Precision medicine in pediatric oncology

Abstract

Outcome in treatment of childhood cancers has improved dramatically since the 1970s. This success was largely achieved by the implementation of cooperative clinical research trial groups that standardized and developed treatment of childhood cancer. Nevertheless, outcome in certain types of malignancies is still unfavorable. Intensification of conventional chemotherapy and radiotherapy improved outcome only marginally at the cost of acute and long-term side effects. Hence, it is necessary to develop targeted therapy strategies.Here, we review the developments and perspectives in precision medicine in pediatric oncology with a special focus on targeted drug therapies like kinase inhibitors and inducers of apoptosis, the impact of cancer genome sequencing and immunotherapy.

Keywords: Childhood cancer; Immunotherapy; T-cell-based therapy; Targeted drug therapies.

Fig. 1

Increase in survival rates in Germany. 2-year-survival until 1980, 5-year-survival from 1980 [1]

Fig. 2

Aberrant activation of tyrosine kinases as a mechanism for malignant transformation. Cancer cells are defined by overactive signaling cascades, often mediated by tyrosine (tyr) kinases. Common therapeutic strategies are either blocking of the tyr kinase receptor by inhibiting antibody/pharmacological inhibitor (which does not work for ligand-independent signals and has reduced potency if the target is overexpressed), or utilizing pharmacological inhibitors that block kinase activity (dependent/independent of mutational status) [42]

Fig. 3

10¹¹ human TCRs have to recognize 10²⁰ peptides: a TCR repertoire (purple sphere) is several magnitudes less diverse than the total set of peptides that are presented by MHC molecules (pMHC) (orange sphere). Hence, a necessary feature of a TCR repertoire is that a T-cell is able to recognize and respond to many peptides, but one TCR only recognizes and responds to peptides closely related to the original agonist peptide (similar colors representing peptide relatedness). Modified from Mandl and Germain 2014 [73]

Fig. 4

Immunoglobulin/T-cell receptor constructs for the generation of CAR T-cells [91]

Fig. 5

Cytotoxic mechanisms by TCR T-cells and CAR T-cells