Immunotherapy in Glioblastoma: Current Shortcomings and Future Perspectives

Glioblastomas are aggressive, fast-growing primary brain tumors. After standard-of-care treatment with radiation in combination with temozolomide, the overall prognosis of newly diagnosed patients remains poor, with a 2-year survival rate of less than 20%. The remarkable survival benefit gained with immunotherapy in several extracranial tumor types spurred a variety of experimental intervention studies in glioblastoma patients. These ranged from immune checkpoint inhibition to vaccinations and adoptive T cell therapies. Unfortunately, almost all clinical outcomes were universally disappointing. In this perspective, we provide an overview of immune interventions performed to date in glioblastoma patients and re-evaluate their performance. We argue that shortcomings of current immune therapies in glioblastoma are related to three major determinants of resistance, namely: low immunogenicity; immune privilege of the central nervous system; and immunosuppressive micro-environment. In this perspective, we propose strategies that are guided by exact shortcomings to sensitize glioblastoma prior to treatment with therapies that enhance numbers and/or activation state of CD8 T cells

Lack of B and T cell reactivity towards IDH1(R132H) in blood and tumor tissue from LGG patients

Purpose Mutations in the isocitrate dehydrogenase-1 gene (IDH1) occur at high frequency in grade II–III gliomas (LGGs). IDH1 mutations are somatic, missense and heterozygous afecting codon 132 in the catalytic pocket of the enzyme. In LGG, most mutations (90%) result in an arginine to histidine substitution (IDH1R132H) providing a neo-epitope that is expressed in all tumor cells. To assess the immunogenic nature of this epitope, and its potential use to develop T cell treatments, we measured IDH1R132H-specifc B and T cell reactivity in blood and tumor tissue of LGG patients. Methods Sera from IDH1R132H-mutated LGG patients (n=27) were assayed for the presence of a neo-specifc antibody response using ELISA. In addition, PBMCs (n=36) and tumor-infltrating lymphocytes (TILs, n=10) were measured for T cell activation markers and IFN-γ production by fow cytometry and ELISA. In some assays, frequencies of CD4 T cells specifc for mutated peptide presented by HLA-DR were enriched prior to T cell monitoring assays. Results Despite high sensitivity of our assay, we failed to detect IDH1R132H-specifc IgG in sera of LGG patients. Similarly, we did not observe CD4 T cell reactivity towards IDH1R132H in blood, neither did we observe such reactivity following preenrichment of frequencies of IDH1R132H-specifc CD4 T cells. Finally, we did not detect IDH1R132H-specifc CD4 T cells among TILs. Conclusions The absence of both humoral and cellular responses in blood and tumors of LGG patients indicates that IDH1R132H is not sufciently immunogenic and devaluates its further therapeutic exploitation, at least in the majority of LGG patients

New ways for our families : Designing an Aboriginal and Torres Strait Islander cultural practice framework and system responses to address the impacts of domestic and family violence on children and young people

Little has been done to understand what works to support First Nations children and young people to heal from their experiences of violence. This research project explores how services and systems can better respond to the needs of Aboriginal and Torres Strait Islander children and young people exposed to DFV who come to the attention of child protection systems. Led by the Queensland Aboriginal and Torres Strait Islander Child Protection Peak (QATSICPP), a team of First Nations researchers, supported by non-Indigenous researchers, utilised a participatory action research methodology – ensuring cultural safety and adherence to cultural values and protocols, including co-creation of knowledge. This report, the first in a series for this project, presents the results of a literature review and the findings from the initial cycles of action research conducted with Aboriginal and Torres Strait Islander chief investigators, community researchers and practitioners working in eight community-controlled child and family services across Queensland. The literature review and the outcomes of the initial action research cycle confirmed that the experience of DFV in childhood is resulting in negative lifelong outcomes for First Nations children, including increased interactions with the child protection and justice systems. The researchers also found that these responses (child protection and justice) are not adequate or culturally safe. To support healing for these children and young people, the report recommends: • holistic healing opportunities • culturally strong and community-led whole-of-family support • therapeutic healing circles and camps • connection to and knowledge about traditional cultural values, systems and traditions • a framework of perpetrator accountability • system changes include procuring place-based and healing responses for Aboriginal and Torres Strait Islander community-controlled services that support self-determination, and working collectively with the whole family. Additionally, cultural capability across the service system needs to be enhanced, and structural racism needs to be eliminated in order to reduce the load on existing Aboriginal and Torres Strait Islander services. Future publications from this research project, due in 2022, will consist of a research report on the remaining action research cycles and a framework for working with Aboriginal and Torres Strait Islander children and young people who have experienced DFV and have also come in contact with the child protection system

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Immunotherapy in Glioblastoma: Current Shortcomings and Future Perspectives

Glioblastomas are aggressive, fast-growing primary brain tumors. After standard-of-care treatment with radiation in combination with temozolomide, the overall prognosis of newly diagnosed patients remains poor, with a 2-year survival rate of less than 20%. The remarkable survival benefit gained with immunotherapy in several extracranial tumor types spurred a variety of experimental intervention studies in glioblastoma patients. These ranged from immune checkpoint inhibition to vaccinations and adoptive T cell therapies. Unfortunately, almost all clinical outcomes were universally disappointing. In this perspective, we provide an overview of immune interventions performed to date in glioblastoma patients and re-evaluate their performance. We argue that shortcomings of current immune therapies in glioblastoma are related to three major determinants of resistance, namely: low immunogenicity; immune privilege of the central nervous system; and immunosuppressive micro-environment. In this perspective, we propose strategies that are guided by exact shortcomings to sensitize glioblastoma prior to treatment with therapies that enhance numbers and/or activation state of CD8 T cells

Low-grade glioma harbors few CD8 T cells, which is accompanied by decreased expression of chemo-attractants, not immunogenic antigens

In multiple tumor types, prediction of response to immune therapies relates to the presence, distribution and activation state of tumor infltrating lymphocytes (TILs). Although such therapies are, to date, unsuccessful in gliomas, little is known on the immune contexture of TILs in these tumors. We assessed whether low and high-grade glioma (LGG and HGG, grade II and IV respectively) difer with respect to number, location and tumor reactivity of TILs; as well as expression of molecules involved in the trafcking and activation of T cells. Intra-tumoral CD8 T cells were quantifed by fow cytometry (LGG: n=12; HGG: n=8) and immunofuorescence (LGG: n=28; HGG: n=28). Neoantigen load and expression of Cancer Germline Antigens (CGAs) were assessed using whole exome sequencing and RNA-seq. TIL-derived DNA was sequenced and the variable domain of the TCRβ chain was classifed according to IMGT nomenclature. QPCR was used to determine expression of T cell-related genes. CD8 T cell numbers were signifcantly lower in LGG and, in contrast to HGG, mainly remained in close vicinity to blood vessels. This was accompanied by lower expression of chemo-attractants CXCL9, CXCL10 and adhesion molecule ICAM1. We did not observe a diference in the number of expressed neoantigens or CGAs, nor in diversity of TCR-Vβ gene usage. In summary, LGG have lower numbers of intra-tumoral CD8 T cells compared to HGG, potentially linked to decreased T cell trafcking. We have found no evidence for distinct tumor reactivity of T cells in either tumor type. The near absence of TILs in LGG suggest that, at present, checkpoint inhibitors are unlikely to have clinical efcacy in this tumor type