Phase I Clinical Trial of ThINKK Adoptive Immunotherapy After Allogeneic Hematopoietic Transplantation in Children With Leukemia or Neuroblastoma

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.

Sex

All

Minimum age

2 Years

Maximum age

12 Years

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

• BACKGROUNDCordeau M, Belounis A, Lelaidier M, Cordeiro P, Sartelet H, Herblot S, Duval M. Efficient Killing of High Risk Neuroblastoma Using Natural Killer Cells Activated by Plasmacytoid Dendritic Cells. PLoS One. 2016 Oct 7;11(10):e0164401. doi: 10.1371/journal.pone.0164401. eCollection 2016. PMID 27716850
• BACKGROUNDBelounis A, Ayoub M, Cordeiro P, Lemieux W, Teira P, Haddad E, Herblot S, Duval M. Patients' NK cell stimulation with activated plasmacytoid dendritic cells increases dinutuximab-induced neuroblastoma killing. Cancer Immunol Immunother. 2020 Sep;69(9):1767-1779. doi: 10.1007/s00262-020-02581-0. Epub 2020 Apr 27. PMID 32342128
• BACKGROUNDPoirier N, Paquin V, Leclerc S, Lisi V, Marmolejo C, Affia H, Cordeiro P, Theoret Y, Haddad E, Andelfinger G, Lavallee VP, Duval M, Herblot S. Therapeutic Inducers of Natural Killer cell Killing (ThINKK): preclinical assessment of safety and efficacy in allogeneic hematopoietic stem cell transplant settings. J Immunother Cancer. 2024 May 15;12(5):e008435. doi: 10.1136/jitc-2023-008435. PMID 38754915
• BACKGROUNDDiaz-Rodriguez Y, Cordeiro P, Belounis A, Herblot S, Duval M. In vitro differentiated plasmacytoid dendritic cells as a tool to induce anti-leukemia activity of natural killer cells. Cancer Immunol Immunother. 2017 Oct;66(10):1307-1320. doi: 10.1007/s00262-017-2022-y. Epub 2017 May 29. PMID 28555259
• BACKGROUNDLelaidier M, Diaz-Rodriguez Y, Cordeau M, Cordeiro P, Haddad E, Herblot S, Duval M. TRAIL-mediated killing of acute lymphoblastic leukemia by plasmacytoid dendritic cell-activated natural killer cells. Oncotarget. 2015 Oct 6;6(30):29440-55. doi: 10.18632/oncotarget.4984. PMID 26320191
• BACKGROUNDCharrier E, Cordeiro P, Brito RM, Mezziani S, Herblot S, Le Deist F, Duval M. Reconstitution of maturating and regulatory lymphocyte subsets after cord blood and BMT in children. Bone Marrow Transplant. 2013 Mar;48(3):376-82. doi: 10.1038/bmt.2012.176. Epub 2012 Oct 15.