Chemoimmunotherapy Combined With Autologous NK Cell Therapy for Pediatric Patients With Refractory and Relapsed High-Risk Neuroblastoma and Ganglioneuroblastoma

Prior treatment

• Absence of comprehensive pre-treatment assessment results at the time of initiation of specific therapy.
• Good response (PR, VGPR, CR) or PD at the end of the induction phase of therapy (applicable only to patients receiving therapy within the framework of the intensified induction phase).
• Requirement for concomitant medications with known cross pharmacodynamic interactions with the drugs used in this clinical trial protocol.
• Pregnancy, due to the high teratogenicity and toxicity of the drugs used in this clinical trial protocol. Female patients of childbearing potential are required to undergo pregnancy testing.

Other illness

• Progressive or relapsed disease with central nervous system involvement and/or leptomeningeal involvement.
• History of acute intolerance reactions to the main chemotherapeutic and immunobiological agents and supportive care drugs used in this clinical trial protocol.
• Presence of complications of the underlying disease and comorbidities that preclude treatment within this protocol, including severe type I hypersensitivity reactions in the medical history.
• Mental illness of the patient or legal guardians that makes it impossible to understand the nature of the study and compromises adherence to medical prescriptions and sanitary-hygienic requirements.

Lab values

• Presence of ultrasonographic signs of heart failure (LVEF ≤ 55%), clinical and laboratory signs of chronic kidney disease of stage ≥ III, or kidney injury of grade I, F or L according to the standardized RIFLE criteria for acute kidney injury (an acronym for "risk, injury, failure, loss, end-stage").

Other

• Lack of a signed voluntary informed consent form for participation in the clinical study.
• Patients with NBL or ganglioneuroblastoma stratified to low or intermediate-risk group

• Signed voluntary informed consent to participate in the clinical trial
• Histologically verified diagnosis of neuroblastoma or ganglioneuroblastoma
• Patients stratified to the high-risk group according to the criteria of the German Society of Pediatric Oncology and Hematology (GPOH) - NB 2004, aged from 18 months to 18 years, and meeting the following conditions:
  • Arm A: Refractory disease - patients who have completed the induction phase of therapy (6 cycles of N5/N6) with a poor response to therapy (MR, SD), with the exception of PD
  • Arm В: Relapsed/progressive disease - patients who develop any new tumor lesions (after having previously achieved СR), or any new tumor lesion; an increase of \>25% in any previously existing measurable lesion; or newly detected bone marrow involvement by NB cells in cases where the bone marrow had previously been free of involvement
• Performance status ≥ 70% (Lansky or Karnofsky scale) at the time of determining the indication for chemoimmunotherapy combined with NK cell therapy.
• Expected life expectancy ≥ 12 weeks.
• No signs of drug-induced neuropathy or neuropathic pain.
• Adequate liver function: alanine aminotransferase (ALT) / aspartate aminotransferase (AST) activity \< 5 × upper limit of normal (ULN).
• Adequate renal function: creatinine clearance or glomerular filtration rate (GFR) \> 60 mL/min/1.73 m².
• Coagulation parameters: prothrombin index (PTI) 70-120%; activated partial thromboplastin time (APTT) \< 36 seconds.
• No clinical signs of heart failure; left ventricular ejection fraction (LVEF) ≥ 55%.
• Adequate respiratory function (oxygen saturation by pulse oximetry \> 94% on room air, no dyspnea at rest), and no pathological findings on chest X-ray.
• Completion of comprehensive assessment to evaluate the extent of the tumor process.