CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria for the Study:

Unless otherwise noted, subjects must meet all of the following criteria to participate in all stages of this study:

* Written informed consent and HIPAA authorization for release of personal health information.
* Adults ≥18 years of age.
* Histologically confirmed B-cell NHL, including the following types defined by WHO 2016:

Aggressive Lymphomas:

* DLBCL not otherwise specified (NOS)
* T cell/histiocyte rich large B cell lymphoma; primary cutaneous DLBCL, leg type; EBV-positive DLBCL NOS; DLBCL associated with chronic inflammation; Large B-cell lymphoma with IRF4 rearrangement; Intravascular large B-cell lymphoma; ALK-positive large B-cell lymphoma
* Primary mediastinal (thymic) large B-cell lymphoma
* High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement; high grade B-cell lymphoma, NOS
* B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma
* Transformation of indolent lymphoma or CLL to DLBCL will also be included
* Burkitt lymphoma
* Primary CNS lymphoma

Indolent Lymphomas:

* Follicular lymphoma
* Splenic marginal zone lymphoma
* Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue
* Nodal marginal zone lymphoma
* Waldenstrom's macroglobulinemia (Lymphoplasmacytic lymphoma)
* Mantle cell lymphoma
* CLL/SLL by International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria
* Subjects with CNS involvement of lymphoma are eligible.

  --For aggressive lymphomas, must have relapsed or refractory disease after having received at least 2 prior lines of systemic therapy, including, at a minimum:
  * An anti-CD20 monoclonal antibody
  * An anthracycline containing chemotherapy regimen (if eligible)
  * An autologous stem cell transplant (if eligible)
* Subjects with primary CNS lymphoma must have failed at least 1 prior line of therapy that included high dose methotrexate.
* For indolent lymphomas, subjects must have received at least 2 prior lines of therapy for their lymphoma
* Subjects with specifically relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma must have received at least 2 prior therapy regimens which can include, but not limited to:

  * A combination of an anti-CD20 monoclonal antibody and an alkylating agent, OR
  * A Bruton's Tyrosine Kinase Inhibitor, OR
* A BCL-2 inhibitor in combination with an anti-CD20 monoclonal antibody.
* Subjects with prior or concurrent malignancies of the same or different tumor type whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational drug are eligible for enrollment at the discretion of the clinical investigator.
* Subjects relapsed after allogeneic stem cell transplant will be eligible if they meet other inclusion criteria and have no active graft vs host disease (GVHD)
* Measurable or assessable disease by Lugano criteria, response criteria for primary CNS lymphoma, or WM criteria, or IWCLL criteria. Subjects with bone marrow-only involvement are eligible.
* Karnofsky score of \> 60%
* Women of childbearing potential (WOCBP) must be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study, and for 6 months after the study is concluded. WOCBP are those who have not been surgically sterilized or have not been free from menses for \> 1 year. The two birth control methods can be composed of: two barrier methods or a barrier method plus a hormonal method to prevent pregnancy. WOCBP subjects will also be instructed to tell their male partners to use a condom.

Exclusion Criteria for the Study:

Subjects meeting any of the following exclusion criteria will not be able to participate in this study (procurement, lymphodepletion, and cell infusion):

* Subject is pregnant or lactating.
* Tumor in a location where enlargement could cause airway obstruction.
* Current use of systemic corticosteroids at doses ≥10mg prednisone daily or its equivalent; those receiving \<10mg daily may be enrolled at the discretion of investigator. Patients with primary CNS lymphoma can receive higher doses of steroids per the investigator's discretion.
* Active infection with HIV, HTLV, HBV, and HCV (can be pending at the time of cell procurement; only those samples confirming lack of active infection will be used to generate transduced cells) defined as not being well controlled on therapy. Subjects are required to have negative HIV antibody, negative HTLV1 and HTLV2 antibodies, negative Hepatitis B surface antigen, and negative HCV antibody or viral load. In addition, subjects with positive Hepatitis B core antibody will have Hepatitis B viral load tested and subjects with positive Hepatitis B viral load will also be excluded.
* Subject must either have core antibody negative HBV (results can be pending at the time of cell procurement) OR if a subject is hepatitis B core antibody positive they must have their hepatitis B viral load checked. These subjects will be excluded if their viral load is positive at baseline. Subjects who are core antibody positive and viral load negative at baseline will be considered eligible.
* A history of intolerance to fludarabine. Note: subjects with history of intolerance to bendamustine may be considered for enrollment at the discretion of the clinical investigator if they are candidates for lymphodepletion with cyclophosphamide and fludarabine.

Eligibility criteria to be met prior to procurement:

* Subjects must sign a consent to undergo cell procurement.
* Life expectancy ≥ 12 weeks.
* Evidence of adequate organ function as defined by:

The following is required within 7 days prior to procurement:

* Bilirubin ≤1.5 times the upper limit of normal (ULN). Subjects with Gilbert's syndrome may be enrolled despite a total bilirubin level \>1.5 mg/dL if their conjugated bilirubin is \<1.5× ULN)
* AST ≤ 3 times ULN
* Creatinine Clearance (CrCl) \>30mL/min per Cockcroft and Gault
* Pulse oximetry of \>90% on room air

  * Left ventricular ejection fraction (LVEF) ≥35% as measured by ECHO, with no additional evidence of decompensated heart failure.
  * In patients with disease assessed by imaging, imaging results from within 90 days prior to procurement to assess the presence of active disease. If disease is not measurable by imaging, evidence of active disease within 90 days of procurement via bone marrow biopsy or SPEP/immunofixation.
  * Negative serum pregnancy test within 72 hours prior to procurement or documentation that the subject is post-menopausal. Post-menopausal status must be confirmed with documentation of absence of menses for \>1 year, or documentation of surgical menopause involving bilateral oophorectomy.

Eligibility criteria to be met prior to lymphodepletion:

* Written informed consent to enroll in the CAR T-cell therapy trial must be obtained prior to lymphodepletion.
* Imaging results from within 7 days prior to lymphodepletion. Imaging must occur at least 3 weeks after most recent therapy (used as baseline measure for documentation of progression before the lymphodepletion) to document measurable or assessable disease. Imaging does not need to be repeated if it is within 7 days prior to lymphodepletion. For WM, imaging does not need to be repeated prior to lymphodepletion if no evidence of disease at screening.
* Evidence of adequate organ function as defined by:

The following are required within 72 hours prior to lymphodepletion:

* Adequate bone marrow function (ANC ≥1.0 x 10\^9/L and platelets ≥50 x 10\^9/L) unless related to lymphoma involvement. Subjects cannot have received platelet transfusion within 7 days of lymphodepletion.
* Bilirubin ≤1.5 times the upper limit of normal (ULN). Subjects with Gilbert's syndrome may be enrolled despite a total bilirubin level \>1.5 mg/dL if their conjugated bilirubin is \<1.5× ULN)
* AST ≤ 3 times ULN
* Creatinine Clearance (CrCl) \>30mL/min per Cockcroft and Gault
* Pulse oximetry of \> 90% on room air
* Negative serum pregnancy test within 72 hours prior to lymphodepletion or documentation that the subject is post-menopausal. Post-menopausal status must be confirmed with documentation of absence of menses for \> 1 year, or documentation of surgical menopause involving bilateral oophorectomy.
* In subjects with CLL/SLL or lymphoma with bone marrow only involvement, a bone marrow biopsy within 28 days prior to lymphodepletion.
* Subjects that have received therapy with murine antibodies must have documentation of absence of human anti-mouse antibodies (HAMA) prior to lymphodepletion. Subjects who have received prior therapy with murine antibodies must have documentation of absence of HAMA within 8 weeks of lymphodepletion or after their most recent murine antibody therapy (whichever is shortest). For subjects that receive murine monoclonal antibodies or murine-human chimeric monoclonal antibodies between procurement and lymphodepletion, HAMA testing should be performed within 4 weeks prior to lymphodepletion and after the last monoclonal antibody dose.
* Available autologous transduced activated T cells product meets the certificate of analysis.
* Has not received any investigational agents or received any tumor vaccines within the previous six weeks prior to lymphodepletion.
* Subject is not taking a prohibited or contraindicated medication prior to lymphodepletion. Contraindicated medications should be discontinued at least two weeks prior to the scheduled lymphodepletion or by at least 5 half-lives of the contraindicated medication, whichever is shorter.
* Subject is not taking strong inhibitors of CYP1A2 (e.g., fluvoxamine, ciprofloxacin) as these may increase plasma concentrations of bendamustine, and decrease plasma concentrations of its metabolites. See http://medicine.iupui.edu/clinpharm/ddis/ for an updated list of strong inhibitors of CYP1A2. (This applies to subjects who receive bendamustine for lymphodepletion (required) up through 72 hours after the last dose of bendamustine).
* Subject has not received chemotherapy within the previous 3 weeks prior to lymphodepletion.

Eligibility criteria to be met prior to cell infusion after lymphodepletion:

* No evidence of uncontrolled infection or sepsis.
* Negative serum pregnancy within 7 days of cell infusion (does not need to be repeated if pre-lymphodepletion pregnancy test is within window).

主要终点：Number of Participants With Treatment-emergent Grade ≥ 3 Adverse Events Per National Cancer Institute's Common Terminology Criteria · Number of participants with treatment-attributed Grade ≥3 adverse events.Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, v5.0). Treatment-emergent Grade ≥ 3 CRS event that is unresponsive to standard of care interventions and does not decrease to Grade ≤ 2 within 7 days will be reported. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. · Up to 4 weeks；Number of Participants With Treatment-emergent Grade ≥ 3 Adverse Events Per Cytokine Release Syndrome (CRS) · Toxicity will be classified and graded as cytokine release syndrome (CRS) according to the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading system. Grade 1 (mild): fever ≥38°C with no hypotension or hypoxia; Grade 2 (moderate): fever ≥38°C with hypotension not requiring vasopressors and/or hypoxia requiring low-flow oxygen (≤6 L/min nasal cannula or blow-by); Grade 3 (severe): fever ≥38°C with hypotension requiring a single vasopressor (± vasopressin) and/or hypoxia requiring high-flow oxygen (\>6 L/min), facemask, nonrebreather, or Venturi mask; Grade 4 (life-threatening): fever ≥38°C with hypotension requiring multiple vasopressors (excluding vasopressin) and/or hypoxia requiring positive pressure ventilation; Grade 5: death. Treatment-emergent Grade ≥ 3 CRS event that is unresponsive to standard of care interventions and does not decrease to Grade ≤ 2 within 7 days will be reported. · Up to 4 weeks；Number of Participants With Treatment-emergent Grade ≥ 3 Adverse Events Per Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS) · Toxicity will be classified and graded according to Immune effector cell-associated neurotoxicity syndrome (ICANS) symptoms will be graded according to the criteria outlined in the protocol on a scale from 1 (mild) to 4 (critical). Cytokine release syndrome (CRS) will be graded according to criteria outlined in the protocol on a scale from 1 (mild) to grade 5 (death). Treatment-emergent Grade ≥ 3 CRS event that is unresponsive to standard of care interventions and does not decrease to Grade ≤ 2 within 7 days will be reported. · Up to 4 weeks
次要终点：Identify a Recommended Phase 2 Dose (RP2D) of iC9-CAR19 T Cells in Subjects With Relapsed or Refractory B-cell Lymphoma or CLL/SLL；Survival of iC9-CAR19 T Cells in Vivo；Overall Response Rate (ORR) (Rate of Complete Response (CR)) Mediated by Autologous iC9-CAR19 T Cells Administered to Subjects With Relapsed or Refractory B-cell Lymphoma or CLL/SLL；Overall Survival (OS) in Subjects With Relapsed or Refractory B-cell Lymphoma or CLL/SLL Following Infusion of iC9-CAR19 T Cells；Progression Free Survival (PFS) in Subjects With Relapsed or Refractory B-cell Lymphoma or CLL/SLL Following Infusion of iC9-CAR19 T Cells；Duration of Response (DOR) in Subjects With Relapsed or Refractory B-cell Lymphoma or CLL/SLL Who Experience an Objective Response Following Infusion of iC9-CAR19 T Cells；Change in Patient-reported Symptoms；Change in Physical Function

• Single Arm iC9.CAR19 T cells · EXPERIMENTAL · The safety of iC9-CAR19 cells will be investigated using the 3+3 design. Dose level (DL) Dose (#transduced cells/kg) -1 1 x 10\^5 1. 1 x 10\^6 2. 2 x 10\^6 DL1 will enroll 3 subjects. If no toxicity within 4 weeks, then DL 2 will enroll 3 subjects. If toxicity in 1/3 subjects in DL 1, 3 more subjects will be enrolled. If DL 1 is not tolerable, a de-escalation to DL -1 will enroll 3 subjects. If 3 subjects at the higher dose do not have DLTs more will be enrolled at that dose to get more information about toxicity. Lymphodepleting chemotherapy of IV bendamustine 70 mg/m2 and IV fludarabine 30 mg/m2/day for 3 consecutive days will be given within 2-14 days prior to cell infusion. AP1903 (0.4 mg/kg), a dimerizing agent to engage and activate the caspase 9 safety switch to trigger iC9-CAR19 T cell death by apoptosis will be given to subjects who develop severe cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS).
• Expansion Cohort iC9-CAR19 cells · EXPERIMENTAL · After the tolerable cell dose (TCD) has been determined in adults, up to 18 additional subjects may be enrolled in an expansion cohort at the TCD. A TCD is defined as the dose at which approximately 0.20 of subjects experience dose limiting toxicity (0 - 1 out of 6 subjects).

This research study combines 2 different ways of fighting disease: antibodies and T cells. Both antibodies and T cells have been used to treat patients with cancers, and both have shown promise, but neither alone has been sufficient to cure most patients. This study combines both T cells and antibodies to create a more effective treatment. The treatment being researched is called autologous T lymphocyte chimeric antigen receptor cells targeted against the CD19 antigen (ATLCAR.CD19) administration. Prior studies have shown that a new gene can be put into T cells and will increase their ability to recognize and kill cancer cells. The new gene that is put in the T cells in this study makes a piece of an antibody called anti-CD19. This antibody sticks to leukemia cells because they have a substance on the outside of the cells called CD19. For this study, the anti-CD19 antibody has been changed so that instead of floating free in the blood part of it is now joined to the T cells. When an antibody is joined to a T cell in this way it is called a chimeric receptor. These CD19 chimeric (combination) receptor-activated T cells seem to kill some of the tumor, but they do not last very long in the body and so their chances of fighting the cancer are unknown. Preliminary results have shown that subjects receiving this treatment have experienced unwanted side effects including cytokine release syndrome and neurotoxicity. In this study, to help reduce cytokine release syndrome and/or neurotoxicity symptoms, the ATLCAR.CD19 cells have a safety switch that, when active, can cause the cells to become dormant. These modified ATLCAR.CD19 cells with the safety switch are referred to as iC9-CAR19 cells. If the subject experiences moderate to severe cytokine release syndrome and or neurotoxicity as a result of being given iC9-CAR19 cells, the subject can be given a dose of a second study drug, AP1903, if standard interventions fail to alleviate the symptoms of cytokine release syndrome and/or neurotoxicity. AP1903 activates the iC9-CAR19 safety switch, reducing the number of the iC9-CAR19 cells in the blood. The ultimate goal is to determine what dose of AP1903 can be given that reduces the severity of the cytokine release syndrome and/or neurotoxicity, but still allows the remaining iC9-CAR19 cells to effectively fight the lymphoma. The primary purpose of this study is to determine whether receiving iC9-CAR19 cells is safe and tolerable in patients with relapsed/refractory B-cell lymphoma, primary central nervous system lymphoma and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).