Medical interview with Professor Li Yang: High-risk neuroblastoma treatment is difficult, comprehensive treatment, innovative drug technology to improve the survival of children

Neuroblastoma (NB) is the most common extrabrain solid tumor in children, about 90% of patients have onset age < 5 years old, accounting for 8% to 10% of children's malignancies, its biological behavior is diverse, and the etiology is complex

01

NB is divided into very low-risk, low-risk, intermediate-risk, and high-risk groups according to factors such as the patient's age of onset, tumor histology type, and tumor stage^[1].

At this stage, the treatment strategy of high-risk NB is comprehensive treatment

According to the latest consensus, a total of 6 courses of chemotherapy are required during the induction period of high-risk NB, mainly including cyclophosphamide (CTX), doxorubicin (DOXO), topocampolican (TOPO) and other drugs

In addition, radiation therapy is required for high-risk NB patients to reduce tumor recurrence in situ in situ in combination with primary tumor lesions and residual metastatic sites^[3]; Maintenance therapy consists mainly of antiganglioside (GD2) monoclonal antibody immunotherapy combined with granulocyte-macrophage colony-stimulating factor (GM⁃CSF) and cis-cis-tretinoin (13⁃CRA) therapy

Figure 1 Comparison of event-free survival (EFS) and overall survival (OS) rates between immunotherapy group and standard therapy group[6]

02

At present, there is no clear effective treatment plan for relapsed NB at home and abroad, so in addition to radiotherapy and chemotherapy, medical centers around the world are constantly exploring more effective treatment methods
to improve the survival rate of children with recurrent NB.

In addition to the salvage chemotherapy treatment program, the current treatment methods for recurrent NB at home and abroad also include radionuclide therapy such as 131I⁃MIBG, targeted drug therapy based on second-generation sequencing results, GD2 monoclonal antibody therapy, chimeric antigen receptor T cell (CAR-T) therapy, auto-HSCT, allo-HSCT, etc
.

At present, the Department of Oncology and the Department of Hematopoietic Stem Cell Transplantation of the Children's Medical Center of Sun Yat-sen Memorial Hospital of Sun Yat-sen University have innovatively used arsenic trioxide (As2O3) combined chemotherapy and allo-HSCT to treat children with relapsed refractory high-risk NB after preliminary research and exploration, which has shown obvious efficacy advantages
over traditional treatment.

03

High-dose chemotherapy combined with hematopoietic stem cell transplantation can improve patient survival

In consolidation therapy in high-risk NB patients, the use of high-dose chemotherapy in combination with auto-HSCT improves patient outcomes
.

In the traditional auto-HSCT, CEM (carboplatin, etoposide, and marfarin) pretreatment protocols were adopted, and 5-year EFS (30±4% vs 19±3%) and OS (37±4% vs 28±4%) were better than chemotherapy alone; The busulfan/muffalan medullary pretreatment protocol further increased the 5-year EFS rate (45%) and OS rate (54%)
compared with the CEM protocol.

However, the efficacy of domestic auto-HSCT in the treatment of high-risk NB is not good, with a 5-year disease-free survival (DFS) rate of only 20.
7% and a 5-year OS rate of about 34.
5%.


In addition, high-risk NB often causes a high proportion of relapses or refractory due to minimal residual lesions (MRD), and there is a clinical urgent need for consolidation therapy that can be more effective in clearing MRD
.

The graft anti-tumor (GVT) effect produced by the donor immune system reconstructed after allo-HSCT can achieve the purpose of clearing MRD and preventing disease recurrence, and it has been confirmed that allo-HSCT can remove residual lesions of auto-HSCT after refractory/recurrent NB patients through the GVT effect and prolong the DFS
of children.

The initial efficacy of allo-HSCT treatment of high-risk NB in stage 4/M at this stage carried out by the Children's Medical Center of Sun Yat-sen Memorial Hospital of Sun Yat-sen University is encouraging, even if a small number of children still have recurrence of bone marrow or bone residual lesions after receiving allo-HSCT, but their recurrence after auto-HSCT is also easier to successfully control through subsequent chemotherapy; In addition, the use of GD2 antibody therapy after allo-HSCT can also provide a stronger alloreactive immune killing effect to high-risk NB children than auto-HSCT, showing that allo-HSCT is a feasible means to break through the current auto-HSCT treatment bottleneck of high-risk NB in stage 4/M, and can overcome the technical disadvantages of not being able to collect enough autologous stem cells for auto-HSCT due to long-term chemotherapy, young age, low body weight, etc.
At the same time, it provides technical bottom and rescue means for children with recurrence after auto-HSCT; With the continuous maturity, development and advancement of hematopoietic stem cell transplantation technology, allo-HSCT may become a new option
for high-risk NB consolidation therapy in stage 4/M in the future.

04

GD2 monoclonal antibody stands out in NB immunotherapy, and the prospect of tumor vaccine is promising

Tumor vaccine belongs to one of the tumor immunotherapy, unlike many classic immune checkpoint inhibitors (ICBs) in adult cancers and the superior efficacy of CAR-T cells in hematological malignancies, most of the children's solid tumors are almost crushed in the sand, for example, NB has not yet found a targeted drug
that can directly act on the high-risk gene - MYCN gene.

The reason may be that children have less mutation load of solid tumor oncogene mutations than adults, relatively insufficient immune effector cells in the tumor microenvironment, and multigerm layer involvement of tumor origin, resulting in a lower
response rate to monoclonal antibody therapy and single-signaling pathway targeted drug therapy.

However, antibody therapy against GD2 is the most specific and widely used targeted immunotherapy
in NB therapy in recent years.

Studies have shown that GD2 is 100% highly expressed in NB cells, which is an ideal immunotherapy target for high-risk NB patients, and many studies have achieved gratifying results, such as the HR-NBL1/SIOPEN study showing the effectiveness of GD2 monoclonal antibody in the treatment of high-risk NB (Figure 2) ^[8].

Figure 2 Comparison of 5-year cumulative recurrence rate or disease progression rate (CIR) in the GD2 monoclonal antibody treatment group and the control group ^[8].

The NB tumor vaccine is an emerging immunotherapy
based on the GD2 target.

As active immunity, tumor vaccines are theoretically superior to monoclonal antibody therapy and can take advantage of the synergistic antibody effect
of monoclonal antibody deficiency.

In addition, compared with a single injection of monoclonal antibodies, after the child is vaccinated with tumor vaccine to form an immune memory, anti-tumor antibodies continue to exist in the body, which can effectively control tumor load such as reducing the tumor microresidue
of NB.

Therefore, the current direction of NB tumor vaccine efforts should be to explore suitable vaccine adjuvants, by enhancing the antigen presentation cell processing and presentation of antigen, stimulating the proliferation and differentiation of lymphocytes, in order to achieve the effect
of enhancing specific immune response.

It is believed that in the future, NB tumor vaccine will become an effective means or even a major means
of treatment for some children with NB.

05

Professor Li Yang concluded

Although hierarchical diagnosis and comprehensive treatment can improve the survival rate of high-risk NB patients to a certain extent, their high degree of malignancy and strong recurrence/metastasis have caused bottlenecks
in current clinical treatment.

At this stage, high-risk NB treatment still has a long way to go, and treatment strategies such as tumor vaccines need to be further explored to bring hope
for a cure for more children with NB.

Expert profile

Professor Li Yang

Sun Yat-sen Memorial Hospital, Sun Yat-sen University

Deputy Director, Chief Physician of the Department of Oncology, Doctoral Supervisor of the Chinese Medical Doctor Association Pediatric Planning Training Base Flight Examination and Evaluation Expert, Chairman of the Pediatric Oncology Professional Committee of the Guangdong Anti-Cancer Association, Vice Chairman of the Pediatric Solid Oncology Professional Committee of the Guangdong Clinical Medical Association published more than 70 first authors (or corresponding authors) papers in related fields, and more than 10 papers were included in SCI

References: (swipe to view)

1.
MONCLAIR T, BRODEUR G M, AMBROS P F, et al.
The international neuroblastoma risk group (INRG) staging system: an INRG task force report[J].
Journal of Clinical Oncology Official Journal of the American Society of Clinical Oncology, 2009, 27 (2) :289-297.

2.
BAKER D L, SCHMIDT M L, COHN S L, et al.
Outcome after reduced chemotherapy for intermediate-risk neuroblastoma[J].
New England Journal of Medicine, 2010, 363 (14) :1313.

3.
Liu KX, Naranjo A, Zhang FF, et al.
Prospective evaluation of radiation dose escalation in patients with high⁃risk neuroblastoma and gross residual disease after surgery: a report from the children's oncology group ANBL0532 study[J].
J Clin Oncol,2020,38(24):2741⁃2752.

4.
Yu AL, Gilman AL, Ozkaynak MF, et al.
Anti⁃GD2 antibody with GM⁃CSF, interleukin⁃2,and isotretinoin for neuroblastoma[J].
N Engl J Med,2010,363(14):1324⁃1334.

5.
MATTHAYK K.
Targeted isotretinoin in neuroblastoma: kinetics, genetics, or absorption[J].
Clinical Cancer Research An Official Journal of the American Association for Cancer Research, 2013, 19 (2) :311-313.

6.
Pandey G K, Kanduri C.
Long noncoding RNAs and neuroblastoma[J].
Oncotarget, 2015, 6(21): 18265.

7.
Matthay K K, Yanik G, Messina J, et al.
Phase II study on the effect of disease sites, age, and prior therapy on response to iodine-131-metaiodobenzylguanidine therapy in refractory neuroblastoma[J].
Journal of clinical oncology, 2007, 25(9): 1054-1060.

8.
Ladenstein R, Pötschger U, Valteau-Couanet D, et al.
Investigation of the Role of Dinutuximab Beta-Based Immunotherapy in the SIOPEN High-Risk Neuroblastoma 1 Trial (HR-NBL1).
Cancers (Basel), 2020 Jan 28, 12(2):309.

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