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

Abstract

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.

Keywords: CAR (chimeric antigen receptor); adoptive cell immunotherapy; immune evasion; solid tumor; tumor microenvironment.

Figure 1

Multiple cell types available to engineer for adoptive cellular therapy. Myeloid cells, NK cells, and T-cell-based therapies each have advantages and disadvantages which should be considered within the context of the histology to be targeted.

Figure 2

“Cold” solid tumors present a number of challenges within their tumor microenvironment including reduced trafficking related to abnormal tumor vasculature and resident inhibitory myeloid cells which recruit regulatory T cells (Treg) and lead to exhaustion of T-cells and NK-cells. Adoptive cellular therapies aim to overcome these challenges through vascular normalization and extracellular matrix (ECM) remodeling to promote improved trafficking, as well as myeloid cell reprogramming to diminish the inhibitory contribution of these cells. Additionally, T-cells which are resistant to inhibition or “armored” T-cells, or NK-cells which can augment T-cell responses may make it possible to overcome the inhibitory tumor microenvironment.