Pediatric Solid Tumors

The purpose of this study is to assess the feasibility and safety of ICG-guided intraoperative lymphography for detecting sentinel lymph nodes (SLN) in pediatric patients with solid tumors who require retroperitoneal lymph node dissection/sampling. This trial is a single-site cross-sectional study. The injection of ICG directly into lymphatics draining the primary tumor will take place at the time of operation after the patient is under anesthesia.

Pediatric patients receiving proton therapy for solid tumors or Hodgkin's lymphoma may experience anatomical changes during treatment that can affect proton therapy accuracy. This prospective single-arm study uses regular low-dose imaging to monitor these changes and adjust treatment plans as needed. Participants will receive weekly or every-other-week CT scans, with MRI when appropriate, to assess whether the original plan remains accurate. Treatment plans will be updated if tumor coverage decreases by more than 5% or if radiation dose to normal tissues increases by more than 10%; otherwise, the original plan will continue. The study aims to determine how often plan adjustments are needed and to identify which disease sites are most likely to experience significant anatomical changes during treatment. Primary Objective: * Define the frequency of replanning necessary to ensure tumor coverage never falls below 95% (or 5% drop) of the prescribed daily dose in participants with intact (gross) tumors to keep the tumor control optimal throughout the multi-week treatment regimen. * Define the frequency of replanning necessary to ensure organs-at-risk (critical organs) do not deviate by more than 10% of the initially approved dose constraints to keep the normal tissue complication minimal throughout the multi-week treatment regimen. Secondary Objectives * Establish a cone beam CT (CBCT)-based framework for quantifying body surface changes throughout the treatment course. This goal will be achieved by developing a novel algorithm that detects and tracks external anatomical variations longitudinally, without requiring CBCT image enhancement, enabling precise assessment of daily participant setup consistency and anatomical stability. * Overcome daily CBCT quality limitations by generating synthetic CT images that accurately represent daily anatomy and support proton dose recalculation or verification planning. This goal will be achieved by developing a hybrid pipeline that integrates deep learning models with the deformable image registration algorithm, trained and validated on disease site-specific data. This will enable precise dose mapping and tissue density estimation, directly supporting adaptive planning decisions without the need of diagnostic- quality CT images.

Cohort A(GAIA-102 alone): Confirm the safety of GAIA-102 alone for refractory/relapse neuroblastoma or pediatric solid tumors with lung metastases, and decide recommended dose for Phase II. Cohort B(GAIA-102 with Dinutuximab): Confirm the safety of GAIA-102 with Dinutuximab, Filgrastim, Teceleukin combination for refractory/relapse neuroblastoma and decide recommended dose for Phase II. Cohort C(GAIA-102 with Nivolumab):Confirm the safety of GAIA-102(Follow the recommended doses in Cohort A) with Nivolumab. Cohort D(GAIA-102 with Nivolumab, Teceleukin): Confirm the safety of GAIA-102(Follow the recommended doses in Cohort A) with Nivolumab, Teceleukin.

Pediatric solid tumors exhibit a low mutational burden, limited availability of neoantigens, and poor infiltration of tumor-infiltrating lymphocytes (TILs) within the tumor microenvironment (TME), characteristics that reduce the effectiveness of immunotherapies in children. However, pediatric tumors express a subgroup of antigens that can be exploited as targets. Stimulating the T lymphocyte response against these antigens could overcome immunosuppressive barriers. The adoption of therapies based on cytotoxic T lymphocytes (CTLs) represents a promising strategy. A total of 42 neoplasms were analyzed, including: 8 neuroblastomas, 7 sarcomas, 4 nephroblastomas, 1 renal carcinoma, 2 rhabdomyosarcomas, 5 lymphomas, 2 ovarian carcinomas, 4 teratomas, 2 thyroid tumors, and 7 other rare tumors. Primary cells from these tumors were preserved, resulting in the stabilization of 5 cell lines used for functional studies in vitro. Currently, 4 tumor-specific CTL lines derived from healthy adult donors have been expanded; tumor antigen-specific T cells showed the ability to recognize and kill commercial tumor cell lines as well as stabilized pediatric tumor lines from osteosarcoma, nephroblastoma, and neuroblastoma. In particular, the G-Rex bioreactor enabled greater expansion of CTLs while maintaining a broad spectrum of specificity for most tumor antigens and a lymphocyte phenotype with an increased composition of early memory T cells, correlated with greater persistence in vivo. The results demonstrate that the use of bioreactors represents a significant advancement in the production of CTLs specific for pediatric tumor antigens. The ability of CTLs derived from bioreactors to express early memory and activation markers makes them particularly promising for clinical applications, where persistence and efficacy are key factors. Based on the presented results, the analysis of in vivo persistence and cytotoxic capacities in preclinical models will be deepened, aiming to confirm the efficacy of the produced cells. The main objective of the project is to develop expansion protocols for CTLs specific to pediatric tumor antigens, proposing innovative protocols for the ex vivo expansion of CTLs targeting pediatric tumor antigens. Finally, standardizing the large-scale process could be another necessary objective to translate these findings into practical clinical applications improving immunotherapy in pediatric cancer with evident benefits for affected children and care givers.

This study will prospectively characterize the molecular, cellular and genetic properties of primary and metastatic neuroblastoma, osteosarcoma, retinoblastoma, Ewing sarcoma family of tumors, soft tissue sarcomas, adrenocortical tumors and liver malignancies. These cell isolates will be used for gene expression array analysis, genomic analysis by \[SNP\] single nucleotide polymorphism chip, array \[CGH\] comparative genomic hybridization and next generation sequencing, and \[TEM\] transmission electron microscopy analysis. Additionally cell lines and orthotopic xenografts will be created from the obtained tumor specimens. The specificity of TCRs will be examined by comparing paired TCR from peripheral blood and tumor infiltrating CD4+ and CD8+ T cells. Epigenetic studies will be performed looking at the methylation profile of these cells and to investigate the anti-tumor T cell response both pre- and post-PD1 inhibition.

The research team will assess the psychological abilities like cognitive(how you think and figure things out) and psycho-social(the well-being at the intersection of the internal workings and external experience) functions of young patients who are diagnosed with solid tumor and their primary caregivers. After assessing the psychological abilities, the research team will provide counseling and educational sessions developed by the team. The sessions are provided on a 1:1 basis to each of the participants to verify whether the sessions helped to improve the quality of life, including mental health.