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.
Highlights
“hot” solid tumors [1] with a tumor microenvironment (TME) marked by infiltrating CD8+ T-cells [2, 3], high programmed death ligand 1 (PD-L1) expression [4], or a high tumor mutational burden have shown remarkable responses to immunotherapy including immune checkpoint inhibitors (ICIs) [5]
Autologous hematopoietic stem cell transplant (HSCT) has enabled maximal chemotherapy dosing in susceptible tumors with varying levels of effectiveness in neuroblastoma [10], Ewing sarcoma [11], breast cancer [12], retinoblastoma [13], hepatoblastoma [14], and other diseases
We will summarize proposed strategies to overcome these challenges (Figure 2). Selection of antigens such as GD2 [78] and cancer/testis antigens (CTAs) [79], which are expressed on numerous solid tumors, leverages the possibility that a single adoptive cellular therapy (ACT) could be active across multiple histologies
Summary
“hot” solid tumors (e.g. melanoma) [1] with a tumor microenvironment (TME) marked by infiltrating CD8+ T-cells [2, 3], high programmed death ligand 1 (PD-L1) expression [4], or a high tumor mutational burden have shown remarkable responses to immunotherapy including immune checkpoint inhibitors (ICIs) [5]. We will summarize proposed strategies to overcome these challenges (Figure 2) Selection of antigens such as GD2 [78] and CTAs [79], which are expressed on numerous solid tumors, leverages the possibility that a single ACT could be active across multiple histologies. Tumors recruit immunosuppressive TAMs and myeloid-derived suppressor cells (MDSCs) [84] which express inhibitory molecules such as PD-L1 [84], secrete inactivating cytokines such as IL-10 [85], and promote a hypoxic TME [86] which can thwart ACT cytotoxicity. These tumor-sustaining programs promote rapid and irreversible ACT exhaustion, inhibit expansion, and result in failure of tumor clearance. Further ACT engineering or combination with agents to allow ACTs to overcome these challenges, will be necessary for ACT optimization in solid tumors
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