Targeting of intracellular oncoproteins with peptide-centric CARs.

The majority of oncogenic drivers are intracellular proteins, constraining their immunotherapeutic targeting to mutated peptides (neoantigens) presented by individual human leukocyte antigen (HLA) allotypes1. However, most cancers have a modest mutational burden that is insufficient for generating responses using neoantigen-based therapies2,3. Neuroblastoma is a paediatric cancer that harbours few mutations and is instead driven by epigenetically deregulated transcriptional networks4. Here we show that the neuroblastoma immunopeptidome is enriched with peptides derived from proteins essential for tumorigenesis. We focused on targeting the unmutated peptide QYNPIRTTF discovered on HLA-A*24:02, which is derived from the neuroblastoma-dependency gene and master transcriptional regulator PHOX2B. To target QYNPIRTTF, we developed peptide-centric chimeric antigen receptors (PC-CARs) through a counter panning strategy using predicted potentially cross-reactive peptides. We further proposed that PC-CARs can recognize peptides on additional HLA allotypes when presenting a similar overall molecular surface. Informed by our computational modelling results, we show that PHOX2B PC-CARs also recognize QYNPIRTTF presented by HLA-A*23:01, the most common non-A2 allele in people with African ancestry. Finally, we demonstrate potent and specific killing of neuroblastoma cells expressing these HLAs in vitro and complete tumour regression in mice. These data suggest that PC-CARs have the potential to expand the pool of immunotherapeutic targets to include non-immunogenic intracellular oncoproteins and allow targeting through additional HLA allotypes in a clinical setting.

Cross-HLA targeting of intracellular oncoproteins with peptide-centric CARs.

The majority of oncogenic drivers are intracellular proteins, thus constraining their immunotherapeutic targeting to mutated peptides (neoantigens) presented by individual human leukocyte antigen (HLA) allotypes1. However, most cancers have a modest mutational burden that is insufficient to generate responses using neoantigen-based therapies2,3. Neuroblastoma is a paediatric cancer that harbours few mutations and is instead driven by epigenetically deregulated transcriptional networks4. Here we show that the neuroblastoma immunopeptidome is enriched with peptides derived from proteins that are essential for tumourigenesis and focus on targeting the unmutated peptide QYNPIRTTF, discovered on HLA-A*24:02, which is derived from the neuroblastoma dependency gene and master transcriptional regulator PHOX2B. To target QYNPIRTTF, we developed peptide-centric chimeric antigen receptors (CARs) using a counter-panning strategy with predicted potentially cross-reactive peptides. We further hypothesized that peptide-centric CARs could recognize peptides on additional HLA allotypes when presented in a similar manner. Informed by computational modelling, we showed that PHOX2B peptide-centric CARs also recognize QYNPIRTTF presented by HLA-A*23:01 and the highly divergent HLA-B*14:02. Finally, we demonstrated potent and specific killing of neuroblastoma cells expressing these HLAs in vitro and complete tumour regression in mice. These data suggest that peptide-centric CARs have the potential to vastly expand the pool of immunotherapeutic targets to include non-immunogenic intracellular oncoproteins and widen the population of patients who would benefit from such therapy by breaking conventional HLA restriction.

Aetiology and Epidemiology of Maxillofacial Injuries during the Stay-At-Home Period Due To the COVID-19 Pandemic: a Single Center Study.

OBJECTIVES: The aim of this retrospective comparative study was to evaluate the effects of implemented social and public health measures during the COVID-19 pandemic on the incidence and aetiology of maxillofacial injuries. MATERIAL AND METHODS: A retrospective chart review of all the patients who had sustained maxillofacial injuries and presented to the emergency department of Strong Memorial Hospital between March 20th and June 24th, 2019 and 2020, were included in our study. The total study sample comprised of 335 patients (n = 140 in 2019 group, n = 195 in 2020 group). The primary outcome variables of the study were the number of cases and aetiology of maxillofacial injuries. Statistical analysis consisted of descriptive statistics, Chi-square, and two sample t-tests. RESULTS: The number of patients in the 2020 group was higher (n = 195) than the number of patients in the 2019 group (n = 140). Comparatively, there was an increase in the maxillofacial injuries during the stay-at-home period by (n = 55 [39.29%]). Although not statistically significant, the aetiology of injuries differed during the stay-at-home period compared to the normal times. CONCLUSIONS: The number of maxillofacial injuries increased during the period of implemented social and public health measures during the early months of the COVID-19 pandemic. Such knowledge can provide valuable information for the establishment of prevention programs and effective health policies and help in the decision-making process pertaining to resource allocation in a dire situation of the pandemic.