Adoptive Cell Therapy in Pediatric and Young Adult Solid Tumors: Current Status and Future Directions.

Advances from novel adoptive cellular therapies have yet to be fully realized for the treatment of children and young adults with solid tumors. This review discusses the strategies and preliminary results, including T-cell, NK-cell and myeloid cell-based therapies. While each of these approaches have shown some early promise, there remain challenges. These include poor trafficking to the tumor as well as a hostile tumor microenvironment with numerous immunosuppressive mechanisms which result in exhaustion of cellular therapies. We then turn our attention to new strategies proposed to address these challenges including novel clinical trials that are ongoing and in development.

Targeting tumor microenvironment and metastasis in children with solid tumors.

PURPOSE OF REVIEW: The prognosis of pediatric patients with metastatic solid tumors remains poor, necessitating development of novel therapeutic strategies. The biology of the pediatric tumor microenvironment (TME) presents obstacles for the efficacy of current therapeutic approaches including immunotherapies. Targeting various aspects of the TME in pediatric patients with solid tumors represents a therapeutic opportunity that may improve outcomes. Here we will discuss recent advances in characterization of the TME, and clinical advances in targeting the immune, vascular, and stromal aspects of the TME. RECENT FINDINGS: Although immunotherapies have shown limited success in the treatment of pediatric solid tumor patients thus far, optimization of these approaches to overcome the TME shows promise. In addition, there is increasing focus on the myeloid compartment as a therapeutic target. Vascular endothelial growth factor (VEGF) targeting has resulted in responses in some refractory pediatric solid tumors. There has been relatively little focus on stromal targeting; however, emerging preclinical data are improving our understanding of underlying biology, paving the way for future therapies. SUMMARY: Although translation of TME-targeting therapies for pediatric solid tumors is in the early stages, we are optimistic that continued exploration of approaches aimed at rebalancing the TME will lead to improved outcomes for this population.

Genetically engineered myeloid cells rebalance the core immune suppression program in metastasis.

Metastasis is the leading cause of cancer-related deaths, and greater knowledge of the metastatic microenvironment is necessary to effectively target this process. Microenvironmental changes occur at distant sites prior to clinically detectable metastatic disease; however, the key niche regulatory signals during metastatic progression remain poorly characterized. Here, we identify a core immune suppression gene signature in pre-metastatic niche formation that is expressed predominantly by myeloid cells. We target this immune suppression program by utilizing genetically engineered myeloid cells (GEMys) to deliver IL-12 to modulate the metastatic microenvironment. Our data demonstrate that IL12-GEMy treatment reverses immune suppression in the pre-metastatic niche by activating antigen presentation and T cell activation, resulting in reduced metastatic and primary tumor burden and improved survival of tumor-bearing mice. We demonstrate that IL12-GEMys can functionally modulate the core program of immune suppression in the pre-metastatic niche to successfully rebalance the dysregulated metastatic microenvironment in cancer.