CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

* Meets clinical criteria for leukapheresis or has a leukapheresis product previously collected and stored per recommended guidelines.
* Provision of signed and dated consent form from parent or guardian (patients \<18), the patient themselves (\>18), or legally authorized representative (patient \>18 who lack decision-making capacity); Pediatric patients will be included in age-appropriate discussions and assent will be obtained for those \> 7 years of age, when appropriate, according to institutional standards.
* Willingness to participate in long term follow up study.
* Stated willingness to comply with all study procedures and be available for the duration of the study.
* Males OR non-pregnant, non-breastfeeding females.

  o Patients of child-bearing potential or capable of fathering a child must agree to use highly effective contraception from the time of initial CAR T cell administration though 12 months following the final administration of investigational product.
* Aged 31 days to 30 years (inclusive) at time of consent and enrollment.
* Acute Lymphoblastic Leukemia (ALL) OR Non-Hodgkin Lymphoma (NHL) of B-cell origin that:

  * Has confirmed expression of CD19 by flow cytometry, immunohistochemistry (IHC), or both.

Cohort One Criteria:

* Meets any one of the following conditions:

  * Relapsed two or more times
  * Relapsed at any time after allogeneic BMT
  * Refractory to standard therapy as determined by the treating physician
  * Meets criteria for BMT but is ineligible as determined by the treating physician Patient and/or parents declining BMT options and would prefer CAR-T Therapy.
* Non-Hodgkin Lymphoma includes all of the following:

  * Diffuse large B-cell lymphoma (DLBCL)
  * Burkitt Lymphoma
  * Intermediate lymphoma between Burkitt and DLBCL
  * Primary Mediastinal B-cell Lymphoma (PMBL)
  * Follicular lymphoma
  * High grade B cell lymphoma
  * Transformed lymphoma

Cohort Two Criteria:

* B-ALL in first relapse with any one of the following conditions:

  * High-risk genomic alterations at initial diagnosis such as KMT2A gene rearrangement, t(17;19), hypodiploidy, Ph-like mutations, BCR-ABL1 fusion (Ph+ ALL), iAMP21, and TP53 inactivating mutation/deletion.
  * Isolated CNS relapse such that cranial radiation would be indicated as a component of standard salvage therapy.
  * Down syndrome.
  * Minimal residual disease (MRD) positivity of \> 0.01% by FACS or \> 0 clonal sequences by NGS in bone marrow post re-induction chemotherapy.
  * Age 18 years or older. OR Newly diagnosed with persistent MRD ≥ 0.01% by flow cytometry in bone marrow at end of consolidation.
* Performance score (Lansky or Karnofsky) of 50% or better;
* Unable to or declined to receive commercially available CD19 CAR-T Therapy.

Exclusion Criteria:

* Evidence of rapidly progressive disease without adequate salvage/bridging regimens as determined by the investigator.
* Active Graft-versus-Host Disease (GvHD).
* Active, uncontrolled, life-threatening infection that at the determination of the treating physician would preclude safe leukapheresis or tolerance of LD chemotherapy, cell infusion, or cytokine release syndrome.
* Evidence of severe organ dysfunction as defined by:

  * Myocardial dysfunction: Ejection fraction ≤ 40% or shortening fraction ≤ 28%, evidence of physiologically significant pericardial effusion as determined by an echocardiogram (ECHO), and clinically significant electrocardiogram (ECG) findings.
  * Baseline oxygen saturation of ≤ 90% on room air
  * Transaminases \> 10x upper limit of normal (ULN) or bilirubin \>2x the ULN, unless thought to be related to primary disease
  * Estimated Cr clearance \<60 mL/min/1.73 m2 (if nuclear medicine GFR or other more specific testing exceeds this level than it can supersede the estimated clearance)
* Post-pubertal females that are pregnant, planning to become pregnant, or unwilling to use birth control (includes abstinence) for the study duration.
* Known HIV infection, or active Hepatitis B or active Hepatitis C infection.

主要终点：Determine the safety and tolerability of UCD19 CAR-T infusion in pediatric patients with B-ALL or B-NHL · DLTs of UCD19 CAR-T will be assessed at each of the dose levels in a standard 3+3 dose-escalation design with a determination of recommended Phase 2 dose (RP2D). · Post UCD19 infusion to Day 28；Determine the preliminary efficacy of UCD19 CAR-T cells in pediatric patients with B-ALL or B-NHL · Following determination of UCD19 CAR-T RP2D, there will be a cohort expansion to determine preliminary efficacy and biological activity by assessment of CR status. · Day 28 (for B-ALL) and Day 90 (for B-NHL) post UCD19 infusion
次要终点：Determine the preliminary efficacy of UCD19 CAR-T cells in pediatric patients with B-ALL during the expansion phase；Determine the preliminary efficacy of UCD19 CAR-T cells in pediatric patients with B-ALL during the expansion phase；Determine the preliminary efficacy of UCD19 CAR-T cells in pediatric patients with B-ALL during the expansion phase；Determine the preliminary efficacy of UCD19 CAR-T cells in pediatric patients with B-ALL during the expansion phase；Determine the preliminary efficacy of UCD19 CAR-T infusion in pediatric patients after first relapse with B-ALL during the expansion phase；Determine the preliminary efficacy of UCD19 CAR-T infusion in pediatric patients after first relapse with B-ALL during the expansion phase；Determine the preliminary efficacy of UCD19 CAR-T infusion in pediatric patients after first relapse with B-ALL during the expansion phase；Determine the preliminary efficacy of UCD19 CAR-T infusion in pediatric patients after first relapse with B-ALL during the expansion phase

• Phase I: Dose Escalation · EXPERIMENTAL · First 4-18 subjects enrolled. Treated with escalating doses of therapy until the recommended phase 2 dose (RP2D) is determined.
• Phase II: Dose Expansion · EXPERIMENTAL · Up to 18 additional subjects will be treated at the recommended Phase 2 dose (RP2D) to allow for 12 total subjects to be treated in each cohort, including those treated within the phase 1 portion at the RP2D.

This phase I/II trial will investigate a new CD19 directed CAR-T therapy manufactured locally with the goals to expedite infusion to wider patient inclusion that includes those who were previously excluded, such as pediatric patients with B-cell NHL and patients in primary relapse.