcL (within 30 days of eligibility review)
• Platelets >= 50,000/mcL without growth factors or transfusions (within 30 days of eligibility review)
• No myocardial infarction within 6 months prior to enrollment or New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any electrocardiogram (ECG) abnormality at screening must be documented by the investigator as not medically relevant (within 30 days of eligibility review)
• Ability to understand and the willingness to sign a written informed consent document
• Hematopoietic cell transplantation (HCT) donor who is willing and cleared to donate starting material for manufacture of EVE-Treg

Exclusion Criteria

• Recipient of umbilical cord blood stem cell graft, as no ability to generate donor-derived EVE-Treg
• Ongoing prednisone requirement > 1 mg/kg/day (or equivalent), as this may impact the efficacy of the EVE-Treg product
• Karnofsky/Lansky < 40%, patients who are moribund, or in the assessment of the investigator, have other medical conditions making them unlikely to survive the three-month treatment period
• Concurrent use of methotrexate, azathioprine, or a calcineurin-inhibitor plus sirolimus (either calcineurin-inhibitor or sirolimus alone is acceptable), as these may impact the efficacy of the EVE-Treg product
• Other investigational agents within 4 weeks prior to enrollment, as these may impact interpretation of the study
• Participant with post-transplant exposure to donor lymphocyte infusion (DLI), or T-cell or IL-2 targeted medications (anti-thymocyte globulin [ATG], alemtuzumab, basiliximab, denileukin diftitox) within 100 days prior to enrollment as this may impact interpretation and safety of the study
• Participants with new immunosuppressive medication, extra-corporeal photopheresis, or rituximab therapy initiated in the 4 weeks prior to enrollment, as these may impact interpretation of the study
• Participants with active malignant relapse or recrudescence of their prior hematologic disorder, since this product is not aimed towards improving a primary disease but rather cGVHD
• Uncontrolled intercurrent illness unrelated to cGvHD, in the opinion of the investigator
• Participants with psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant patients are excluded from this study because IL-2 is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with IL-2, breastfeeding should be discontinued if the mother is treated with IL-2. Should a subject or their partner become pregnant or suspect they are pregnant while the subject is participating in this study, the treating physician should be informed immediately. All subjects treated or enrolled on this protocol with the potential to become pregnant or make a partner pregnant must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of IL-2 administration