CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

1. Subjects with CD19+ B-cell lymphoma or B-Cell Acute Lymphoblastic Leukemia (B-ALL) with no currently available curative treatment option (such as autologous or allogeneic Hematopoietic stem cell transplantation (HSCT)) who have a limited prognosis (\<2-year projected survival) will be enrolled. Participation on this trial is permitted as a bridge to HSCT.
2. Peripheral blood CD3 count \> 200/µL by flow cytometry. Please note that this test might need to be repeated multiple times as standard practice to optimize collection efficiency.
3. Subjects will have a diagnosis of Diffuse Large B Cell Lymphoma (DLBCL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL), CLL, Marginal Zone Lymphoma (MZL), Lymphoplasmacytic Lymphoma (LPL) or B-ALL and will have failed at least 2 lines of therapy in the case of lymphoma and one line if the diagnosis is B-ALL or be refractory (no response or progressive disease) to first line therapy. A line of therapy must include conventional (immuno) chemotherapy (e.g. rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP) or Bendamustine plus Rituximab (BR) in the case of lymphoma) administered for at least 2 cycles. Second or greater lines of therapy must be administered for at least two cycles. Single agent anti-CD20 monoclonal antibody (e.g. rituximab, obinutuzumab) is not considered for the purposes of these criteria to count as a line of therapy. The definition of a line of therapy is taken according to recommended regimens for first and second line therapy in the relevant sections of the National Comprehensive Cancer Network (NCCN) guidelines. The most recent version of the guidelines will be used for eligibility determination. In the unlikely event that a subject received a first or second line regimen no longer listed in the most recent guidelines, but previously present in the version of the guidelines active at the time the therapy was administered, then the subject would be deemed to have received a line of therapy.
4. Subjects with pathological and clinical evidence of transformed indolent lymphoma (FL, CLL, MZL or LPL) are eligible for participation on this trial if they have received at least one line of therapy for transformed disease for at least two cycles regardless of response.
5. Demonstration of CD19 expression by immunohistochemistry or flow cytometry on a pathological specimen of lymphoma or ALL cells at any time in the course of prior treatment.
6. Subjects who are unable to receive commercially available CD19-CAR T-cell therapy.
7. Patients with lymphoma must have measurable or assessable disease. Patients in complete remission with no evidence of disease are not eligible.
8. Patients with B-ALL must have at least measurable detectable disease on two separate occasions at least 2 weeks apart to be eligible.
9. Subjects who relapse at \> 100 days after autologous or allogeneic HSCT are eligible for participation on this trial. Allogeneic HSCT recipients must be off all immunosuppression for a minimum of 4 weeks before leukapheresis is performed and be free of active acute and chronic Graft Versus Host Disease (GVHD).
10. Subjects will be ≥ 18 and \< 80 years of age.
11. Female subjects of childbearing potential must have a negative urine or serum pregnancy test and if sexually active must use an acceptable method of contraception, including abstinence, a barrier method (diaphragm or condom), Depo-Provera, or an oral contraceptive. Active contraception should continue for at least one year after CAR T-cell infusion.
12. Male participants must be willing to practice birth control from the time of enrollment on this study and for 6 months after receiving the preparative regimen.
13. Cardiac ejection fraction ≥ 0.45 by MUGA (multigated acquisition) or echocardiography.
14. No requirement for supplemental oxygen and no dyspnea at rest. DLCO (diffusing capacity of the lungs for carbon monoxide) and FEV (forced expiratory volume)1 ≥ 0.65 of predicted.
15. Karnofsky performance score ≥ 70.
16. Subjects must have an expected survival \> 12 weeks.
17. Subjects must be able to comprehend the risks and methods used in this clinical trial and independently consent to participate.
18. Subjects must consent to anonymous reporting of data to the CIBMTR (Center for International Blood and Marrow Transplant Research).

Exclusion Criteria:

1. Infection with HIV (human immunodeficiency virus) and active viral replication. Patients with an undetectable viral load on ART (antiretroviral treatment) can be considered for participation on this protocol.
2. Infection with hepatitis B and active viral replication.
3. Infection with hepatitis C and active viral replication.
4. Active untreated CNS (central nervous system) leukemia or lymphoma. Patients with treated CNS leptomeningeal or parenchymal disease might be eligible if the CNS disease is inactive. The CSF (cerebrospinal fluid) must be clear on two separate occasions at least 4 weeks apart. Brain imaging must demonstrate no evidence of progressive disease on two separate occasions at least 4 weeks apart.
5. Active bacterial, fungal or viral infection.
6. Concurrent second malignancy requiring active therapy. Patients with breast or prostate cancer stable on hormonal therapy might be considered for participation if otherwise unimpaired.
7. Documented myocardial infarction within 6 months of study participation and/or symptomatic coronary artery or valvular disease or uncontrolled arrhythmia.
8. Investigational drug use within 30 days before leukapheresis.
9. Anti-cancer therapy administration within 4 weeks of leukapheresis including antiCD19 directed therapy, monoclonal antibody therapy, bi-specific T-cell engager therapy and targeted therapy such as Abelson tyrosine kinase inhibitors, Bruton's tyrosine kinase inhibitors, venetoclax and Lenalidomide or other IMiD (Immunomodulatory Drug).
10. Involved field radiation therapy is permitted if it terminates at least 15 days before leukapheresis and associated toxicity is grade 2 or less. Radiation therapy within 14 days of leukapheresis would make the subject ineligible.
11. Checkpoint inhibitor therapy within 4 weeks before leukapheresis.
12. Corticosteroid therapy at pharmacological dose (\> 10 mg of prednisone or biological equivalent) within 4 weeks before leukapheresis.
13. Immunosuppressive therapy that cannot be stopped for 4 weeks prior to leukapheresis as deemed by the prescribing physician.
14. Laboratory abnormalities that indicate clinically significant hematological, hepatobiliary, or renal disease:

    AST (Aspartate transaminase)/SGOT(serum glutamic-oxaloacetic transaminase) \> 2.0 times the upper limit of normal ALT (alanine aminotransferase)/SGPT (serum glutamic-pyruvic transaminase) \> 2.0 times the upper limit of normal Total bilirubin \> 2.0 times the upper limit of normal, unless subject has Gilbert's Syndrome (\>3.0 times the upper limit of normal) Hemoglobin \< 8 gm/dL or dependent upon transfusion to maintain ≥ 8 gm/dL White blood cell count \< 2,000/mm3 Platelet count \< 50,000/mm3 or dependent upon transfusion to maintain ≥ 50,000 mm Creatinine \> 2.0 times the upper limit of normal or calculated creatinine clearance ≤ 40 mL/min.
15. Pregnant or lactating females.
16. Subjects who, in the opinion of the Investigator, will be non-compliant with study schedules or procedures.
17. Subjects who belong to a vulnerable population such as the homeless, the developmentally disabled and prisoners or have any condition that impairs their ability to provide informed consent or comply with study schedules or procedures.

主要终点：Successful local CAR T-cell manufacturing · To demonstrate the feasibility of reliably producing CD19-targeted CAR T-cells at our site using the Prodigy device. · 48 months；Safety of administration · To demonstrate the safety of administering the manufactured product to subjects as measured by adverse events. · 15 years；Safety of administration · Cytokine Release Syndrome score · 30 days；Safety of administration · Immune Effector Cell Associated Neurotoxicity Syndrome Grading for Adults (score) - A score of 10 represents no impairment, 7-9 grade 1 ICANS, 3-6 grade 2 ICANS, and 0-2 grade 3 ICANS. A score of 0 due to patient being unarousable and unable to perform assessment corresponds to grade 4 ICANS. · 30 days；Safety of administration · Immune Effector Cell Associated Encephalopathy Score - A score of 10 represents no impairment, 7-9 grade 1 ICANS, 3-6 grade 2 ICANS, and 0-2 grade 3 ICANS. A score of 0 due to patient being unarousable and unable to perform assessment corresponds to grade 4 ICANS. · 30 days
次要终点：Response to therapy；Response to therapy；CAR T-cell kinetics

• Treatment Arm · EXPERIMENTAL · CAR -T-cell collection, infusion

This trial aims to demonstrate the feasibility of this approach to reliably generate product and to safely administer the product to patients who have B-Cell Lymphoma and B-Acute Lymphoblastic Leukemia.