Current treatments for relapsed/refractory hematopoietic malignancies such as B-cell lymphomas (BCLs) and peripheral T-cell lymphomas (PTCLs) are far from satisfactory. CD5 is widely expressed in multiple subtypes of BCLs and PTCLs but rarely found in normal tissues except certain types of lymphocytes. Chimeric antigen receptor (CAR) T cells against CD5 offer another potential therapeutic option for patients with relapsed/refractory CD5 positive hematopoietic malignancies. In the current study, the safety and efficacy of a novel CAR T cell therapy, termed CT125A cells, are evaluated in patients with relapsed/refractory CD5+ hematopoietic malignancies. The endogenous CD5 in CT125A cells is knocked out via CRISPR/Cas9 genome editing technology to prevent fratricide during CAR T cells manufacturing.

Inclusion Criteria:

1.Subjects with CD5 positive B-cell lymphomas must meet the diagnostic criteria from National Comprehensive Cancer Network (NCCN) guidelines for B-Cell Lymphomas (2020.V1) and have CD5 expression on lymphoma cells (results within 60 days before informed consent signing are acceptable if current clinical condition is not suitable for sampling, and the investigator will judge whether the test results from other hospitals are acceptable and whether they can be enrolled); according to Lugano 2014 criteria, patients with B-cell lymphomas have at least one measurable lesion with the longest diameter ≥ 1.5 cm or bone marrow involvement detected by flow cytometry .

Including:

1. Chronic lymphocytic leukemia/small lymphocytic lymphoma: any BTK inhibitor have been given for at least 6 months and the treatment has failed (SD or PD).
2. Mantle cell lymphoma (MCL): patients with MCL must have relapsed/refractory diseases after receiving at least one treatment regimen. Previous treatment must include chemotherapy with anthracyclines or bendamustine, anti-CD20 monoclonal antibody, and any BTK Inhibitor therapy.
3. Diffuse large B-cell lymphoma: patients with diffuse large B-cell lymphoma who have failed or relapsed after at least two lines of therapy (a standard chemotherapy and a rescue chemotherapy); and meet one of the following conditions: a. unable to receive autologous hematopoietic stem cell transplantation (autoHSCT); b. refuse to receive autoHSCT; c. relapse after autoHSCT.

2.Subjects with CD5 positive peripheral T-cell lymphomas (PTCLs) are diagnosed according to criteria from World Health Organization classification for tumors of the hematopoietic and lymphoid tissues (2016 Edition) and have CD5 expression on lymphoma cells (results within 60 days before informed consent signing are acceptable if current clinical condition is not suitable for sampling, and the investigator will judge whether the test results from other hospitals are acceptable and whether they can be enrolled); according to Lugano 2014 criteria, patients with T-cell lymphomas must have at least one measurable lesion with the longest diameter ≥ 1.5 cm and no bone marrow involvement confirmed by flow cytometry and gene rearrangement (TCR/IGH) tests (and PET-CT results, if any, that must indicate no increased bone marrow metabolism); patients must fail or relapse after at least one line of therapy; including but not limited to the following PTCLs:

1. Peripheral T cell lymphoma - not otherwise specified (PTCL-NOS)
2. Angioimmunoblastic lymphoma
3. ALK negative anaplastic large cell lymphoma
4. Extranodal NK/T cell lymphoma
5. Enteropathy-associated T-cell lymphoma
6. Large granular T lymphocyte leukemia
7. Adult T cell leukemia

3.Age ≥18 and ≤70 years old, regardless of gender.

4.Expected life expectancy ≥12 weeks.

5.Serum total bilirubin ≤ 37.2 μmol/L (Gilbert syndrome patients ≤ 3.0 ULN, direct bilirubin ≤ 1.5 ULN), estimated glomerular filtration rate eGFR (CKD-EPI) ≥ 30 ml/min/1.73m2, alanine aminotransferase and aspartate aminotransferase less than 2.5 times the upper limit of normal range.

6.ECOG score 0-1 points.

7.Echocardiography suggests left ventricular ejection fraction (LVEF) ≥50%; blood oxygen saturation >91%.

8.After signing the informed consent form, subjects and their partners must be willing to use effective and reliable method of contraception, devices or medicines, within one year after CAR T cell infusion (excluding contraception safety periods). A negative pregnancy test must be obtained for female subjects.

Subjects must provide written informed consent before the study begin.

Exclusion Criteria:

Subjects who meet any of the following criteria will be excluded:

1. History of allergies to any of the ingredients in cell products.
2. Patients with acute GVHD judged to be grade II-Ⅳ by Glucksberg criteria or grade B-D by IBMTR index; acute or chronic GVHD patients who need systemic treatment within four weeks before enrollment.
3. Injected with live vaccines within 4 weeks before enrollment.
4. Central nervous system diseases not associated with lymphoma CNS invasion (such as cerebral aneurysm, epilepsy, stroke, senile dementia, psychosis, etc.). Lymphoma CNS invasion or digestive tract invasion is not considered as an exclusion criterion, but whether to be enrolled in the group is determined by the investigator.
5. Severe active infection (except simple urinary tract infection and bacterial pharyngitis), or currently receiving intravenous antibiotic treatment. However, preventive antibiotics, antiviral and antifungal infection treatments are permitted.
6. Hepatitis B surface antigen (HBsAg) positive or hepatitis B core antibody (HBcAb) positive and peripheral blood hepatitis B virus (HBV) DNA > 100 IU/mL.
7. Hepatitis C virus (HCV) antibody positive and peripheral blood hepatitis C virus (HCV) RNA positive.
8. Subjects with other acquired and congenital immunodeficiency diseases, including but not limited to human immunodeficiency virus (HIV) antibody positive; subjects with cytomegalovirus (CMV) DNA > 400 copy/mL; subjects with syphilis test positive.
9. Cardiac insufficiency of grade III or IV according to the New York Heart Association (NYHA) cardiac function classification criteria.
10. History of other primary cancers, except for the following conditions:

1)Non-melanoma skin cancer with complete resection, such as basal cell carcinoma; 2)Cured carcinoma in situ such as cervical cancer, bladder cancer or breast cancer; 3)No recurrence of other primary cancers has been found for more than 5 years after treatment.

11.History of solid organ transplantation.

12.Subjects with previous autoimmune diseases (mainly abnormality of cellular immunity), immunodeficiency or subjects requiring immunosuppressive therapy.

13.Received other interventional clinical trial treatment within 3 months before signing ICF.

14.Pregnant or lactating women.

15.Suffer from mental illness or disturbance of consciousness or central nervous system disease.

16.The toxicity of previous treatment has not been relieved to baseline or ≤2 (NCI-CTCAE v5.0, except for hair loss).

17.Drug use:

1. Steroid drugs: therapeutic dose of steroids used within 72 hours before CAR-T cell infusion, but physiological doses of steroid supplementation are allowed (<12mg/m2/day of hydrocortisone or its equivalent dose);
2. Systemic anti-tumor therapy is not ended at least 2 weeks or 5 drug half-lives before apheresis (except for BTK inhibitors in CLL); interval between apheresis and immune checkpoint inhibitor treatment is less than 3 drug half-lives.

18.Active lung infection.

19.Contraindications for peripheral blood apheresis.

20. Subjects considered unsuitable for enrollment by the investigator for other reasons after careful consideration.

Individual deidentified participant data that underlie the results published will be shared in the publication. Data will be available upon request and after the approval of data request proposal.