CELL INTELLIGENCE · 肿瘤细胞治疗研究

Procurement Inclusion Criteria:

• Diagnosis of recurrent T-cell acute lymphoblastic leukemia (T-ALL), T-cell acute lymphoblastic lymphoma (T-LL), 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

Relapsed post-allogeneic related donor (matched, mismatched, or haploidentical) HSCT from whom allogeneic CD7.CAR T cells can be manufactured.

AND

* suitable for allogeneic hematopoietic stem cell transplant (HSCT)
* with a suitable donor identified by a FACT accredited transplant center
* willing to proceed to transplant if the CD7.CAR treatment induces complete remission and the patient/donor remain suitable candidates.

Using NMDP donor assessment criteria, suitability is defined as "during the search process, a donor is fit to proceed to the next step- whether high-resolution or confirmatory HLA testing OR donor work-up." Documentation of suitability will be confirmed by the investigator prior to treatment.

\*For T-NHL subjects, eligibility will be confined to disease stages where allogeneic HSCT is indicated.

* CD7-positive tumor (≥20% CD7 positive blasts by flow cytometry or immunohistochemistry (tissue) assessed by a CLIA certified Flow Cytometry/Pathology laboratory).
* Age ≤75 years old.
* Hgb ≥ 7.0 g/dL (can be transfused)
* Life expectancy greater than 12 weeks
* 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.
* Informed consent explained to, understood by and signed by patient/LAR. Patient/LAR given copy of informed consent.

Procurement Exclusion Criteria:

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

Prior HSCT Donor Procurement Criteria:

• Donor must be prior hematopoietic stem cell transplant donor for patient relapsed post-allogeneic HSCT who meets patient screening eligibility criteria and has signed screening informed consent.

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 principal investigator or appropriate designee to confirm/provide final eligibility determination and documented in the donor's medical record.

• Informed consent explained to, understood by and signed by donor/LAR. Donor/LAR given copy of informed consent.

Treatment Inclusion Criteria:

• Diagnosis of recurrent T-cell acute lymphoblastic leukemia (T-ALL), T-cell acute lymphoblastic lymphoma (T-LL), 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

Relapsed post-allogeneic related donor (matched, mismatched, or haploidentical) HSCT AND prior allogeneic donor available to donate blood for allogeneic CD7.CAR T-cell manufacture

AND

* suitable for allogeneic hematopoietic stem cell transplant (HSCT)
* with a suitable donor identified by a FACT accredited transplant center
* willing to proceed to transplant if the CD7.CAR treatment induces complete remission and the patient/donor remain suitable candidates.

Using NMDP donor assessment criteria, suitability is defined as "during the search process, a donor is fit to proceed to the next step- whether high-resolution or confirmatory HLA testing OR donor work-up." Documentation of suitability will be confirmed by the investigator prior to treatment.

\*For T-NHL subjects, eligibility will be confined to disease stages where allogeneic HSCT is indicated.

* CD7-positive tumor (≥20% CD7+ blasts or tumor cells by flow cytometry or immunohistochemistry (tissue) assessed in a CLIA certified Flow Cytometry/Pathology laboratory.
* Age ≤75 years old.
* Bilirubin less than 3 times the upper limit of normal.
* AST less than 5 times the upper limit of normal.
* Estimated GFR ≥ 50 mL/min.
* Pulse oximetry of \> 90% on room air
* Karnofsky or Lansky score of ≥ 60%.
* Recovered from acute toxic effects of prior treatments (i.e. chemotherapy) at least one week before entering this study.
* ≥ 60 days post-allogeneic HSCT at time of treatment.
* 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.
* 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.
* Informed consent explained to, understood by, and signed by patient/guardian. Patient/guardian given copy of informed consent.

Treatment Exclusion Criteria:

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

主要终点：Dose limiting toxicity rate · Defined as the proportion of subjects in each group with DLT evaluated as per the CTCAE 5.0 with the exception of Cytokine Release Syndrome (CRS) and neurological toxicities that are related to T cell infusions. · 4 weeks
次要终点：Overall Response Rate

• CD7.CAR/28zeta T Cells · EXPERIMENTAL · Four dose levels will be evaluated. The T cells will be administered following lymphodepleting chemotherapy with cyclophosphamide and fludarabine.

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. This study combines two different ways of fighting disease with antibodies and T cells. Antibodies are types of 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 been used to treat cancer; they have shown promise, but have not been strong enough to cure most patients. T cells 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 is called anti-CD7. This antibody sticks to T-cell leukemia or lymphoma cells because of a substance on the outside of these cells called CD7. CD7 antibodies have been used to treat people with T-cell leukemia and lymphoma. For this study, anti-CD7 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 laboratory, investigators have also found that T cells work better if they also add proteins that stimulate T cells, 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, investigators attach the CD7 chimeric receptor with CD28 added to it to T cells. Investigators will then test how long the cells last. These CD7 chimeric receptor T cells with CD28 are investigational products not approved by the Food and Drug Administration.