Written by | Yuan Hongling editor-in-charge | Wang Yanwen
Neuroblastoma (NB) is a common extracranial solid tumor in children, and is the third most malignant pediatric tumor after leukemia and brain cancer (about 1.3 cases per 100,000 cases in children aged 0 to 14 years). The tumor is classified as low-risk, medium-risk, and high-risk; for high-risk children, the tumor is easy to metastasize and the recurrence rate is high, and the long-term survival rate of patients is not optimistic.
NB cells are able to specifically express ganglioside GD2 at high levels, resulting in immunosuppression of the tumor microenvironment. Therefore, monoclonal antibody drugs targeting GD2 have significant efficacy in patients at high risk of recurrence or refractory treatment, and the 5-year survival rate of patients can reach 50% to 60%. Recently, GD2 monoclonal antibodies have been included in the standard treatment in the high-risk group. However, some challenges remain with monoclonal antibody drugs. First, more than 50% of patients will relapse; second, because normal tissues also express GD2, monoclonal antibody drugs have some serious side effects, such as pain, fever, nerve damage, infection, and bone marrow suppression.
The use of vaccines to treat cancer is a process of effectively blocking and killing tumor cells by injecting related antigens into the human body, stimulating the body to produce a specific immune response, and mobilizing the immune system to attack cancer cells. There are advantages in cooperation between polyclonal antibodies produced by anti-cancer vaccines over monoclonal antibody drugs. Vaccines are able to continuously induce antibody production and promote the production of memory lymphocytes, which can work quickly when the disease recurs. In addition, anti-cancer vaccines can also reduce autoimmune epitopes as much as possible through mechanisms such as cutting and tolerance, and avoid attacking normal organs.
On January 20, 2021, the Brian H. Kushner team published an article titled Survival Impact of Anti-GD2 Antibody Response in a Phase II Ganglioside Vaccine Trial Among Patients With High-Risk at the Journal of Clinical Oncology Neuroblastoma With Prior Disease Progression article. The team developed a GD2/GD3 divalent vaccine for the treatment of NB, and previous Phase I clinical trials found that the GD2/GD3 vaccine improved long-term survival rates in high-risk patients with a history of disease progression and had a good safety profile, and this article further disclosed the data of the Phase II clinical study of this GD2/GD3 vaccine.
The study eventually enrolled 102 high-risk patients with NB who had previously experienced disease progression in remission. Of these, 7% were younger than 18 months of age; 93% had bone marrow or bone metastases, and 5% had central nervous system metastases. Enrolled subjects had previously received induction chemotherapy, second-line therapy, myeloablative therapy for stem cell transplantation, immunotherapy against GD2 monoclonal antibodies, and some salvage therapy. 63%, 21%, and 16% of patients had a history of previous disease progression once, 2 times, and 3 to 6 times, respectively, and 82% of them received anti-GD2 monoclonal antibody therapy before the last progression.
Participants enrolled in this study were required to receive the GD2/GD3 vaccine seven times over a year. Oral β-dextran begins at week 6. Subsequently, the researchers followed these subjects for a period of 6 years. The primary endpoint of this study was progression-free survival (PFS) after completion of the 4th dose (week 8), and the secondary endpoint was anti-GD2/GD3 antibody response and its correlation with PFS and overall survival (OS).
The median follow-up for this study was 3.4 years. At 6 months of use of the combination vaccine, the PFS rate was 76.5% ± 4.2%, the OS rate was 99% ± 1.0%, and after 2 years, the PFS rate was 45.3% ± 5.0%, the OS rate was 88.4% ± 3.3%, and the 5-year PFS rate was 32.2% ± 6.4%, and the OS rate was 70.7% ± 6.7%. Subgroup analysis found that patients with only one disease progression before enrolling in this study had PFS and OS outperformed those who had multiple disease progressions. For those patients who did not progress with monoclonal antibodies before receiving treatment in this study, their PFS was better than those who had previously failed monoclonal antibody therapy, but there was no significant difference in OS between the two. It is important to note that vaccine therapy has a better survival prognosis for patients who have a response time greater than or equal to 12 months after the last post-progression salvage therapy before enrollment.
Survival curves for patients after receiving vaccine treatment: PFS and OS (A) in all patients; PFS (B) and OS (C) in patients who had had one and multiple progressions prior to treatment in this study; PFS (D) and OS (E) in patients who had previously used anti-GD2 monoclonal antibodies without progression and failure of monoclonal therapy; response times ≥ to salvage therapy after the last disease progression before enrollment ≥ PFS (F) and OS (G) for patients who had < 12 months.
Anti-GD2-IgM and anti-GD3-IgG1 appeared earlier, with titers increasing significantly after oral β-glucan at week 6, and anti-GD2-IgG1 titers peaking after 6-7 doses of the vaccine. After stopping vaccination and β-dextran, IgG was able to persist for a long time, although IgG levels in 62 patients who received all 7 doses of the vaccine gradually decreased over a period of several months. Subgroup analysis found that anti-GD2-IgG1 content (150 ng/mL) in patients at week 8 was a prognostic factor for survival. This cut-off point was chosen because in vitro studies have found that this concentration maximizes the induction of ADCC and complement-mediated cytotoxicity. The above results indicate that the epitopes of GD2 and GD3 are immunogenic, which can induce not only IgM, but also IgG production. For pediatric tumor patients whose immune system has been damaged by high-dose chemotherapy and have not yet recovered, an effective antibody response can still be produced.
The side effects of the combined vaccine are mainly pain at the injection site, and the adverse reactions are lower than grade 3. Fever can be controlled within 48 hours with antipyretic drugs, and all adverse reactions resolve within one week without long-term side effects. Notably, the pain and other neurologic adverse effects common to anti-GD2 monoclonal antibodies were not observed in the trial. This may mean that there is a certain antibody concentration threshold for inducing such adverse reactions, and vaccine therapy differs from monoclonal antibody therapy in this regard.
Antibody titer response in vaccine therapy: anti-GD2-IgG1 titer (A); anti-GD2-IgG1 titer (B) during and after vaccination in 62 patients receiving all 7 doses of the vaccine; anti-GD3-IgG1 titer (C); anti-GD2-IgM titer (D); vaccine non-combined β-dextran-induced anti-GD2-IgG1 titer (E).
β-dextran acts as a vaccine adjuvant and activates multiple receptors on immune cells. This trial further investigated three SNPs of the β-dextran receptor directin-1. The results showed that SNP rs3901533 was related to anti-GD2-, GD3-IgG1 titer, but not anti-GD2-IgM. This suggests that β-dextran receptors may be involved in the seroconversion of antibodies, while the SNP rs3901533 locus of decin-1 can act as a biomarker molecule for antibody responses.
In summary, the Phase II clinical study shows that for high-risk NB patients with a history of disease progression, the combination of GD2/GD3 vaccine plus β-dextran can induce patients to produce a lasting and effective antibody response, and the safety is good. GD2/GD3 is also expressed in other childhood and adult tumors, which also means that the therapeutic strategy of vaccine antibodies deserves further attention and research.
However, as a single-arm, single-center study, this study may have some selection bias; many patients have used monoclonal antibody drugs before receiving vaccine treatment, and the relationship between the two treatments is unclear. More rigorous future randomized clinical studies may be able to further confirm the effectiveness of vaccine therapies.
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