CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

1. Participants (Men and Women) ≥ 18 and ≥ 80 years of age.
2. Participants capable of understanding and voluntarily signing the informed consent forms (prescreening and study forms) prior to any study-related evaluation or procedure, and able to adhere to the study visit schedule and other protocol requirements.
3. CD19+ hematologic malignancy with a histologically documented diagnosis.
4. Inclusion criteria according to the type of CD19+ hematologic malignancy measurable by the 2014 Lugano criteria (NHL) or IWCLL criteria (CLL) or EWALL criteria (ALL).
5. B-cell precursor acute lymphoblastic leukemia (B-ALL relapsed/refractory (R/R)): Second-line or later relapse (including patients with prior blinatumumab use), second-line or later non-candidate for allogeneic transplantation, or relapse post-allogeneic transplantation.
6. For patient inclusion, the disease must have progressed after the last regimen or the patient must not have achieved partial or complete remission with the last regimen, defined by the presence of at least 5% blasts in bone marrow or peripheral blood in an evaluation confirmed by flow cytometry or immunohistochemistry at least 2 weeks prior to recruitment (prescreening visit).
7. The consideration of non-candidacy for allogeneic transplantation will be based on functional status, comorbidities, and persistence. Minimal Residual Disease (MRD) or lack of a donor.
8. Relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and high-grade lymphoma (R/R): Refractory to first-line treatment or relapsed within the first 12 months after completion of first-line chemoimmunotherapy, including an anti-CD20 monoclonal antibody, not a candidate for autologous transplantation; or refractory after two or more lines of systemic therapy; in second (or higher) relapse post-autologous transplantation; grade 3b follicular lymphoma or transformed to relapsed or refractory large B-cell lymphoma after at least one line of standard treatment.
9. Symptomatic relapsed/refractory follicular lymphoma (FL): In third-line therapy (after at least two treatment regimens), including anti-CD20 therapy, and with a progression-free interval of less than two years; or in Relapse after autologous or allogeneic transplantation.
10. Relapsed/refractory (R/R) mantle cell lymphoma, including Bruton's tyrosine kinase inhibitor (BTKi) therapy: In first (or higher) relapse, not a candidate for autologous or allogeneic transplantation; or in second (or higher) relapse following autologous or allogeneic transplantation.
11. Symptomatic chronic lymphocytic leukemia (CLL): Relapse after two treatment regimens (including BTKi and BCL2 inhibitor in combination with anti-CD20) and with a progression-free interval of less than two years (POD24); or transformation to Richter syndrome, see inclusion criteria for DLBCL.
12. Eastern Cooperative Oncology Group (ECOG) functional status ≤ 2.
13. Life expectancy \> 6 months, as determined by the Principal Investigator.
14. Adequate organ function, defined as the following parameters at visit 2 Selection criteria:

    1. Absolute neutrophil count (ANC) ≥ 1,000/mm3
    2. Platelet count ≥ 50,000/mm3
    3. Hemoglobin ≥ 10 g/dL
    4. Total bilirubin ≤ 1.5 x the institutional upper limit of normal (ULN).
    5. AST (SGOT)/ALT (SGPT) ≤ 3 x the institutional ULN
    6. Serum creatinine ≤ 2 x the institutional ULN or eGFR \> 30 mL/min/1.73 m2
    7. Left ventricular ejection fraction \> 45% as determined by echocardiogram
    8. Pulmonary function tests: FEV1 (forced expiratory volume in 1 second): ≥ 50% of predicted and FVC (forced vital capacity): ≥ 50% of predicted Predicted value and FEV1/FVC ratio: ≥ 0.7 (or without significant obstruction) and SpO2 (oxygen saturation): ≥ 89% on room air at rest and hemoglobin-corrected DLCO: ≥ 70% of the predicted value.
15. Have adequate venous access.
16. Participants of reproductive potential must meet the following criteria:

    1. Negative pregnancy test 14 days before trial enrollment and subsequently every month for the duration of the trial, or evidence of postmenopausal status or surgical sterilization.
    2. Postmenopausal status is defined as the absence of menstruation for 12 months without an alternative medical cause. The following age-specific requirements apply:

       * \< 50 years: Amenorrhea for ≥12 months after discontinuation of exogenous hormonal treatments; and luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels within the postmenopausal range as defined by the institution.
       * ≥ 50 years: Patient with amenorrhea for 12 months or more after discontinuation of all exogenous hormonal treatments; or radiation-induced menopause with last menstrual period more than 1 year ago; or chemotherapy-induced menopause with last menstrual period more than 1 year ago.
17. All participants of reproductive potential and those with a sexual partner of reproductive potential must agree to use a highly effective contraceptive method from the start of trial therapy until 12 months after the last infusion dose. Options for adequate contraception with a failure rate of \<1% per year include: bilateral tubal ligation/occlusion; partner vasectomy; intrauterine device (IUD) or hormonal delivery system (IUS); any hormonal contraceptive (estrogen combined with progesterone or progesterone alone) combined with ovulation inhibition: implanted, oral, intravaginal, transdermal, or injectable; spermicide with a compatible barrier method (e.g., diaphragm, sponge, or condoms). Alternatively, two methods (e.g., two barrier methods, such as a condom and a cervical cap) may be combined to achieve a failure rate of \<1% per year. Barrier methods must always be supplemented with the use of spermicide. Abstinence is acceptable only if it is consistent with the patient's preferred and usual lifestyle. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulatory methods) and withdrawal are not acceptable contraceptive methods. If pregnancy is suspected or confirmed in a female patient or a female partner of a male patient during trial participation or within 12 months of ARI-0001 cell infusion, the Principal Investigator must be informed immediately.
18. Participants with prior or resolved HBV infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of HBsAg) are eligible.

\*Specific Inclusion Criteria Before Lymph Depletion\*

The following criteria must be confirmed 7 days prior to lymph depletion:

1. Confirmation of successful CAR-T cell fabrication.
2. No evidence or suspicion of infection.
3. Serum creatinine ≤ 2 times the institutional upper limit of normal (ULN) or eGFR \>30 mL/min/1.73 m².
4. Confirmation of compliance with washout periods.
5. No worsening of the patient's clinical status compared to the initial eligibility criteria that, in the opinion of the treating physician, significantly increases the risk due to lymph depletion chemotherapy or excludes them from treatment with the trial CAR-T cell therapy.

\*Specific inclusion criteria prior to CAR-T cell infusion.\*

Participants must meet the following criteria (Failure to meet these criteria will result in the individual subject's enrollment being halted or suspended entirely at the discretion of the CES and the Principal Investigator):

1. No evidence or suspicion of infection.
2. Confirmation of compliance with the washout periods.
3. No worsening of clinical status compared to the initial eligibility criteria that, in the opinion of the treating physician, significantly increases the risk due to lymphodepleting chemotherapy or excludes them from treatment with the ARI-0001 CAR-T therapy in the trial.

Exclusion Criteria:

The presence of any of the following will exclude the subject from trial enrollment:

1. Failure to comply with the washout periods.
2. Autologous or allogeneic stem cell transplantation or CAR-T cell therapy within 6 weeks prior to CAR-T cell infusion.
3. Subjects with an active infection requiring systemic treatment. This definition excludes participants with Hepatitis B (known positive hepatitis B surface antigen \[HBsAg\] result), latent Tuberculosis, Hepatitis C, or HIV seropositivity.
4. History of autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus) requiring immunosuppressive medication within the past 6 months.
5. Pregnant or breastfeeding women are excluded from this trial because CAR-T cell therapy may be associated with teratogenic or abortifacient effects. Women of childbearing potential must have a negative serum pregnancy test. Due to the unknown, but potential, risk of adverse events in infants from maternal CAR-T cell therapy, breastfeeding should be discontinued. These potential risks may also apply to other agents used in this trial.
6. Participation in another interventional research study.
7. Major surgery within 4 weeks prior to enrollment from which the patient has not fully recovered, as determined by the investigator.
8. Active central nervous system (CNS) involvement due to leukemia or lymphoma, including leptomeningeal lymphoma. Patients with a history of CNS or meningeal involvement must be in documented remission, as determined by cerebrospinal fluid (CSF) evaluation, for at least 90 days prior to enrollment.
9. Diagnosis of another malignancy within ≤ 5 years prior to trial enrollment, except for those considered adequately treated with no evidence of disease or symptoms and/or not requiring therapy during the trial (e.g., basal cell or squamous cell skin cancer, carcinoma in situ of the breast, bladder, or cervix, or low-grade prostate cancer with a Gleason score ≤ 6).
10. Known brain metastases or cranial epidural disease. Note: Patients with brain metastases or cranial epidural disease adequately treated with radiotherapy and/or surgery and stable for at least 4 weeks prior to the first dose of trial treatment will be eligible for the trial. Subjects must be neurologically asymptomatic and not receiving corticosteroid treatment at the time of the first dose of trial treatment.
11. Current evidence of significant uncontrolled comorbidity, including, but not limited to, the following conditions:

    * New York Heart Association Class III or IV congestive heart failure, unstable angina, serious cardiac arrhythmias.
    * Stroke (including transient ischemic attack \[TIA\]), myocardial infarction (MI), or other ischemic events, or thromboembolic event (e.g., deep vein thrombosis, pulmonary embolism) within 3 months prior to the first dose.
    * QTc prolongation defined as QTcF \> 500 ms.
    * Known congenital long QT syndrome.
    * Left ventricular ejection fraction \< 45%.
    * Uncontrolled hypertension, defined as ≥ 140/90 mmHg as assessed by the average of three consecutive blood pressure measurements taken over 10 minutes.
    * Any other condition that, in the Investigator's judgment, contraindicates the subject's participation in the clinical trial due to safety concerns or issues with compliance with clinical trial procedures (e.g., infection/inflammation, bowel obstruction, inability to swallow medication \[subjects cannot receive the medication via a feeding tube\], social/psychological problems, etc.).

主要终点：1. Clinical Safety Outcome (Pilot Cohort) · Proportion of patients experiencing grade ≥3 treatment-related adverse events, including cytokine release syndrome (CRS), CAR-T cell-associated neurotoxicity (ICANS), and prolonged cytopenias beyond 30 days post-infusion (ICAHT). · This outcome will be assessed 30 days post-infusion.；2. Clinical Safety Outcome (Pilot Cohort) · Proportion of patients developing infections within the first 12 months after CAR-T cell infusion. · 12 months after CAR-T cell infusion.；3. Clinical Safety Outcome (Pilot Cohort) · Early mortality, defined as death occurring within the first 30 days post-infusion. · 30 days post-infusion.
次要终点：Overall response rate (ORR)；Disease-free survival (DFS)；Overall survival (OS)

• Single-arm, non-randomized pilot clinical trial in patients aged between 18 and 80 years · EXPERIMENTAL · Patients over 18 years of age with recurrent/refractory (R/R) CD19+ hematopoietic lymphoid neoplasms, including R/R non-Hodgkin lymphoma (NHL), R/R B-cell acute lymphoblastic leukemia (B-ALL), and R/R mantle cell lymphoma; and R/R chronic lymphocytic leukemia (CLL) (including CLL with Richter transformation). 1. Collection of autologous T lymphocytes by apheresis Day -4 ± 7 2. Transport of cellular material to IDCBIS 3. Manufacture of ARI-0001 using CliniMACS Prodigy according to GMP 4. Cryopreservation of ARI-0001 cells 5. Transport of ARI-0001 cells to the INC 6. Temporary storage of ARI-0001 cells at the INC 7. Administration of lymphodepletion regimen to patient Days -5, -4, -3 8. Thawing of ARI-0001 cell product 9. ARI-0001 infusion Days 1, 2, 3 10. Outpatient follow-up 11. Inpatient monitoring for 14 days 12. Collection of samples for paraclinical analysis Days 4-7, 9, 12, 14 13. Visit on day 22, biweekly days 22-90, monthly days 91-360

This is a hybrid type two study, with two simultaneous development phases. Phase A involves developing a public-private partnership to create the conditions for implementing CAR-T cell therapies in Colombia. Phase B will be a single-arm, non-randomized pilot clinical trial in patients over 18 years of age with recurrent/refractory (R/R) CD19+ hematopoietic lymphoid neoplasms, including R/R non-Hodgkin lymphoma (NHL), R/R B-cell acute lymphoblastic leukemia (B-ALL), and R/R mantle cell lymphoma; and R/R chronic lymphocytic leukemia (CLL) (including CLL with Richter transformation). This trial aims to determine the safety of administering autologous anti-C19 cells (ARI-0001) and the feasibility of local CAR-T cell production. Phase A of implementation aims to gather information on the domains of the multilevel model, including organizational context, suppliers, infrastructure, and institutional capacities, to identify barriers and facilitators in the implementation of CAR-T cell therapy in Colombia. National consensus will also be developed in the scientific, clinical, administrative, and regulatory spheres. Phase B will involve a pilot clinical trial in patients with relapsed/refractory CD19-positive hematopoietic lymphoid neoplasms. The production of ARI-0001 cells consists of the genetic modification of autologous T cells through lentiviral transduction of a chimeric antigen receptor (CAR) targeting the CD19 surface antigen. The process is carried out in the CliniMACS Prodigy® closed transduction system, which for this study will be located at and operated by staff from the District Institute of Science, Biotechnology, and Innovation in Health (IDCBIS). This pilot clinical trial will use an open-label, single-arm, staggered enrollment design with a safety observation period. The patient will receive the cell product infusion following administration of a lymphodepletion regimen at the National Cancer Institute (NCI). The patient will remain hospitalized for 14 days after the CAR-T cell infusion ARI-001 for medical monitoring, with subsequent outpatient follow-up until 12 months post-infusion. Subsequently, the patient will be offered a new informed consent process to participate in outpatient follow-up for up to 15 years.