Neuroblastoma (NB) is a malignant neoplasm of the sympathetic nervous system, occurring in 1 in 8,000 live births, accounting for 6-10% of all childhood malignant neoplasms and responsible for 12-15% of mortality -, making it the most common and life-threatening extracranial tumor in childhood.
Patients with stage 4 high-risk NB is the subgroup with the poorest prognosis. Within this group, two subgroups with an extremely unfavorable disease course are distinguished: patients with a poor response to the induction phase of therapy (refractory disease) and patients with relapsed or progressive disease.
Nowadays, 10-15% of patients show a poor end-induction response, whereas achieving a good end-induction response associated with better long-term survival. Improvement of the response to induction therapy may contribute to better treatment outcomes in newly diagnosed high-risk NB patients and can be achieved by intensification of the induction phase to decrease the number of patients with refractory disease. Also intensification of the second-line therapy may contribute to better responses in patients with relapsed and progressive disease.
Protocol aimed to overcome heterogeneous tumor drug resistance through the synergistic interaction of cytostatic and immunobiological agents in combination with NK cell therapy.
This approach combines cytotoxic agents with anti-GD2 monoclonal antibodies (mAb) to enhance antitumor activity. Cultured, ex vivo-activated autologous NK cells are infused to compensate for effector cell depletion during therapy and to augment antibody-dependent cellular cytotoxicity (ADCC), potentially improving clinical outcomes.
This comprehensive approach opens novel prospects for enhancing treatment efficacy in patients with refractory and relapsed high-risk NB.
The expected outcomes of this protocol include a significant increase in therapeutic efficacy indicators - objective response rate (ORR), overall survival (OS), progression-free survival (PFS) and relapse-free survival (RFS), as well as in patient quality of life.
Signed voluntary informed consent to participate in the clinical trial
Histologically verified diagnosis of neuroblastoma or ganglioneuroblastoma
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
Lack of a signed voluntary informed consent form for participation in the clinical study.
Absence of comprehensive pre-treatment assessment results at the time of initiation of specific therapy.
Patients with NBL or ganglioneuroblastoma stratified to low or intermediate-risk group
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).
Parallel
Dinutuximab beta, temozolomide, irinotecan, autologous NK cell
Combination productAs part of the intensified induction, a procedure for the collection of mononuclear cells for the cultivation and expansion of the autologous NK cell product (Day -1) is planned, followed by one course of chemotherapy according to the IT regimen (irinotecan + temozolomide) and four courses of chemoimmunotherapy in combination with autologous NK cell therapy according to the DIT regimen (irinotecan + temozolomide + dinutuximab beta + NK-cell product), with an inter-cycle interval of 21 days. Transfusion of the autologous NK cell product will be performed on Day 7 of each DIT course.
irinotecan, temozolomide, dinutuximab beta, NK-cell product
Combination productPatients who meet the inclusion criteria will undergo an intensified induction phase within the framework of this clinical trial protocol, while the preceding induction phase and subsequent consolidation and post-consolidation phases will be performed outside of this protocol in accordance with the current clinical practice. As part of the intensified induction, a procedure for the collection of mononuclear cells for the cultivation and expansion of the autologous NK cell product (Day -1) is planned, followed by one course of chemotherapy according to the IT regimen (irinotecan + temozolomide) and four courses of chemoimmunotherapy in combination with autologous NK cell therapy according to the DIT regimen (irinotecan + temozolomide + dinutuximab beta + NK-cell product)
Tolerability and toxicity of chemoimmunotherapy in combination with NK cell therapy.
(Proportion of patients receiving at least 80% of the planned doses without grade ≥ 3 adverse immunological reactions (ADRs) related to the NK cell product, assessed acc
ORR after completion of chemoimmunotherapy courses in combination with NK cell therapy.
(The proportion of patients with a good response (CR, VGPR and PR) to therapy, assessed in accordance with the International Response Criteria for Patients with NB)
ORR after completion of study therapy.
(The proportion of patients who achieved a good response (CR, VGPR and PR) to therapy, assessed in accordance with the International Response Criteria for Patients with NB)).
OS and EFS at 1 year, 3 years, and 5 years after completion of study therapy.
For patients with refractory disease: The proportion of surviving patients, regardless of disease status (for OS) and the proportion of patients without adverse events, such as relapse, progression or death (for EFS)).
OS, PFS, and RFS at 1 and 3 years after completion of the study therapy.
For patients with progression/relapsed disease: The proportion of surviving patients from the time of diagnosis, regardless of disease status (for OS); the proportion of patients without disease relapse (for RFS) or disease progression (for PFS) from the time of the relapse or progression).
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