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.
Primary Objective: To assess the safety and tolerability of ThINKK adoptive immunotherapy by determination of the Maximum Tolerated Dose (MTD) in patients who has undergone allogenic HSCT for acute leukemia (ALL or AML) or neuroblastoma. * Secondary Objectives: * To demonstrate the feasibility of delivering (manufacturing and administrating) ThINKK adoptive immunotherapy after HSCT. * To assess biological effect at MTD (pharmacodynamic studies).
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
12
This study uses an adaptation of the classical 3+3 dose-escalation model. The Maximum Tolerated Dose (MTD) is determined as the highest dose level at which six patients are treated with no unacceptable increase in acute GvHD risk and with no more than one patient experiencing a DLT. The first cohort (3 patients) will receive 7.5 M ThINKK/m2 weekly for 4 weeks. Dose distribution for the escalation levels will be guided by the pharmacodynamic data from the initial cohort.. If the preliminary data show that TRAIL expression remains stable at Day +8, dose level 2 will be set at 15 × 10\^6 / m2 BSA weekly, and dose level 3 at 30 × 10\^6 / m2 BSA weekly. If the data instead indicate the need to shorten the dosing interval to maintain TRAIL expression, dose level 2 will be set at 7.5 × 10\^6 / m2 BSA bi-weekly and dose level 3 at 15 × 10\^6 / m2 BSA bi-weekly.
The Hospital for Sick Children
Toronto, Ontario, Canada
CHU Sainte-Justine
Montreal, Quebec, Canada
Incidence and severity of treatment-emergent adverse events and serious adverse events
Time frame: 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)
Time frame: From first study drug administration to 4 weeks after last administration
Incidence and severity of treatment-related adverse events
Time frame: From first study drug administration to 4 weeks after last administration
Number of patients who received all infusions
Time frame: At the end of week 4
Number of infusions received per patient
Time frame: At the end of week 4
Time elapsed between confirmation of eligibility and first infusion
Time frame: At day 1
Percentage (%) of viable ThINKK cells at the time of infusion
Time frame: Day of infusion
Assessment of NK surface biomarkers
Time frame: From first study drug administration to 1 week after last administration
Assessment of plasmatic biomarkers by Olink®
Time frame: From first study drug administration to 1 week after last administration
Assessment of the global immune responses by single cell RNA sequencing
Time frame: Prior to first infusion and up to 1 week post last infusion
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