clinical study of ebv-tcr-t cells for ebv-associated hemophagocytic lymphohistiocytosis or ebv infection

Conditions: EBV-associated Hemophagocytic Lymphohistiocytosis; EBV Infection

Summary: this is a multi-center, single arm, open-label, phase i study to determine the safety and effectiveness of ebv-tcr-t cell immunotherapy in treating ebv-associated hemophagocytic lymphohistiocytosis (ebv-hlh) or ebv infection

epstein-barr virus (ebv) is a widely disseminated herpesvirus that is spread by intimate contact between susceptible persons and asymptomatic ebv shedders. the inability to control ebv infection can lead to some patients developing ebv-positive b-cell lymphomas, chronic active ebv infections, and hemophagocytic lymphohistiocytosis (hlh). in this prospective study, hla-a\*02:01/11:01/24:02-restricted ebv-specific t cell receptor (tcr) will be introduced into the t cells of donors by ex vivo lentiviral transduction to generate ebv-tcr-t cells. an escalated dose ranging from 1×10\^6/kg to 1×10\^8/kg of ebv-tcr-t cells will be infused into patients with ebv-hlh or ebv infection. the safety, efficacy, pharmacokinetics and cytokine levels of allogenic ebv-tcr-t cell therapy will be evaluated.

Eligibility criteria:
inclusion criteria: * age 1-60 years, gender unlimited. * diagnosed with ebv associated-hemophagocytic lymphohistiocytosis (hlh) or ebv infection. * fully understood and informed the study and signed the icf. * karnofsky score ≥ 70(age ≥16y) or lansky score ≥ 50(age\<16y). * tcrt-t cell donor inclusion criteria: 1)age \>=8 years, gender unlimited; 2) understand and voluntarily sign informed consent and are willing to comply with laboratory tests and other research procedures; 3) ≥ 3/6 hla match with tcr-t cell recipients enrolled; 4) lymphocyte count = (0.8\~4) × 10\^9/l; 5) have sufficient venous circulation, without any symptoms that do not allow blood cell isolation. exclusion criteria: * patients with uncontrolled active agvhd one day before tcr-t cell infusion. * patients with severe kidney disease (cr \> 3×normal value), liver damage (tbil \>2.5×upper limit of normal value, alt and ast \> 3×upper limit of normal value) or heart failure (nyha heart function grade iv or left ventricular ejection fraction\<50%) one week before tcr-t cell infusion. * anticipated to take immunosuppressive hormones on the day of tcr-t cell infusion. * use of immunosuppressive drugs or g-csf within 2 weeks before pbmc blood collection. * have tumours, active and uncontrolled malignant diseases. * serologically positive for hiv-ab or tap-ab. * pregnant or lactating women. * men and their partners or women of childbearing potential refused contraception during the study period. * anticipated to have other cell therapies in 4 week post tcr-t cell infusion. * participated in any other clinical study of drugs and medical devices before 4 weeks of enrollment. * allergy to albumin. * tcrt-t cell donor exclusion criteria: 1) pregnant woman; 2) serologically positive for hbsag, hcv-ab, hiv-ab or tap-ab; 3) ebv-dna or cmv-dna positive; 4) other uncontrolled infection; 5) use of immunosuppressive drugs or g-csf within 2 weeks before pbmc blood collection.