CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria for Procurement and T-cell Production:

* Age ≤21 years old
* Relapsed/refractory CD123+ disease defined as follows:

AML/MDS

* Relapsed disease: Patients developing recurrent disease after a first complete remission (CR)
* Refractory disease: Patients not achieving a CR after 2 cycles of induction chemotherapy

B-cell ALL

* Relapsed disease that is CD123 positive and CD19 negative/dim or patients otherwise ineligible for CD19 directed therapies including

  * Patients in 2nd or greater relapse
  * Patients with relapse after allogeneic HSCT
* Refractory disease that is CD123 positive and CD19 negative/dim or patients otherwise ineligible for CD19 directed therapies

T-cell All • Relapsed refractory disease that is CD123 positive

BPDCN

• Relapsed/refractory disease that has failed front-line therapy

* Estimated life expectancy of \>12 weeks
* Karnofsky or Lansky (age-dependent) performance score ≥50
* Patients with a history of prior allogeneic HCT must be clinically recovered from prior HCT therapy, have no evidence of active GVHD and have not received a donor lymphocyte infusion (DLI) within the 28 days prior to apheresis
* Patient must have an identified, suitable HCT donor
* For females of child-bearing age:
* Not lactating with intent to breastfeed
* Not pregnant with negative serum pregnancy test within 7 days prior to enrollment
* Meets eligibility criteria to undergo autologous apheresis, or have previously undergone autologous apheresis

Exclusion Criteria:

* Known primary immunodeficiency
* History of HIV infection
* Severe intercurrent uncontrolled bacterial, viral or fungal infection (e.g. active hepatitis B or C infection or adenovirus infection)
* History of hypersensitivity reactions to murine protein-containing products
* Patients with acute promyelocytic leukemia (APL, t (15;17))
* Known contraindication to the protocol defined lymphodepleting chemotherapy regimen of fludarabine/cyclophosphamide.

Inclusion Criteria for Treatment:

* Age≤21 years old
* Detectable disease that is CD123+ (at least MRD+ disease)
* Estimated life expectancy of \>8 weeks
* Karnofsky or Lansky (age-dependent) performance score≥50
* Patients with a history of prior allogeneic HCT must be clinically recovered from prior HCT therapy, have no evidence of active GVHD and have not received a donor lymphocyte infusion (DLI) within the 28 days prior to planned infusion
* Patient must have an identified, suitable HCT donor
* Adequate cardiac function defined as left ventricular ejection fraction \>40%, OR shortening fraction ≥25%
* EKG without evidence of clinically significant arrhythmia
* Adequate renal function defined as creatinine clearance or radioisotope GFR ≥50 ml/min/1.73m2 (GFR ≥40 ml/min/1.73m2 if \< 2 years of age)
* Adequate pulmonary function defined as forced vital capacity (FVC)≥50% of predicted value; or pulse oximetry≥92% on room air if patient is unable to perform pulmonary function testing
* Total Bilirubin≤3 times the upper limit of normal for age, except in subjects with Gilbert's syndrome
* Alanine aminotransferase (ALT) OR aspartate aminotransferase (AST) ≤5 times the upper limit of normal for age
* Has recovered from all NCI CTAE grade III-IV, non-hematologic acute toxicities from prior therapy
* For females of child-bearing age

  * Not lactating with intent to breastfeed
  * Not pregnant with negative serum pregnancy test within 7 days prior to enrollment
* If sexually active, agreement to use birth control until 3 months after T- cell infusion. Male partners should use a condom.
* Available autologous transduced T-cell product that has met GMP release criteria

Exclusion Criteria:

* Known primary immunodeficiency
* History of HIV infection
* Severe intercurrent uncontrolled bacterial, viral or fungal infection
* History of hypersensitivity reactions to murine protein-containing products
* History of severe hypersensitivity reactions to cornstarch or hydroxyethyl starch.
* Receiving systemic steroids therapy exceeding the equivalent of 0.5 mg/kg/day of methylprednisolone, in the 7 days prior to CD123-CAR T- cell infusion
* Receiving systemic therapy in the 14 days prior to CD123-CAR T-cell infusion, which will interfere with the activity of the CD123-CAR T cells in vivo (in the opinion of the study PI(s))
* Receiving rituximab therapy in the 30 days prior to CD123-CAR T cell infusion. (This exclusion criterion is intended to prevent premature exposure of CD123-CAR T cells to rituximab, which would activate the safety switch and promote CAR T-cell apoptosis).
* Receiving intrathecal chemotherapy in the 7 days prior to CD123-CAR T cell infusion.
* Known contraindication to the protocol defined lymphodepleting chemotherapy regimen of fludarabine/cyclophosphamide.
* Active CNS disease

主要终点：Maximum tolerated dose of CD123-CAR T cells (CATCHAML) · A phase I design to determine the maximum tolerated dose (MTD) of autologous, CD123- CAR T cells. Four dose levels (3x10\^5/kg, 1x10\^6/kg, 3x10\^6/kg, and 1x10\^7/kg) will be evaluated. · 4 weeks after CD123-CAR T-cell infusion

• ARM A CD123-CAR T cell therapy · OTHER · For patients who have not received an allogeneic transplant or for patients who have received allogeneic transplant and do not have a transplant donor available CD123-CAR T-cell dose and infusion Up to 4 Dose levels will be evaluated with a maximum dose of 2.5 x 10\^8 CAR+ T cells. If dose limiting toxicities (DLTs) are observed on Dose level 1 then the cell dose is de- escalated.
• ARM B CD123-CAR T cell therapy · EXPERIMENTAL · For patients who relapsed following allogeneic transplant and whose CAR T-cells will be manufactured from the previous transplant donor, when available. CD123-CAR T-cell dose and infusion Up to 4 Dose levels will be evaluated with a maximum dose of 2.5 x 10\^8 CAR+ T cells. If dose limiting toxicities (DLTs) are observed on Dose level 1 then the cell dose is de- escalated.

The CD123-CAR T-cell therapy is a new treatment that is being investigated for treatment of AML/myelodysplastic syndrome (MDS), T- or B- acute lymphoblastic leukemia (ALL) or blastic plasmacytoid dendritic cell neoplasia (BPDCN). The purpose of this study is to find the maximum (highest) dose of CD123-CAR T cells that is safe to give to these patients. This would include studying the side effects of the chemotherapy, as well as the CD123-CAR T-cell product on the recipient's body, disease and overall survival. Primary Objective: * To determine the safety of one intravenous infusion of escalating doses of autologous, CD123-CAR T cells in patients (≤21 years) with recurrent/refractory CD123+ disease (AML/MDS, B-ALL, T-ALL or BPDCN) after lymphodepleting chemotherapy. * To determine the safety of an intravenous infusion of escalating doses of donor derived, CD123-CAR T cells in patients (≤21 years) with recurrent/refractory CD123+ disease (AML/MDS, B-ALL, T-ALL, BPDCN or MPAL) after lymphodepleting chemotherapy. Secondary Objectives \- To evaluate the antileukemia activity of CD123-CAR T cells. Exploratory Objectives * To assess the immunophenotype, clonal structure and endogenous repertoire of CD123-CAR T cells and unmodified T cells * To characterize the cytokine profile in the peripheral blood and CSF after treatment with CD123-CAR T cells * To characterize tumor cells post CD123-CAR T-cell therapy * To compare in vivo properties of donor-derived versus autologous CD123- CAR T cells