Towards Immunotherapy for Pediatric Brain Tumors.

Pediatric brain tumors are the leading cause of childhood cancer-related death. Immunotherapy is a powerful new approach for treating some refractory cancers; applying this 'fourth pillar' of cancer treatment to pediatric brain tumors is an exciting but challenging prospect. This review offers new perspectives on moving towards successful immunotherapy for pediatric brain tumors, focusing on pediatric high-grade glioma (HGG), a subgroup with universally poor outcomes. We cover chimeric antigen receptor T cell (CAR-T) therapy, vaccine therapy, and checkpoint inhibition in this context, and focus on the need for intimately understanding the growing brain and its immune system. We highlight the challenges associated with the application of immunotherapy in pediatric neuro-oncology, as well as the tissue-specific challenges to be overcome, to achieve improved outcomes.

A Novel Peptide-MHC Targeted Chimeric Antigen Receptor T Cell Forms a T Cell-like Immune Synapse.

Chimeric Antigen Receptor (CAR) T cell therapy is a promising form of adoptive cell therapy that re-engineers patient-derived T cells to express a hybrid receptor specific to a tumour-specific antigen of choice. Many well-characterised tumour antigens are intracellular and therefore not accessible to antibodies at the cell surface. Therefore, the ability to target peptide-MHC tumour targets with antibodies is key for wider applicability of CAR T cell therapy in cancer. One way to evaluate the effectiveness and efficiency of ligating tumour target cells is studying the immune synapse. Here we generated a second-generation CAR to targeting the HLA-A*02:01 restricted H3.3K27M epitope, identified as a possible therapeutic target in ~75% of diffuse midline gliomas, used as a model antigen to study the immune synapse. The pMHCI-specific CAR demonstrated specificity, potent activation, cytokine secretion and cytotoxic function. Furthermore, we characterised killing kinetics using live cell imaging as well as CAR synapse confocal imaging. Here we provide evidence of robust CAR targeting of a model peptide-MHC antigen and that, in contrast to protein-specific CARs, these CARs form a TCR-like immune synapse which facilitates TCR-like killing kinetics.

Addition of a prominent epitope affects influenza A virus-specific CD8+ T cell immunodominance hierarchies when antigen is limiting.

A reverse genetics strategy was used to insert the OVA peptide (amino acid sequence SIINFEKL; OVA(257-264)) into the neuraminidase stalk of both the A/PR8 (H1N1) and A/HKx31 (H3N2) influenza A viruses. Initial characterization determined that K(b)OVA257 is presented on targets infected with PR8-OVA and HK-OVA without significantly altering D(b) nucleoprotein (NP)366 presentation. There were similar levels of K(b)OVA257- and D(b)NP366-specific CTL expansion following both primary and secondary intranasal challenge. Interestingly, while variable, the presence of the immunodominant K(b)OVA257-specific response resulted in diminished D(b) acidic polymerase224- and K(b) basic polymerase subunit 1(703)-, but not D(b)NP366-specific responses and didn't alter endogenous influenza A virus-specific immunodominance hierarchies. However, challenging PR8-OVA-primed mice with HK-OVA via the i.p. route, and thereby limiting Ag dose, led to a reduction in the magnitude of all the influenza A virus-specific responses measured. A similar reduction in CTL response to native epitopes was also seen following primary respiratory HK-OVA infection of mice that received substantial numbers of K(b)OVA257-specific TCR transgenic T cells. Thus, during the course of infection, the generation of individual virus-specific CTL responses is independently regulated. However, in cases in which Ag is limiting, or high precursor frequency, the presence of immunodominant CTL responses can impact on the magnitude of other specific populations. Therefore, depending on both the size of the T cell precursor pool and the mode of Ag presentation, the addition of a major epitope can diminish the size of endogenous, influenza-specific CD8+ T cell responses, although never to the point that these are totally compromised.