CELL INTELLIGENCE · 肿瘤细胞治疗研究

PROCUREMENT Inclusion Criteria:

1. Diagnosis of relapsed/refractory HL or NHL.
2. CD30 positive tumor as assayed in a CLIA certified pathology laboratory (result can be pending at this time)
3. Hgb ≥ 7.0 (may be a transfused value)
4. Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent.
5. Karnofsky or Lansky score of \> 60%

TREATMENT Inclusion Criteria:

1. Diagnosis of relapsed/refractory HL or NHL.
2. CD30-positive tumor as assayed in a CLIA certified pathology laboratory.
3. Age 16 to 75 for the first three patients on a dose level; thereafter, if no DLT, patients aged 12 to 75 can be treated on that dose level.
4. Bilirubin 1.5 times or less than the upper limit of normal.
5. AST 3 times or less than the upper limit of normal.
6. Estimated GFR \> 70 mL/min.
7. Pulse oximetry of \> 90% on room air
8. EKG shows no significant arrhythmias
9. Karnofsky or Lansky score of \> 60%.
10. Available autologous T cells with greater than or equal to 15% expression of CD30CAR determined by flow-cytometry.
11. Recovered from all acute non-hematologic toxic effects of all prior chemotherapy.
12. Adequate pulmonary function with FEV1, FVC and DLCO (or DLCO/VA, as clinically appropriate) greater than or equal to 50% of expected corrected for hemoglobin.
13. 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.
14. Informed consent explained to, understood by and signed by patient or guardian.

PROCUREMENT Exclusion Criteria:

1. Active infection with HIV or HTLV (can be pending at this time).
2. Active bacterial, fungal or viral infection.

TREATMENT Exclusion Criteria:

1. Currently receiving any investigational agents or received any tumor vaccines within the previous six weeks.
2. Received anti-CD30 antibody-based therapy within the previous 4 weeks.
3. Subjects with rapidly progressive disease, defined as kinetic failure to previous chemotherapy.
4. Bulky disease (defined as a 10 cm or greater mass or mediastinal disease with a transverse diameter exceeding 33% of the transthoracic diameter).
5. History of hypersensitivity reactions to murine protein-containing products.
6. Pregnant or lactating.
7. Tumor in a location where enlargement could cause airway obstruction.
8. Current use of systemic corticosteroids at a dose equivalent to 0.5 mg/kg/day of prednisone or higher.
9. Active hemorrhagic cystitis.
10. Active bacterial, viral or fungal infection.
11. Symptomatic cardiac disease (NYHA Class III or IV disease).

主要终点：Number of Patients with Dose-Limiting Toxicities (DLT) · Each treated patient will be followed for 6 weeks post the T-cell infusion for the evaluation of DLTs. · 6 weeks
次要终点：Median Number of T cells transduced with the vector；Overall Response Rate；Mean Number of T cells transduced with the vector

• CD30.CAR T Cells · EXPERIMENTAL · Each patient will receive one infusion of CAR modified T cells. Unless post autologous transplant, patients will receive lymphodepleting chemotherapy as three daily doses of cyclophosphamide (Cy: 500mg/m2/day) together with fludarabine (Flu:30mg/m2/day) from 48 hours to 2 weeks before T cell infusion. Clofarabine (20 mg/m2/day) may be substituted for fludarabine.

The subject has a type of lymph gland cancer called Lymphoma. The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancer. This research study combines two different ways of fighting disease: antibodies and T cells. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including tumor cells or cells that are infected with germs. Both antibodies and T cells have been used to treat patients with cancers; they both have shown promise, but have not been strong enough to cure most patients. Investigators hope that both will work better together. Investigators have found from previous research that they can put a new gene into T cells that will make them recognize cancer cells and kill them. They now want to test whether these genetically modified T cells given after chemotherapy will be more effective at killing cancer cells. The gene that will be put into the T cells makes an antibody called anti-CD30. This antibody sticks to lymphoma cells because of a substance on the outside of the cells called CD30. Anti-CD30 antibodies have been used to treat people with lymphoma, but have not been strong enough to cure most patients. For this study, the anti-CD30 antibody 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. These CD30 chimeric receptor-activated T cells (CD30.CAR T cells) seem to kill some of the tumor, but they don't last very long and so their chances of fighting the cancer are unknown. Several studies suggest that the infused T cells need room to be able to multiply and grow to accomplish their functions, and that this may not happen if there are too many other T cells in circulation. Because of that, doctors may use chemotherapy drugs to decrease the level of circulating T cells prior to the CD30.CAR T cells infusion. This is called "lymphodepletion" CD30.CAR T cells have previously been studied in lymphoma patients.