Pediatric oncology, cancer vaccine: promising results from Institut Curie presented at the AACR congress

Immunotherapy, new targeted therapy, epigenetic mechanisms: Institut Curie at the forefront of pediatric oncology

Pediatric cancers, the leading cause of death by disease in children, are rare tumors that affect almost 2,500 young patients a year in France. While considerable progress has been made in pediatric oncology in recent decades, 20% of these cancers remain without a satisfactory therapeutic solution. Internationally recognized, teams at Institut Curie's SIREDO center (Soins, Innovation, Recherche en oncologie de l'Enfant, de l'aDOlescent et de l'adulte jeune) are exploring the biology of these pediatric tumors to develop new treatments.

• Pediatric immunotherapy: towards new treatments for Ewing's sarcoma

While the benefits of immunotherapy have been demonstrated in several adult cancers, this strategy is still not very effective in the treatment of pediatric tumors. However, the results presented at the AACR by Dr. Olivier Delattre, director of the SIREDO center and the Cancer, Heterogeneity, Instability and Plasticity unit (U830 - Institut Curie/Inserm), confirm that new prospects are opening for pediatric immunotherapy, particularly for Ewing's sarcoma, the second most common bone tumor in adolescents and young adults.

Nearly 95% of these Ewing's tumors are due to a characteristic genetic fusion - identified in Dr. Olivier Delattre's laboratory - which results in the synthesis of an abnormal protein: the transcription factor EWS-FLI-1. In 2022, Dr. Olivier Delattre and his colleagues demonstrated that this EWS-FLI-1 protein can induce the expression of "neogenes" coding for novel peptides that are absent from healthy cells and strictly specific to cancer cells[1].

Using proteomics, immunopeptidomics[2] and immunology approaches, Institut Curie teams have since studied in detail the nature of these neogenes and peptides likely to be recognized by the immune system. "This work is the fruit of collaboration with the teams of Dr. Olivier Lantz and Dr. Joshua Waterfall at Institut Curie. We have gone a step further by confirming the potential of the identified targets to generate an effective anti-tumor response. The high specificity and recurrent expression of these peptides in a wide variety of childhood sarcomas make them promising targets for the development of immunotherapies for the treatment of pediatric cancers", enthuses Dr. Olivier Delattre.

• Genomics to better understand the origins of medulloblastoma

Medulloblastoma is the most common brain cancer in children. It develops in the cerebellum and constitutes a highly heterogeneous group of tumors. However, this tumor develops from a cell type that is present only during fetal development of the human brain. This discovery, published in Nature[3] in 2022 by Dr. Olivier Saulnier and his colleagues, opens hitherto unexplored avenues of research to better understand the mechanisms behind these cancers, and in particular the mapping of this cell type during human embryonic development. Today, at Institut Curie, the Genomics and Development of Childhood Cancers team led by Dr. Olivier Saulnier (U830, Institut Curie/Inserm) is particularly interested in this theme. "We've all played the game of dropping a marble onto an inclined board with nails attached, so that it hits the target square at the bottom. This perfectly illustrates the multitude of possible trajectories a cell takes during development. In the case of childhood cancers, the original cell stops in the middle of the tray and doesn't continue its journey, causing abnormal differentiation at the root of many pediatric cancers. Our aim in the laboratory is to use single-cell omics technologies to identify where, when and why this cell stopped. This is the focus of the work presented at the AACR, in particular the mapping of this cell at the origin of medulloblastoma tumors", explains Dr. Olivier Saulnier, winner of the AACR's NextGen Stars 2024 program.

• A new targeted therapy in very rare pediatric cancers

In children and adolescents, malignant tumors with fusions involving the ALK gene - such as certain high-grade childhood gliomas and sarcomas - continue to have a poor prognosis. Inflammatory myofibroblastic tumors (non-malignant but locally invasive) also often display this type of fusion. While alectinib, an ALK inhibitor, has been shown to be effective in adult cancers (particularly non-small cell lung cancers with ALK fusion), this drug has never been evaluated in these pediatric tumors (apart from certain lymphomas).

Prof. François Doz, Deputy Director of Clinical Research, Innovation and Teaching at Institut Curie's SIREDO center, is the first author of the first presentation to the AACR of the results of a study using alectinib in children and adolescents with ALK-fused central nervous system tumors or non-lymphomatous solid tumors. "Alectinib was well tolerated in young patients with these very rare ALK-fused tumours. No toxicity was reported. Above all, the efficacy results, although still very preliminary, are promising, with most patients achieving a response, demonstrating a favorable benefit-risk profile", explains Prof. François Doz.

Chez les enfants et les adolescents, les tumeurs malignes présentant des fusions qui impliquent le gène ALK – telles que certains gliomes infantiles de haut grade et certains sarcomes – demeurent des cancers de mauvais pronostic. De plus, les tumeurs myofibroblastiques inflammatoires (non malignes mais localement envahissantes) présentent également souvent ce type de fusion. Si l’alectinib, un inhibiteur de ALK, a démontré son efficacité dans des cancers de l’adulte (en particulier des cancers du poumon non à petites cellules avec fusion de ALK), ce médicament n’a jusqu’à présent jamais été évalué dans ces tumeurs pédiatriques (en dehors de certains lymphomes).

• Epigenetics to better understand and target the onset of neuroblastoma

Neuroblastoma is a pediatric cancer that develops from the sympathetic nervous system, mainly in the abdomen, sometimes along the spine or in the adrenal glands. This solid extra-cerebral malignant tumor is the most common in young children, and its prognosis is poor.

The team led by Dr. Gudrun Schleiermacher, Deputy Director of Translational Research at the SIREDO center, in collaboration with Dr. Isabelle Janoueix-Lerosey, researcher at the CHIP Unit (Institut Curie/Inserm), is interested in epigenetic mechanisms (capable of activating or deactivating the expression of certain genes) in the development and progression of neuroblastoma. The work presented at the AACR shows that scientists have identified for the first time some of these processes, which lead to the deactivation of certain genes and result in the development of cancer. By providing new insights into the development and clinical sub-classifications of the disease, these results point to potential new therapeutic targets, which may in the longer term improve the prognosis of young patients.

Anti-cancer vaccine: encouraging results from a novel personalized therapy to prevent relapse in ENT cancer patients

Immunotherapy has a limited impact on ENT cancer patients, for whom the risk of relapse is unfortunately high. However, a new strategy is under study, and initial clinical results are encouraging: personalized vaccines.

Using artificial intelligence and machine learning tools, the researchers were able to design each vaccine individually, based on the sequencing of each patient's tumors. The results of a Phase 1 clinical trial involving 33 patients will be presented at the AACR by Dr. Olivier Lantz, Deputy Director of the Immunity and Cancer Unit (Institut Curie / Inserm). "Our results show that the personalized vaccine induced specific immune responses and led to low relapse rates," he says. Patient follow-up, in addition to in-depth immunological data, supports the study's positive results. "Our work demonstrates the potential of therapeutic vaccines, which could not only prevent relapse in ENT cancers but also make the tumor more receptive to other forms of immunotherapy. We look forward to continuing the study of this vaccine," concludes Prof. Christophe Le Tourneau, Head of Institut Curie's Early Clinical Trials Department and international co-coordinator of this clinical trial.

[1] Oncogenic chimeric transcription factors drive tumor-specific transcription, processing, and translation of silent genomic regions. Molecular Cell (2022), https://doi.org/10.1016/j.molcel.2022.04.019

[2] Immunopeptidomics is an emerging field of science - notably in the development of vaccines or cancer immunotherapies - that studies peptides involved in the T cell-mediated immune response.

[3] Hendrikse, L.D., Haldipur, P., Saulnier, O. et al. Failure of human rhombic lip differentiation underlies medulloblastoma formation. Nature 609, 1021–1028 (2022). https://doi.org/10.1038/s41586-022-05215-w