CELL INTELLIGENCE · 肿瘤细胞治疗研究

PROCUREMENT

Inclusion Criteria:

1. Diagnosis of primary refractory or relapsed Acute Myeloid Leukemia (AML) with the exception of acute promyelocytic leukemia (APL) AND suitable for consideration of allogeneic Hematopoietic Stem Cell Transplant with confirmation of an identified eligible donor by a FACT accredited transplant center
2. CLL-1 positive tumor with at least 30% CLL-1 blasts by flow cytometry or immunohistochemistry (tissue) assessed by a CLIA certified Flow Cytometry/Pathology laboratory
3. Age ≤75 years NOTE: The first six (6) patients treated on the study will be adults (≥18 yrs of age).
4. Hgb ≥ 7.0 g/dL(can be transfused)
5. Life expectancy greater than 12 wks
6. If apheresis required to collect blood

   * PT and APTT \<1.5x ULN
   * Serum Creatinine \< 1.5 x ULN
   * AST \< 1.5 x ULN
7. Informed consent

Exclusion Criteria:

1. Diagnosis of acute promyelocytic leukemia (APL)
2. Active infection (bacterial, fungal or viral) requiring ongoing treatment without improvement.
3. Active infection with HIV or HTLV (results may be pending)
4. Active second cancer (except non-melanoma skin cancer or in situ breast cancer or cervix cancer)or other cancer treated ≤ 2 years prior to enrollment
5. Ongoing treatment with immune suppression for prophylaxis or treatment of GVHD including high dose steroids (e.g. prednisone \> 0.25mg/kg)

TREATMENT

Inclusion Criteria:

1. Diagnosis of primary refractory or relapsed Acute Myeloid Leukemia (AML) with the exception of acute promyelocytic leukemia (APL). Patients with targetable mutations should have failed or be ineligible for targeted therapies (e.g. FLT3 inhibitors, IDH inhibitors, or anti-CD33 drug conjugate). AND patients should be suitable for consideration of allogeneic Hematopoietic Stem Cell Transplant with confirmation of an identified eligible donor by a FACT accredited transplant center and with confirmation that the center plans to proceed with transplant if CLL-1.CAR treatment induces a response they consider adequate to proceed to allogeneic HSCT.
2. CLL-1 positive tumor with at least 30% CLL-1 blasts by flow cytometry or immunohistochemistry (tissue) assessed by a CLIA certified Flow Cytometry/Pathology laboratory
3. Age ≤75 years NOTE: The first six (6) patients treated on the study will be adults (≥18 yrs of age).
4. AST/ALT less than 5 times the upper limit of normal
5. Bilirubin less than 3 times the upper limit of normal
6. Estimated GFR ≥ 60ml/min
7. Pulse oximetry of \> 92% on room air
8. Karnofsky/Lansky ≥ 60
9. No systemic chemotherapy at least 2 weeks prior to treatment on study and must be recovered from all acute toxic effects of prior chemotherapy at time of treatment
10. Available autologous transduced activated peripheral blood T-cell product with ≥ 20% expression of CLL-1.CAR.28z by flow cytometry
11. Life expectancy \> 12 weeks
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.

Exclusion Criteria:

1. Diagnosis of acute promyelocytic leukemia (APL)
2. Currently receiving any investigational agents or having received any tumor vaccines within the previous 6 weeks.
3. History of hypersensitivity reactions to murine protein-containing products.
4. Pregnant or lactating.
5. Active infection with HIV or HTLV.
6. Clinically significant bacterial, viral or fungal infection requiring ongoing antifungal therapy without improvement,.
7. Fever of unknown origin without complete work-up including imaging (CT head, sinus, chest, abdomen/pelvis)
8. Cardiac criteria: Prolonged QTc with maximum interval as defined by age; Uncontrolled atrial fibrillation/flutter; Myocardial infarction; 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 6 months of treatment.
9. CNS abnormalities: Presence of CNS disease defined as detectable cerebrospinal blast cells in a sample of CSF with ≥ 5 WBCs per mm\^3 or chloroma on imaging, History or presence of an underlying CNS disorder such as a seizure disorder requiring current use of antiepileptic medications, cerebrovascular ischemia/hemorrhage within prior 6 months, dementia, cerebellar disease, or any autoimmune disease with CNS involvement.
10. Use of serotherapy with Campath or Anti-Thymocyte Globulin (ATG) within the last 28 days
11. Use of Donor Lymphocyte Infusion (DLI) or other cellular therapy product within 30 days
12. Acute GVHD ≥ Grade 2 or moderate to severe (formerly extensive) chronic GVHD
13. Administration of high dose steroids \>1 mg/kg within the preceding 5 days or currently receiving \> 0.25 mg/kg of Prednisone equivalent
14. Hyperleukocytosis (WBC ≥50K) or rapidly progressive disease that in the estimation of the investigator would compromise the ability of the patient to complete the study.

主要终点：Dose limiting toxicity (DLT) rate · To assess dose limiting toxicities per protocol-defined CLL-1.CAR T related adverse events and CTCAE v5.0 · 4 weeks post T cell infusion
次要终点：Overall Response Rate

• CLL-1.CAR · EXPERIMENTAL · Group A

Patients eligible for this study have a type of blood cancer Acute Myeloid Leukemia (AML) which has come back or has not gone away after treatment. The body has different ways of fighting disease and infection, and this research study combines two different ways of fighting cancer with antibodies and T cells with the hope that they will work together. T cells (also called T lymphocytes) are special infection-fighting blood cells that can kill other cells including tumor cells. Antibodies are types of proteins that protect the body from bacterial and other infectious diseases. Both antibodies and T cells have been used to treat patients with cancers; they have shown promise, but have not been strong enough to cure most patients when used alone. T lymphocytes can kill tumor cells but there normally are not enough of them to kill all the tumor cells. Some researchers have taken T cells from a person's blood, grown more of them in the laboratory and then given them back to the person. The antibody used in this study targets CLL-1. This antibody sticks to AML cells because of a substance (protein) on the outside of these cells called CLL-1. For this study, the antibody to CLL-1 has been changed so that instead of floating free in the blood, it is now joined to the T cells. When T-cells contain an antibody that is joined to them, they are called chimeric antigen receptor T-cells or CAR-T cells. In the laboratory, the investigators have also found that T cells work better if proteins that stimulate T cells are also added, such as one called CD28. Adding the CD28 makes the cells grow better and last longer in the body, thus giving the cells a better chance of killing the leukemia or lymphoma cells. In this study we are going to attach the CLL-1 chimeric receptor that has CD28 added to it to the patient's T cells. We will then test how long the cells last. These CLL-1 chimeric antigen receptor T cells with CD28 are investigational products not approved by the Food and Drug Administration.