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). Patients with targetable mutations should have failed or be ineligible for targeted therapies (e.g. FLT3 inhibitors, IDH inhibitors or anti-CD33 drug conjugate)

   OR

   Patients with other relapsed or refractory CD70+ leukemia that would be considered an indication for allogeneic Hematopoietic Stem Cell Transplant (HSCT) if remission can be achieved. (CD19+ leukemia only: Patients must have failed or be ineligible to receive commercial CD19.CAR T cell treatments.)

   Primary refractory or resistant disease, for purposes of procurement, defined as not achieving complete remission (CR) (i.e., a remaining blast count of 5% or more) after 1 to 2 cycles of intense induction therapy.

   Relapse is defined as (1) hematologic relapse after complete remission based on bone marrow blasts \>=5%, or reappearance of blasts in the blood, or development of extramedullary disease; (2) molecular relapse after minimal residual disease (MRD) negative, complete remission based on reoccurrence of MRD as assessed by RT-qPCR or by multi-parametric flow cytometry (MFC)
2. CD70 positive leukemia with at least 26% CD70+ blasts by flow cytometry or immunohistochemistry (staining can be pending at time of procurement)
3. Age ≤75 years. NOTE: The first three (3) patients treated on the study will be adults (≥18 years of age)
4. Hemoglobin ≥ 7.0 g/dL (can be transfused)
5. If apheresis required to collect blood

   * PT and aPTT \<1.5x ULN
   * Serum Creatinine \< 2 x ULN
   * AST \< 5 x ULN
6. Informed consent

Procurement Exclusion Criteria:

1. Diagnosis of acute promyelocytic leukemia (APL)
2. Active infection (bacterial, fungal, or viral) requiring ongoing treatment without improvement.
3. Known active infection with HIV or HTLV (collected blood will be sent for HIV/HTLV testing, separate testing prior to procurement not required). Patients with HIV are eligible if viral load is undetectable on therapy and CD4 count is \>350 mm3.
4. Active second cancer (except non-melanoma skin cancer or in situ breast cancer or cervical cancer) or other cancer treated ≤ 2 years prior to enrollment
5. Ongoing treatment with immune suppression for prophylaxis/treatment of GVHD including high dose steroids (e.g. prednisone equivalent \> 0.5 mg/kg/day)

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).

   OR

   Patients with other relapsed or refractory CD70+ hematological leukemias that would be considered an indication for allogeneic Hematopoietic Stem Cell Transplant (HSCT) if remission can be achieved. Patients with CD19+ malignancies must have failed or be ineligible to receive commercial CD19.CAR T cell treatments.

   Primary refractory or resistant disease as defined by not achieving complete remission (CR) (i.e., a remaining blast count of 5% or more) after 1 to 2 cycles of intense induction therapy. Patients with no reduction in blast count after the first cycle or with p53 mutations without CR after the first cycle of intense induction therapy are also considered primary refractory.

   Relapse is defined as (1) hematologic relapse after complete remission based on bone marrow blasts \>=5%, or reappearance of blasts in the blood, or development of extramedullary disease; (2) molecular relapse after minimal residual disease (MRD) negative, complete remission based on reoccurrence of MRD as assessed by RT-qPCR or by multi-parametric flow cytometry (MFC)
2. Confirmation from the patient's primary physician team of a suitable allogeneic hematopoietic stem cell transplant (HSCT) donor. OR Documentation that patient declines a potential subsequent HSCT)
3. CD70 positive leukemia with at least 26% CD70+ cells by flow cytometry or immunohistochemistry (tissue)
4. 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.
5. Age ≤ 75 years. NOTE: The first three (3) patients treated on the study should be adults (≥18 years of age). Thereafter, a thorough review of the safety data will be performed and submitted to the FDA for approval prior to enrolling pediatric patients.
6. Hemoglobin ≥ 7.0 g/dL (can be transfused)
7. Total bilirubin \< 3 times the upper limit of normal
8. AST/ALT \< 5 times the upper limit of normal
9. Estimated GFR ≥ 60ml/min
10. Pulse oximetry of \> 90% on room air
11. Karnofsky/Lansky score of ≥ 60%
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. Male partner should use a condom
13. Informed consent obtained

Treatment Exclusion Criteria:

1. Diagnosis of acute promyelocytic leukemia (APL)
2. Currently receiving any investigational agents or received any tumor vaccines within the previous 6 weeks.
3. Pregnant or lactating.
4. Uncontrolled infection with HIV, or HTLV. Patients with HIV are eligible if viral load is undetectable on therapy and CD4 count is \>350 mm3.
5. Clinically significant bacterial, fungal, or viral infection requiring ongoing therapy without improvement.
6. Cardiac abnormalities: Cardiac echocardiography with LVEF\<50%; Cardiac dysfunction NYHA III or IV; Clinically significant pericardial effusion. Confirmation of absence of these conditions within 6 months of treatment.
7. Presence of CNS disease: Defined as detectable cerebrospinal blast cells in a sample of CSF with ≥ 5 WBCs per mm3 or known CNS tumors/chloromas (repeat spinal tap within 4 weeks only required for leukemia patients with known CNS disease)
8. Use of serotherapy with Campath or Anti-Thymocyte Globulin (ATG) within the last 28 days
9. Use of Donor Lymphocyte Infusion (DLI) or other cellular therapy product within 28 days
10. Acute GVHD ≥ Grade 2 or moderate to severe (formerly extensive) chronic GVHD
11. High dose steroids \>1 mg/kg within preceding 5 days or currently receiving \>0.5mg/kg/day prednisone equivalent
12. Hyperleukocytosis (WBC ≥ 50K) or rapidly progressive disease that in the estimation of the investigator would compromise the ability of the patient to complete the initial 6 weeks of the study

主要终点：Dose limiting toxicity (DLT) rate · 1\. Dose-limiting toxicity (CTCAE v5.0) is defined as any grade 3 or 4 non-hematologic toxicities (including allergic reactions and ICANS) that fails to return to Grade 2 within 72 hours or any grade 5 toxicity (additional assessment criteria may apply). · Time Frame 4 weeks post infusion
次要终点：Overall Response Rate

• Treatment Arm A · EXPERIMENTAL · Patients will initially be consented for procurement of blood for generation of the transduced T-cells. Three dose levels will be evaluated and a possible dose level -1 in case of unexpected toxicity at dose level 1. Each patient will receive one T cell infusion.

This study is for patients who have a type of blood cancer that expresses the protein CD70, which includes acute myeloid leukemia (AML), T-cell leukemia or B-cell leukemia (and the leukemia has come back or has not gone away after standard of care treatment). As there are limited or no remaining standard treatments available to treat this cancer, subjects are being asked to volunteer to be in a gene transfer research study using special immune cells to create a specialized immune cell that will recognize a protein called CD70 that is expressed on the outside surface of the leukemia cells in a subject's body. The body has different ways of fighting infection and disease. No one way seems perfect for fighting cancers. This research study combines different ways of fighting disease by using T cells and "arming" them to recognize a specific protein on cancer cells. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells including tumor cells. T cells by themselves have been used to treat patients with cancers and have shown promise, but have not been strong enough to cure most patients. 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 protein used in this study is called anti-CD70. It has been developed from human CD27 on normal T cells, since it is the natural binding partner that can connect with CD70. This anti-CD70 protein sticks to leukemia cells when it binds to CD70. CD70 binders have been used to treat people with leukemia. For this study, anti-CD70 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 or "CAR T cell". The doctors then made another change to cause these T cells to kill any cell that has CD70. This causes the "CAR T cells" to kill blood cancer cells which are confirmed to have CD70. In the laboratory, investigators have found that T cells work better if there are proteins added which stimulate T cells. The anti-CD70 (CD27) protein is unique because it can bind to CD70 on leukemia cells but also stimulates the T cells that express it. Adding the CD27 makes the cells grow better and may help them to last longer in the body, thus giving the cells a better chance of killing the leukemia cells. These CD70 "CAR" T cells are investigational products not approved by the Food and Drug Administration. The purpose of this study is to find a dose of CAR T cells that is safe, to learn what the side effects are and to see whether this therapy might help people with leukemia.