CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

1. Between 2 and less than 13 years old at time of informed consent form signature.
2. Diagnosis of acute leukemia or neuroblastoma.
3. Allogenic hematopoietic stem cell transplantation 30 to 90 days prior to eligibility confirmation.
4. Blood NK cell counts ≥ 100 x 10E+6 cells/L at least once before eligibility confirmation.
5. Life expectancy of ≥ 3 months per investigator's judgment at time of eligibility confirmation.
6. Patient or legally acceptable representative has provided informed consent based on local regulations and/or guidelines prior to any study-specific activities/procedures being initiated.

Exclusion Criteria:

1. Current grade 3 or 4 acute GvHD (per MAGIC criteria).
2. Relapse of primary malignancy, or any other active malignancy.

   1. For leukemia, defined as either morphological relapse or Minimal Residual Disease (MRD) ≥0.01% as measured by flow cytometry. MRD detected by polymerase chain reaction (PCR) does not constitute an exclusion criterion.
   2. For neuroblastoma, defined as a progressive disease.
3. Ongoing therapy with systemic corticosteroids (equivalent to a prednisone dose \>0.5 mg/kg/day). Patients actively undergoing corticosteroid tapering during Screening may be enrolled once they have reached a prednisone-equivalent dose ≤ 0.5 mg/kg/day with Sponsor-Investigator approval, with the expectation that the taper will continue.
4. Ongoing systemic therapy with cyclosporine.
5. Administration or planned administration of any prohibited treatment listed in ad hoc section.
6. Aspartate aminotransferase and alanine aminotransferase serum levels ≥5 times the upper limit of normal.
7. Direct bilirubin serum levels ≥3 times the ULN (unless due to Gilbert syndrome).
8. Baseline estimated glomerular filtration rate \< 50 mL/min/1.73 m2, as determined using the Bedside Schwartz equation for \< 18 years of age.
9. Grade 4 diarrhea (ie, life-threatening consequences with urgent intervention indicated).
10. O2 Sat saturation \<90% on room air by pulse oximetry.
11. Uncontrolled life-threatening symptomatic infection(s).
12. Blood pressure below the 5th percentile for age, sex, and height last 24 hours.
13. Ongoing therapy with intravenous vasopressor agent.
14. Any condition that, in the opinion of the Investigator, would compromise the safety of the patient, would prevent full participation in this study, or would interfere with the evaluation of any study endpoints.
15. Pregnancy or breastfeeding or absence of highly effective methods of contraception for males and females of childbearing potential who engage in heterosexual intercourse

主要终点：Incidence and severity of treatment-emergent adverse events and serious adverse events · From first study drug administration to 4 weeks after last administration；Incidence of dose-limiting toxicities · Defined as: (1) Adverse event (excluding cytopenias) grade ≥ 3 considered to be possibly, probably or definitively related to the investigational product, (2) Cytopenia (anemia, neutropenia or thrombocytopenia) grade ≥ 4 considered to be possibly, probably or definitively related to the investigational product, (3) Grade ≥ 3 ICANS, (4) Grade ≥ 3 CRS and (5) Overall clinical grade ≥ 3 acute GvHD (MAGIC criteria) · From first study drug administration to 4 weeks after last administration；Incidence and severity of treatment-related adverse events · From first study drug administration to 4 weeks after last administration
次要终点：Number of patients who received all infusions；Number of infusions received per patient；Time elapsed between confirmation of eligibility and first infusion；Percentage (%) of viable ThINKK cells at the time of infusion；Assessment of NK surface biomarkers；Assessment of plasmatic biomarkers by Olink®；Assessment of the global immune responses by single cell RNA sequencing

• Treatment · EXPERIMENTAL

A first-in-class adoptive immunotherapy we called ThINKK, for Therapeutic Inducers of Natural Killer (NK) cell Killing, have been designed for use after hematopoietic stem cell transplantation (HSCT), where the proper stimulation of graft-derived NK cells has been shown to prevent relapse. ThINKK immunotherapy builds on our earlier research on NK cells and plasmacytoid dendritic cells (PDC) in cord blood and after HSCT. PDC are the sentinels of the immune system. Upon viral nucleic acids detection, PDC secrete a vast array of chemokines and cytokines that stimulate NK cells. PDC stimulation enhances NK cells killing of infected cells that express stress-induced molecules. Cancer cells also express stress-related molecules at their surface. However, NK cells do not receive PDC stimulation when fighting cancer. ThINKK therapy is designed to provide this necessary stimulation.