Immunotherapy for solid tumors in children

Immunotherapy for solid tumors in children.  Immunotherapy has been widely used in the treatment of a variety of adult malignant tumors. Children’s solid tumors-related signaling pathways and targets. We have summarized the related signaling pathways and targets of childhood tumors. This issue will continue to share with you-the application of immunotherapy in childhood solid tumors.

Immunotherapy has been widely used in the treatment of a variety of adult malignant tumors. At present, there is still a lack of information on its safety and effectiveness in pediatric patients. Compared with adult tumors, somatic coding mutations in childhood tumors are less common.

In other words, this situation is likely to result in a lack of neoantigens that can be recognized by T cells in childhood tumors. This difference in mutation burden may be the basis for the lower immunogenicity of childhood tumors compared with adult tumors. It is precisely because of this that the efficacy of immune checkpoint inhibitors in childhood tumors is far lower than that of adults.

Immunotherapy for malignant solid tumors in children

Figure 1 Immunotherapy for malignant solid tumors in children (picture source: REVIEWS)

Immune checkpoint blocking therapy (left side of Figure 1) is most suitable for tumors with a large number of non-synonymous mutations, that is, tumors with high tumor mutation burden (TMB). Among them, the expression of immune checkpoint molecules such as PD-1, PD-L1, and CTLA-4 is another feature that carries high TMB. Research suggests that a combination of multiple immunotherapies or a combination with other targeted compounds is a more effective method.

For common childhood tumors that have neither high TMB nor high expression of PD-1 or PD-L1, cell-based therapy for such “cold” tumors, such as chimeric antigen receptor (CAR)-T cells Treatment (right side of Figure 1) is a potential option for childhood tumor immunotherapy.

From a clinical point of view, the most effective immunotherapy method for childhood solid tumors is the GD2 antibody targeting ganglioside GD2. At the same time, in the preclinical study of H3K27M mutant midline glioma, CAR-T cell therapy targeting GD2 is more effective, and this method is used to target B7-H3 in a variety of xenograft models of childhood solid tumors Demonstrates significant anti-tumor activity.

Current status of immunotherapy for solid tumors in children

1 Targeted therapy based on monoclonal antibodies

Monoclonal antibodies currently under development or in clinical trials for malignant tumors of the lymphatic system in children include anti-CD19, anti-CD22, anti-CD25, anti-CD30, anti-CD33, anti-CD45, anti-CD52 monoclonal antibodies and anti-CD3/CD19 double antibodies.

Among them, in solid tumors, the use of anti-disialoganglioside GD2 antibody to treat pediatric neuroblastoma (NB) is relatively mature.

On November 26, 2020, following the launch of the drug dinutuximabbeta (trade name: Qarziba) for the treatment of children with high-risk neuroblastoma in children aged 12 months and older, Y-mAbsTherapeutics announced that the FDA approved the GD2 antibody naxitamab (40mg/ 10ml size) was launched and combined with granulocyte-macrophage colony stimulating factor (GM-CSF) to treat children, adults, and elderly patients aged 1 and over with high-risk myelogenous neuroblastoma that are relapsed or refractory .

2 Adoptive T cell immunotherapy

In the field of pediatric oncology, clinical adoptive T cell immunotherapy methods include Epstein-Barr virus-specific T cell infusion to treat Epstein-Barr virus-related tumors and genetically modified T cell infusion to treat hematological tumors and solid tumors.

In recent years, the hottest CAR-T cell therapy is none other than CAR-T cell therapy. At present, three CAR-T cell therapies have been approved for marketing in the world, namely: Novartis Kymriah, Gilead Yescarta and Tecartus. In September 2019, 14 children with acute lymphoblastic leukemia who underwent the CAR-T immune cell therapy experiment at Great Ormond Street Hospital in London (none of which could be cured by traditional therapies), 12 recovered within 3 months, of which 5 The name is still healthy.

GD2 is also one of the main research targets for CAR-T treatment of solid tumors in recent years. A data from the Clinicaltrials.gov database shows that as of July 2020, according to the number of clinical trials carried out, the GD2 target ranks fourth in the domestic CAR-T clinical trials for the treatment of solid tumors, and it is even more important in foreign countries. In the first place (see Figure 2).

Figure 2 Target distribution of CAR-T treatment of solid tumors (Source: Clinicaltrials)

3 NK cell infusion immunotherapy

Immune cells-NK cells (natural killer cells) and T cell therapy constitute the double sword of immunotherapy, and are another anti-cancer potential stock.

In 2017, scientists discovered that chemotherapy combined with NK immunotherapy has a good effect on brain tumors. Among the 11 patients participating in the trial: 4 people have detected lesions, 1 person has a good treatment effect, and 3 people have a general treatment effect.

In February 2020, researchers from the University of Texas MD Anderson Cancer Center published clinical trial results in the journal New England Journal of Medicine, showing that CAR-NK cells targeting CD19 can treat blood system cancers with a remission rate of up to 73% (8/11), of which 7 cases were completely relieved! This effect is no less than that of CD19CAR-T cell therapy products on the market.

Immunotherapy and organoids

Today, tumor immunotherapy is in full swing, due to the species specificity, the complexity of the humanized system, the partial or ineffective reconstruction of the immune system, etc., the immune tumor model is facing huge challenges, and there is an urgent need for clinical use. An in vitro model for individualized verification of efficacy. However, in view of the complexity of the tumor microenvironment, in vitro experiments of immunotherapy drugs have not been able to match the clinical efficacy.

Tumor organoids are in vitro models derived from direct patient tissues and become an emerging tool in the evaluation of in vitro immunotherapy. In 2018, researchers from Stanford University in the United States published a paper on Organoid Modeling of the Tumor Immune Microenvironment in Cell. The researchers used the gas-liquid interaction method to cultivate patient-derived tumor organoids to reproduce the patient’s tumor immune microenvironment, and the model was successfully retained The inherent fibrous matrix and diverse immune cell components in the original tumor tissue are eliminated, and the T cell receptor spectrum in the original tumor is accurately retained (see Figure 3).

Figure 3 Tumor organoids and immune cell population

Figure 4 Bright field photo of immunococultivation

(source:internet, reference only)

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