CELL INTELLIGENCE · 肿瘤细胞治疗研究

Procurement Inclusion Criteria for the Patient

Referred patients (Group A - NOW CLOSED) or their previous HSCT donors (Group B) will initially be consented for procurement of blood for generation of the transduced ATL. Patient eligibility criteria at this stage include:

1. Diagnosis of recurrent T-cell acute lymphoblastic leukemia (T-ALL), T-cell acute lymphoblastic lymphoma (T-LLy), or T-non-Hodgkin lymphoma (T-NHL, including Angioimmunoblastic T-cell lymphoma (AITL), Enteropathy-associated T-cell lymphoma (EATL), Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), Peripheral T-cell lymphoma (PTCL) NOS, Anaplastic large cell lymphoma (ALCL), Adult T-cell leukemia/lymphoma, T cell prolymphocytic leukemia with symptomatic disease, Extranodal NK/T cell lymphoma, Mycosis fungoides/ Sezary Syndrome Stage IIB or higher))

   AND

   Group A (auto arm - NOW CLOSED): Transplant naïve or relapsed post-allogeneic HSCT OR

   Group B (allo arm): Relapsed post-allogeneic HSCT with previous HSCT donor from whom allogeneic MAGENTA CAR T cells can be manufactured

   AND
   * Suitable for allogeneic hematopoietic stem cell transplant (HSCT) with confirmation of an identified eligible allo-HSCT donor by FACT accredited institution
   * Confirmation that the center plans to proceed with transplant if CD5.CAR treatment induces a complete remission.

     * For T-NHL subjects, eligibility will be confined to disease stages where allogeneic HSCT is indicated.
2. CD5-positive tumor (result can be pending at this time). \> 50% CD5 + blasts by flow cytometry or immunohistochemistry (tissue) assessed by a CLIA certified Flow Cytometry/Pathology laboratory.
3. Age ≤75 years old. NOTE: The first six (6) patients treated on the study should be adults (\>18 yrs of age).
4. Life expectancy of greater than 12 weeks.
5. Patients must have an available partially-HLA matched allogeneic EBV-specific T cell line on a BCM IRB approved protocol which can be used as treatment in the event of uncontrolled EBV reactivation
6. Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent.
7. Hgb greather than or equal to 7.0 g/dL (can be transfused)
8. If pheresis required to collect blood:

   * Creatinine \<1.5 × upper limit normal
   * AST \<1.5 × upper limit normal
   * PT and APTT \<1.5 × upper limit normal

Procurement Exclusion Criteria for the Patient (Group A)

1. Active infection requiring antibiotics.
2. Active infection with HIV
3. History of other cancer (except non-melanoma skin cancer or in situ breast cancer or cervix cancer) unless the tumor was successfully treated with curative intent at least 2 years before trial entry.

Procurement Inclusion Criteria for Normal Healthy Donor (Group B):

1. Donor must be prior hematopoietic stem cell transplant donor for patients relapsed post-allogeneic HSCT. Prior transplant donors will be screened with the standard blood bank donor questionnaire, medical history, and testing for infectious disease markers (IDMs; which may be pending at the time of blood collection). Medical history may be obtained by the patient's primary/referring transplant team if collection is being done remotely. The physician assessment, donor questionnaire, and IDMs will be reviewed by the principle investigator or appropriate designee to confirm/provide final eligibility determination and documented in the donor's medical record.
2. Informed consent explained to, understood by and signed by donor/LAR. Donor/LAR given copy of informed consent.

Treatment Inclusion Criteria

Patients must meet the following eligibility criteria to be included for treatment:

1. Diagnosis of recurrent T-cell acute lymphoblastic leukemia (T-ALL), T-cell acute lymphoblastic lymphoma (T-LLy), or T-non-Hodgkin lymphoma (T-NHL, including Angioimmunoblastic T-cell lymphoma (AITL), Enteropathy-associated T-cell lymphoma (EATL), Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), Peripheral T-cell lymphoma (PTCL) NOS, Anaplastic large cell lymphoma (ALCL), Adult T-cell leukemia/lymphoma, T cell prolymphocytic leukemia with symptomatic disease, Extranodal NK/T cell lymphoma, Mycosis fungoides/ Sezary Syndrome Stage IIB or higher))

   AND

   Group A (auto arm - NOW CLOSED): Transplant naïve or relapsed post-allogeneic HSCT OR

   Group B (allo arm): Relapsed post-allogeneic HSCT with previous HSCT donor from whom allogeneic MAGENTA CAR T cells can be manufactured

   AND
   * Suitable for allogeneic hematopoietic stem cell transplant (HSCT) with confirmation of an identified eligible allo-HSCT donor by FACT accredited institution
   * Confirmation that the center plans to proceed with transplant if CD5.CAR treatment induces a complete remission.

     * For T-NHL subjects, eligibility will be confined to disease stages where allogeneic HSCT is indicated.
2. CD5-positive tumor. \>50% CD5 + blasts by flow cytometry or immunohistochemistry (tissue) assessed by a CLIA certified Flow Cytometry/Pathology laboratory.
3. Age \<75 years old. NOTE: The first six (6) patients treated on the study should be adults (\>18 yrs of age).
4. Bilirubin less than 3 times the upper limit of normal.
5. AST less than 5 times the upper limit of normal.
6. Estimated GFR \> 60 mL/min.
7. Pulse oximetry of \> 90% on room air.
8. Karnofsky or Lansky score of ≥ 60%.
9. Recovered from acute toxic effects of prior chemotherapy at least one week before entering this study.
10. ≥ 60 days post-allogeneic HSCT at time of treatment.
11. Patients must have an available partially-HLA matched allogeneic EBV-specific T cell line on a BCM IRB approved protocol which can be used as treatment in the event of uncontrolled EBV reactivation.
12. Sexually active patients must be willing to utilize one of the more effective birth control methods during the study and for 6 months after the study is concluded. The male partner should use a condom.
13. Informed consent explained to, understood by, and signed by patient/guardian. Patient/guardian given copy of informed consent.

Treatment Exclusion Criteria

1. Currently receiving any investigational agents or having received any tumor vaccines within the previous 6 weeks.
2. History of hypersensitivity reactions to murine protein-containing products.
3. Pregnant or lactating.
4. Tumor in a location where enlargement could cause airway obstruction.
5. Active infection with HIV.
6. Clinically significant viral infection or uncontrolled viral reactivation of EBV, CMV, Adv, BK-virus, or HHV-6.
7. Evidence of acute GVHD \> Grade II or active chronic GVHD \> mild global severity score
8. Currently taking corticosteroids for therapy of GVHD at a dose of \>0.5mg/kg prednisone equivalent
9. Patients who have received Immunosuppressive Treatment (IST) for GVHD within 28 days of infusion
10. Patients who have received donor lymphocyte infusion (DLI) within 28 days of infusion
11. Any of the following cardiac criteria: Atrial fibrillation/flutter; Myocardial infarction within the last 12 months; Prolonged QT syndrome or secondary prolonged QT, per investigator discretion. Cardiac echocardiography with LVSF\<30% or LVEF\<50%; or clinically significant pericardial effusion. Cardiac dysfunction NYHA III or IV (Confirmation of absence of these conditions within 12 months of treatment)
12. CNS abnormalities: Presence of CNS-3 disease defined as detectable cerebrospinal blast cells in a sample of CSF with ≥ 5 WBCs per mm3; History or presence of any CNS disorder such as a uncontrolled seizure disorder, cerebrovascular ischemia/hemorrhage within prior 6 months, dementia, cerebellar disease, or any autoimmune disease with CNS involvement.

主要终点：Dose limiting toxicity (DLT) rate · Defined as the proportion of subjects in each group with DLT evaluated as per the CTCAE 4.0 with the exception of Cytokine Release Syndrome (CRS) and neurological toxicities that are related to T cell infusions. · 6 weeks post-infusion
次要终点：Overall Response Rate

• Autologous CD5.CAR/28zeta CAR T cells (Group A) - NOW CLOSED · EXPERIMENTAL · Three dose levels will be evaluated. The T cells will be administered with Cytoxan and fludarabine.If patients have experienced either a partial response or stable disease and completed the 6 week toxicity evaluation without evidence of DLT or other infectious complications, they will be eligible to receive up to 3 additional infusions of CD5 CAR.T cells. Patients remain eligible for up to 3 additional infusions as long as they continue to have a clinical response and absence of safety concerns. If patients experience a complete response following an additional infusion, investigators will recommend they proceed to allogeneic HSCT. Once dose escalation is completed, the trial will be expanded and treat up to an additional 6 patients (2 cohorts) at the MTD in each group to gather additional safety data and preliminary efficacy data.
• Allogeneic CD5.CAR/28zeta CAR T cells (Group B) · EXPERIMENTAL · Three dose levels will be evaluated. The T cells will be administered with Cytoxan and fludarabine.If patients have experienced either a partial response or stable disease and completed the 6 week toxicity evaluation without evidence of DLT or other infectious complications, they will be eligible to receive up to 3 additional infusions of CD5 CAR.T cells. Patients remain eligible for up to 3 additional infusions as long as they continue to have a clinical response and absence of safety concerns. If patients experience a complete response following an additional infusion, investigators will recommend they proceed to allogeneic HSCT. Once dose escalation is completed, the trial will be expanded and treat up to an additional 6 patients (2 cohorts) at the MTD in each group to gather additional safety data and preliminary efficacy data.

Patients eligible for this study have a type of blood cancer called T-cell leukemia or lymphoma (lymph gland cancer). The body has different ways of fighting infection and disease. No one way seems perfect for fighting cancers. This research combines two different ways of fighting disease, antibodies and T cells. Antibodies are proteins that protect the body from bacterial and other diseases. T cells, or T lymphocytes, are special infection-fighting blood cells that can kill other cells including tumor cells. Both antibodies and T cells have shown promise treating patients with cancers, but have not been strong enough to cure most patients. T lymphocytes can kill tumor cells but there normally are not enough of them. Some researchers have taken T cells from a person's blood, grown more in the lab then given them back to the person. In some patients who've had recent bone marrow or stem cell transplant, the number of T cells in their blood may not be enough to grow in the lab. In this case, T cells may be collected from their previous transplant donor, who has a similar tissue type. The antibody used in this study, called anti-CD5, first came from mice that have developed immunity to human leukemia. This antibody sticks to T-cell leukemia or lymphoma cells because of a substance on the outside of these cells called CD5. CD5 antibodies have been used to treat people with T-cell leukemia and lymphoma. For this study, anti-CD5 has been changed so that instead of floating free in the blood 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. In the lab, investigators have also found that T cells work better if stimulating proteins, such as one called CD28, are also added. Adding the CD28 makes the cells grow better and last longer in the body, giving them a better chance of killing the leukemia or lymphoma cells. In this study investigators will attach the CD5 chimeric receptor with CD28 added to it to the patient's T cells or the previous bone marrow transplant donor's T cells. The investigators will then test how long the cells last. The decision to use the bone marrow transplant donor's T cells instead of the patient's will be based on 1) whether there is an available and willing donor and 2) the likelihood of the patient's T cells being able to grow in the lab. These CD5 chimeric receptor T cells with CD28 are investigational products not approved by the FDA. UPDATE: Please note that the Autologous Arm of this study is now closed.