Dunn Laboratory

Despite some success in secondary brain metastases, targeted or immune-based therapies have shown limited efficacy against primary brain malignancies such as glioblastoma (GBM). While the intratumoral heterogeneity of GBM is implicated in treatment resistance, it remains unclear whether this diversity is observed within brain metastases and to what extent cancer-cell intrinsic heterogeneity sculpts the local immune microenvironment. Here, we profiled the immunogenomic state of 93 spatially distinct regions from 30 malignant brain tumors through whole exome, RNA, and TCR-sequencing. Our analyses identified differences between primary and secondary malignancies with gliomas displaying more spatial heterogeneity at the genomic and neoantigen level. Additionally, this spatial diversity was recapitulated in the distribution of T cell clones where some gliomas harbored highly expanded but spatially restricted clonotypes. This study defines the immunogenomic landscape across a cohort of malignant brain tumors and contains implications for the design of targeted and immune-based therapies against intracranial malignancies.

Read more here: https://pubmed.ncbi.nlm.nih.gov/34610950/

We characterized the microenvironment and neoantigen landscape of the aggressive CT2A GBM model in order to develop a platform to test combination checkpoint blockade and neoantigen vaccination. Whole exome DNA and RNA sequencing of the CT2A murine GBM was employed to identify expressed, somatic mutations for vaccine development. Survival analysis showed that therapeutic neoantigen vaccination with Epb4H471L, Pomgnt1R497L, and Plin2G332R, in combination with αPD-L1 treatment was superior to αPD-L1 alone. These observations provide important preclinical correlates for GBM immunotherapy trials and support further investigation into the effects of multi-modal immunotherapeutic interventions on anti-glioma immunity

Read more here: https://www.ncbi.nlm.nih.gov/pubmed/32133512

As immunotherapy assumes a central role in the management of many cancers, ongoing work is directed at understanding whether immune-based treatments will be successful in patients with glioblastoma (GBM). Despite several large studies conducted in the last several years, there remain no FDA-approved immunotherapies in this patient population. Nevertheless, there are a range of exciting new approaches being applied to GBM, all of which may not only allow us to develop new treatments but also help us understand fundamental features of the immune response in the central nervous system. In this review, we summarize new developments in the application of immune checkpoint blockade, from biomarker-driven patient selection to the timing of treatment. Moreover, we summarize novel work in personalized immune-oncology by reviewing work in cancer immunogenomics–driven neoantigen vaccine studies. Finally, we discuss cell therapy efforts by reviewing the current state of chimeric antigen receptor T-cell therapy.

Read more here: https://www.ncbi.nlm.nih.gov/pubmed/32615600

Neoantigens represent promising targets for personalized cancer vaccine strategies. However, the feasibility of this approach in lower mutational burden tumors like glioblastoma (GBM) remains unknown. We report the application a cancer immunogenomics pipeline to identify candidate neoantigens and guide screening for neoantigen-specific T cell responses in a patient with GBM treated with a personalized synthetic long peptide vaccine. Following vaccination, reactivity to 3 HLA class I- and 5 HLA class II-restricted candidate neoantigens were detected. These data demonstrate the feasibility and translational potential of a therapeutic neoantigen-based vaccine approach in patients with primary CNS tumors.

Read more here: https://www.ncbi.nlm.nih.gov/pubmed/30906654

Recent interest has been focused on the identification of tumor-specific mutations, termed neoantigens, which can serve as immunodominant targets for antitumor immune effector cells to maximize “on-tumor” effect and minimize “off-tumor” toxicities. In this review, we discuss: (1) the current perspective on CNS immunosurveillance, (2) the process of neoantigen identification focusing on the cancer immunogenomics approach, and (3) how this strategy can be used to target GBM specifically.

Read more here: https://www.ncbi.nlm.nih.gov/pubmed/28899059

We present the case of a patient with a left frontal glioblastoma with primitive neuroectodermal tumor features and hypermutated genotype in the setting of a POLE germline alteration. Using whole-exome DNA sequencing and clonal analysis, we report changes in the subclonal architecture throughout treatment. Furthermore, a persistently high neoantigen load was observed within all tumors. Interestingly, following initiation of pembrolizumab, brisk lymphocyte infiltration was observed in the subsequently resected metastatic spinal lesion and an objective radiographic response was noted in a progressive intracranial lesion, suggestive of active central nervous system (CNS) immunosurveillance following checkpoint blockade therapy.

Read more here: https://www.ncbi.nlm.nih.gov/pubmed/27683556

We applied a cancer immunogenomics approach to identify tumor-specific "neoantigens" in the C57BL/6-derived GL261 and VM/Dk-derived SMA-560 tumor models. Following DNA whole-exome and RNA sequencing, high-affinity candidate neoepitopes were predicted and screened for immunogenicity by ELISPOT and tetramer analyses. We confirmed H-2D^b-restricted endogenous tumor-specific neoantigens that are functionally immunogenic. By establishing the immunogenicities of predicted high-affinity neoepitopes in these models, we extend the immunogenomics-based neoantigen discovery pipeline to glioblastoma models and provide a tractable system to further study the mechanism of action of T cell-activating immunotherapeutic approaches in preclinical models of glioblastoma

Read more here: https://www.ncbi.nlm.nih.gov/pubmed/27799140