Immunotherapy Trials Research Articles

Integrative multi-omics analysis uncovers tumor-immune-gut axis influencing immunotherapy outcomes in ovarian cancer

Recurrent ovarian cancer patients, especially those resistant to platinum, lack effective curative treatments. To address this, we conducted a phase 2 clinical trial (NCT02853318) combining pembrolizumab with bevacizumab, to increase T cell infiltration into the tumor, and oral cyclophosphamide, to reduce the number of regulatory T cells. The trial accrued 40 heavily pretreated recurrent ovarian cancer patients. The primary endpoint, progression free survival, was extended to a median of 10.2 months. The secondary endpoints demonstrated an objective response rate of 47.5%, and disease control in 30% of patients for over a year while maintaining a good quality of life. We performed comprehensive molecular, immune, microbiome, and metabolic profiling on samples of trial patients. Here, we show increased T and B cell clusters and distinct microbial patterns with amino acid and lipid metabolism are linked to exceptional clinical responses. This study suggests the immune milieu and host-microbiome can be leveraged to improve antitumor response in future immunotherapy trials.

Cancer research in South Asian Association for Regional Cooperation (SAARC) countries.

Cancer is a major global health threat, with 35 million new cases projected by 2050, predominantly in low-income and middle-income-countries. Within South Asian Association for Regional Cooperation (SAARC) countries, a notable gap in cancer research investment and output compared with high-income countries highlights the need to strengthen research capacity. The rising cancer incidence across SAARC countries is not being matched by local research, particularly in clinical trials in molecular biology, targeted therapy, immunotherapy, and cancer vaccines. This paucity of research is problematic as guidelines and therapies developed in high-income countries might not be directly applicable to low-income and middle-income countries due to distinct regional sociocultural, genetic, and environmental factors and are often impractical in these countries due to cost and implementation challenges. This Series paper examines the cancer research landscape within SAARC countries, focusing on Bangladesh, Nepal, Sri Lanka, India, Pakistan, Afghanistan, Bhutan, and Maldives. We analyse PubMed publication rates and examine available infrastructure, current research (including clinical trials), and limitations and disparities among SAARC countries in terms of cancer research. Key challenges include disparities in health-care access, cultural and economic barriers, and little funding and infrastructure. Strengthening cancer research in SAARC countries requires building collaborative networks, improving research facilities and training, focusing on local epidemiological studies, and developing affordable technologies and treatments. Effective policy and stakeholder engagement could greatly advance cancer care in the region.

Post hoc analysis of ADAMANT, a phase 2 clinical trial of active tau immunotherapy with AADvac1 in patients with Alzheimer’s disease, positive for plasma p-tau217

BackgroundThe spread of tau pathology closely correlates with the disease course and cognitive decline in Alzheimer’s disease (AD). Tau-targeting immunotherapies are being developed to stop the spread of tau pathology and thus halt disease progression. In this post hoc analysis of the ADAMANT clinical trial, we examined the performance of AADvac1, an active immunotherapy targeting the microtubule-binding region (MTBR) of tau, in a subgroup of participants with elevated plasma p-tau217, indicating AD-related neuropathological changes.MethodsADAMANT was a 24-month, randomized, placebo-controlled, parallel-group, double-blinded, multicenter, phase 2 clinical trial in subjects with mild AD. The trial participants were randomized 3:2 to receive six doses of AADvac1 or placebo at 4-week intervals, followed by five booster doses at 14-week intervals. The primary outcome was safety. The secondary outcomes were the Clinical Dementia Rating-Sum of Boxes (CDR-SB), the Alzheimer’s Disease Cooperative Study – Activities of Daily Living score for Mild Cognitive Impairment 18-item version (ADCS-ADL-MCI-18), and immunogenicity. Volumetric MRI, plasma neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) were exploratory outcomes. The inclusion criterion for this post-hoc analysis was a baseline plasma p-tau217 level above the cutoff for AD.ResultsAmong 196 ADAMANT participants, 137 were positive for plasma p-tau217 (mean age 71.4 years, 59% women). AADvac1 was safe and well tolerated in this subgroup. AADvac1 reduced the rate of accumulation of log-plasma NfL by 56% and that of GFAP by 73%. The treatment differences in the CDR-SB and ADCS-ADL-MCI-18 scores favored AADvac1 but were not statistically significant. AADvac1 had no effect on whole-brain volume but nonsignificantly reduced the loss of brain cortical tissue in several regions. Importantly, the impact on the study outcomes was more pronounced in participants with higher anti-tau antibody levels.ConclusionsThese results suggest that AADvac1 tau immunotherapy can reduce plasma biomarkers of neurodegeneration and neuroinflammation. These findings and possible observations on brain atrophy and cognition are hypothesis-generating and warrant further evaluation in a larger clinical trial.Trial registrationEudraCT 2015–000630-30 (primary) and NCT02579252.

Patient and Caregiver Experience of Diagnosis, Treatment, and Living With Recurrent Oropharyngeal Cancer

The management of recurrent oropharyngeal cancer (rOPC) is complex. Curative options carry considerable risk of morbidity with overall poor prognosis. Little data exist on function and quality of life (QoL) outcomes for noncurative treatments. Even less is known about patient and carer experiences of function and QoL change over time when undergoing curative or noncurative treatment(s) for rOPC. To investigate the patient and caregiver experience of diagnosis, treatment, and living with recurrent oropharyngeal cancer and changes to function/QoL. A longitudinal prospective and retrospective qualitative study was carried out at a specialist cancer center in the United Kingdom. Participants with a biopsy proven diagnosis of recurrent OPC and their caregivers were included. Participants were recruited between December 2022 and November 2023. Concurrent data analysis took took place between November 2023 and January 2024. Curative salvage surgery or noncurative immunotherapy, chemotherapy, or clinical trials of investigational agents. A framework-approach thematic analysis of semistructured, in-depth interviews. Twenty-two patients and 7 caregivers were recruited. Demographic data was collected via medical record review. The longitudinal sample included 8 male and 2 female individuals, and the median age was 62 (range, 47-77) years. The retrospective sample included 11 male individuals and 1 female individual, and the median age was 64 (range, 59-70) years. Eleven participants (50%) underwent curative treatment, and 11 (50%) noncurative treatment.Treatments included salvage surgery, immunotherapy, chemotherapy, or clinical trials. Patients and their caregivers contextualize their experience of recurrent disease in their past experience of primary disease diagnosis and treatment. Patients want to survive and when the options to choose between are cure or functional outcomes impacting health-related QoL, cure appears to be favored. However, when cure is not an option, patients appear to want to survive as long as possible. However, as the prognosis gets shorter there appears to be a shift in priorities where function/QoL take precedence over survival. This qualitative study found that treatment decision-making is extremely complex in the setting of rOPC. Quite often, decisions are made based on what is perceived by health care professionals to be functionally "too morbid" with salvage surgery, or "kinder" with life-prolonging noncurative treatments. However, patients are not always fully involved in these decisions and so shared decision-making does not always happen. To facilitate shared decision-making and informed consent, patients need to be given clear and accurate information on survival and function/QoL outcomes for the various treatment modalities for rOPC.

DISP-16. EXPLORING SEX-BASED DIFFERENCES IN RESPONSE TO IMMUNOTHERAPY IN GLIOBLASTOMA: A RETROSPECTIVE REVIEW

Abstract BACKGROUND The prognostic implication of sex is unclear in glioblastoma. A recent preclinical study suggested that T-cell exhaustion in males confers improved response to anti-PD1 therapy (PMID: 37378557). We conducted a retrospective study of patients with newly diagnosed (nGBM) and recurrent (rGBM) glioblastoma enrolled on immunotherapy trials at Dana-Farber Cancer Institute from 2014 to 2022 to determine whether sex influences the response to immunotherapy. METHODS Clinical, molecular, and radiographic data were collected, and their association with progression-free survival (PFS) and overall survival (OS) was evaluated using log-rank. RESULTS We evaluated 299 subjects with nGBM (172 male, 127 female) and 539 with rGBM (329 male, 210 female). In the nGBM cohort, median PFS for males vs females was 9.1 [7.2, 13.8] months vs 8.8 [6.5, 10.1] months (p=0.59) among subjects on immunotherapy trials (N=106), and 6.9 [6.1, 8.0] vs 6.5 [5.8, 8.1] months (p=0.44) in those on non-immunotherapy trials (N=193). Median OS was 18.6 [15.4, 24.0] in males vs 18.8 [15.9, 23.1] months in females (p=0.85) in immunotherapy trials and 15.6 [14.7, 17.3] vs 15.3 [13.1, 16.9] months (p=0.77) in non-immunotherapy trials. There was also no statistically significant difference in OS and PFS between sexes in the rGBM cohort: median PFS was 3.6 [3.0, 4.1] months in males vs 4.1 [3.8, 5.2] months in females and median OS was 8.4 [7.4, 9.6] vs 9.6 [8.2, 12.1] months in immunotherapy trials (N=254); median PFS was 1.8 [1.7, 2.1] vs 1.9 [1.8, 2.4] months and median OS was 8.6 [7.5, 9.6] vs 8.5 [7.3, 9.6] months in non-immunotherapy trials (N=285). CONCLUSION Sex did not have a prognostic impact on survival outcomes, regardless of the treatment modality. The impact of other clinical variables such as corticosteroid use, performance status, lymphocyte counts, and tumor burden will be reported.

IMMU-16. ANTI-VEGF TREATMENT EFFECT AGAINST GLIOMA IS IMMUNE DEPENDENT AND MEDIATED BY ENHANCED T CELL ACTIVITY

Abstract Immunotherapy trials in glioblastoma patients increasingly avoid immunosuppressive steroids and consider bevacizumab as alternative anti-edema treatment. Since VEGF is also a potent immunosuppressive factor, we explored the dimension and mechanisms of immune-mediated effects of anti-VEGF treatment. Murine glioma cells were injected intracerebrally into C57BL/6 wild-type mice or immunodeficient Pfp/Rag2 knockout mice and animals were treated with B20 (anti-murine VEGF) or dexamethasone. Immune cells were profiled by flow cytometry, and RNAseq was performed on sorted tumor and immune cells at different timepoints. B20 prolonged the survival of immunocompetent mice but not of Pfp/Rag2 knockout mice, indicating that the immune system is essential for its effect. At an early timepoint when controls became symptomatic, B20 “early” tumors (B20-ea) showed increased infiltration with T cells and myeloid cells, and decreased vascularization, whereas B20 tumors at the survival endpoint resembled IgG-controls. Gene expression in B20-ea tumor cells was dominated by hypoxia, neural development, invasion, TGF-β, Notch and Wnt signatures as well as concerted upregulation of Kmt2 H3K4 methyltransferases. In CD11b+ myeloid cells from B20-ea tumors, M1 hallmark genes and T cell activation genes were upregulated, while M2 genes were downregulated. Deconvolution revealed a transient shift towards pro-immune microglia/macrophages as well as increased NK cells and DCs. In CD8+ and CD4+ T cells, B20 increased the expression of S1pr1 and α/β TCR genes. The proportion of progenitor-like exhausted CD8+ cells, which are responsive to PD-1 blockade, was increased in B20-ea. In CD4+ cells, B20 caused skewing towards TFH, while dexamethasone increased TH2 cytokine expression. Depletion experiments demonstrated that CD8+ and CD4+ T cells but not NK cells were necessary for the survival-prolonging effect of B20. To conclude, anti-VEGF therapy has significant immunostimulatory effects which are, however, largely transient, so that an early treatment window of opportunity may exist during which it could actively support immunotherapy.

PCI for Patients with Small Cell Lung Cancer: A New Perspective in the Immunotherapy Era

Prophylactic cranial irradiation (PCI) has long been used for small-cell lung cancer (SCLC) to reduce the risk of brain metastases and potentially improve overall survival. However, recent immunotherapy trials have provided limited data on its impact, as few patients were treated with PCI. The ADRIATIC trial demonstrated improved outcomes with consolidation immunotherapy in limited-stage SCLC, and PCI was a stratification factor. Notably, patients receiving PCI in both arms had better outcomes compared to those who did not. Ongoing studies, such as EORTC-1901 PRIMALung (NCT04790253) and SWOG 1827-MAVERICK (NCT04155034), are further investigating PCI's role in the era of immunotherapy, highlighting its potential importance in evolving treatment strategies.

Landscape of subsequent therapies in perioperative immunotherapy trials across multiple cancer types

Landscape of subsequent therapies in perioperative immunotherapy trials across multiple cancer types

The challenges and clinical landscape of glioblastoma immunotherapy.

Glioblastoma is associated with a dismal prognosis with the standard of care involving surgery, radiation therapy and temozolomide chemotherapy. This review investigates the features that make glioblastoma difficult to treat and the results of glioblastoma immunotherapy clinical trials so far. There have been over a hundred clinical trials involving immunotherapy in glioblastoma. We report the survival-related outcomes of every Phase III glioblastoma immunotherapy trial with online published results we could find at the time of writing. To date, the DCVax-L vaccine is the only immunotherapy shown to have statistically significant increased median survival compared with standard-of-care in a Phase III trial: 19.3months versus 16.5months. However, this trial used an external control group to compare with the intervention which limits its quality of evidence. In conclusion, glioblastoma immunotherapy requires further investigation to determine its significance in improving disease survival.

Amyloid-β (Aβ) immunotherapy induced microhemorrhages are linked to vascular inflammation and cerebrovascular damage in a mouse model of Alzheimer’s disease

BackgroundAnti-amyloid-β (Aβ) immunotherapy trials have revealed amyloid-related imaging abnormalities (ARIA) as the most prevalent and serious adverse events linked to pathological changes in cerebral vasculature. Recent studies underscore the critical involvement of perivascular macrophages and the infiltration of peripheral immune cells in regulating cerebrovascular damage. Specifically, Aβ antibodies engaged at cerebral amyloid angiopathy (CAA) deposits trigger perivascular macrophage activation and the upregulation of genes associated with vascular permeability. Nevertheless, further research is needed to understand the immediate downstream consequences of macrophage activation, potentially exacerbating CAA-related vascular permeability and microhemorrhages linked to Aβ immunotherapy.MethodsThis study investigates immune responses induced by amyloid-targeting antibodies and CAA-induced microhemorrhages using RNA in situ hybridization, histology and digital spatial profiling in an Alzheimer's disease (AD) mouse model of microhemorrhage.ResultsIn the present study, we have demonstrated that bapineuzumab murine surrogate (3D6) induces profound vascular damage, leading to smooth muscle cell loss and blood–brain barrier (BBB) breakdown. In addition, digital spatial profiling (DSP) reveals that distinct immune responses contribute to vascular damage with peripheral immune responses and perivascular macrophage activation linked to smooth muscle cell loss and vascular fibrosis, respectively. Finally, RNA in situ hybridization identifies two distinct subsets of Trem2+ macrophages representing tissue-resident and monocyte-derived macrophages around vascular amyloid deposits. Overall, these findings highlight multifaceted roles of immune activation and vascular damage in driving the development of microhemorrhage.ConclusionsIn summary, our study has established a significant link between CAA-Aβ antibody immune complex formation, immune activation and vascular damage leading to smooth muscle cell loss. However, the full implications of this cascade on the development of microhemorrhages requires further exploration. Additional investigations are warranted to unravel the precise molecular mechanisms leading to microhemorrhage, the interplay of diverse immune populations and the functional roles played by various Trem2+ macrophage populations in response to Aβ immunotherapy.

Post-intervention control in HIV immunotherapy trials.

While post-treatment control following interruption of standard-of-care antiretroviral therapy (ART) is well described, post-intervention control following immunotherapy in HIV cure-related clinical trials is less well understood. We provide an overview of recent studies that have identified post-intervention controllers and review the mechanisms that may drive this biologically important phenotype. Post-intervention controllers have been identified in recent immunotherapy trials testing broadly neutralizing antibodies, immune modulators, modified T cells, checkpoint inhibitors, and gene therapy administered individually or in combination. Currently, there is substantial variability in how each trial defines post-intervention control, as well as in how the mechanisms underlying such control are evaluated. Such mechanisms include ongoing activity of both exogenous and autologous antibodies, as well as changes in HIV-specific T cell function. While no therapeutic strategy to date has succeeded in definitively inducing HIV control, many studies have identified at least a small number of post-intervention controllers. The field would benefit from a standardized approach to defining and reporting this phenotype, as well as standardization in the approach to assessment of how it is achieved. Such efforts would allow for comparisons across clinical trials and could help accelerate efforts toward an HIV cure.

Blinded independent central review versus local investigator assessment of PFS in RCTs of immunotherapy in advanced cancers: A systematic review and meta-analysis

BackgroundAssessment of Progression-free survival (PFS) events by investigators might be inaccurate in randomized controlled trials (RCTs) with open-label design. We explored differences in PFS evaluated by blinded independent central review (BICR) or local investigator assessment (IA) in trials testing immunotherapy (IO) in advanced cancers. MethodsWe systematically reviewed articles of RCTs investigating IO in advanced tumors, published in PubMed-indexed journals up to December 2023. For each RCT, we collected PFS results by BICR and by local IA. We calculated the discrepancy index (DI) as the ratio of BICR and IA Hazard Ratios (HRBICR/HRIA) for PFS. An overall DI and relative confidence interval (CI) were calculated using a fixed-effect model weighted for the inverse of variance. FindingsOnly 32/140 (22.9 %) RCTs reported both BICR and local IA PFS data, including 17,054 patients. PFS was the sole primary endpoint in 19/32 (59.4 %) and a co-primary endpoint 9/32 (28.2 %) trials. The study design was open label or double-blind in 17/32 (53.1 %) and 15/32 (46.9 %) RCTs, respectively. The overall DI was 1.07 (95 % CI 1.01–1.13; I2 =0, p = 0.02), revealing a more optimistic analysis of results in favor of local IA. In the 17 open-label trials, the overall DI was 1.09 (95 % CI 1.02–1.17, I2 =0, p = 0.02), revealing a more favorable interpretation of PFS results by local investigators. InterpretationWe found a statistically significant difference between BICR and local IA of PFS in trials of IO in cancer. These results suggest that the double assessment is recommended in RCTs testing IO, especially in open-label trials. FundingThis work was supported by the MFAG27826–2022 grant (Dr. Alberto Servetto).

BACE Inhibitor Clinical Trials for Alzheimer's Disease.

The amyloid hypothesis posits that the amyloid-β aggregates in the brain initiate a cascade of events that eventually lead to neuron loss and Alzheimer's disease. Recent clinical trials of passive immunotherapy with anti-amyloid-β antibodies support this hypothesis, because clearing plaques led to better cognitive outcomes. Orally available small molecule BACE1 inhibitors are another approach to slowing the buildup of plaques and thereby cognitive worsening by preventing the cleavage of amyloid-β protein precursor (AβPP) into amyloid-β peptide, the major component of plaques. This approach is particularly attractive because of their ease of use, low cost, and advanced clinical stage. However, although effective in preventing amyloid-β production in late-stage clinical trials, BACE inhibitors have been associated with early, non-progressive, likely reversible, cognitive decline. The clinical trials tested high levels of BACE inhibition, greater than 50%, whereas genetics suggest that even a 30% inhibition may be sufficient to protect from Alzheimer's disease. Aside from AβPP, BACE1 cleaves many other substrates in the brain that may be contributing to the cognitive worsening. It is important to know what the cause of cognitive worsening is, and if a lower level of inhibition would sufficiently slow the progress of pathology while preventing these unwanted side effects. Should these side effects be mitigated, BACE inhibitors could rapidly move forward in clinical trials either as a primary prevention strategy in individuals that are at risk or biomarker positive, or as a maintenance therapy following amyloid clearance with an anti-amyloid antibody.

PET/CT/MRI in Clinical Trials of Alzheimer's Disease.

With the advent of PET imaging in 1976, 2-deoxy-2-[18F]fluoro-D-glucose (FDG)-PET became the preferred method for in vivo investigation of cerebral processes, including regional hypometabolism in Alzheimer's disease. With the emergence of amyloid-PET tracers, [11C]Pittsburgh Compound-B in 2004 and later [18F]florbetapir, [18F]florbetaben, and [18F]flumetamol, amyloid-PET has replaced FDG-PET in Alzheimer's disease anti-amyloid clinical trial treatments to ensure "amyloid positivity" as an entry criterion, and to measure treatment-related decline in cerebral amyloid deposits. MRI has been used to rule out other brain diseases and screen for 'amyloid-related imaging abnormalities' (ARIAs) of two kinds, ARIA-E and ARIA-H, characterized by edema and micro-hemorrhage, respectively, and, to a lesser extent, to measure changes in cerebral volumes. While early immunotherapy trials of Alzheimer's disease showed no clinical effects, newer monoclonal antibody trials reported decreases of 27% to 85% in the cerebral amyloid-PET signal, interpreted by the Food and Drug Administration as amyloid removal expected to result in a reduction in clinical decline. However, due to the lack of diagnostic specificity of amyloid-PET tracers, amyloid positivity cannot prevent the inclusion of non-Alzheimer's patients and even healthy subjects in these clinical trials. Moreover, the "decreasing amyloid accumulation" assessed by amyloid-PET imaging has questionable quantitative value in the presence of treatment-related brain damage (ARIAs). Therefore, future Alzheimer's clinical trials should disregard amyloid-PET imaging and focus instead on assessment of regional brain function by FDG-PET and MRI monitoring of ARIAs and brain volume loss in all trial patients.

PRECISE-GBM: A RADIOGENOMIC MACHINE LEARNING BASED STUDY TO IDENTIFY PREDICTIVE RADIOMICS FOR EVALUATION OF CANCER IMMUNE SIGNATURE IN IDHW GLIOBLASTOMA

Abstract AIMS The aim of the study is to identify machine learning model based on radiological biomarkers that can predict immune status within tumor microenvironment of IDH wildtype glioblastoma. METHOD This is a retrospective multicenter machine learning based study utilizing open access anonymized matched radiogenomic data of TCGA-GBM, CPTAC, Ivy GAP and REMBRANDT datasets. REMBRANDT data acted as hold out dataset. Imaging data consisted of MRI based radiomics features extracted from deep learning based segmented tumors and transcriptomic (RNA seq/microarray) data consisted of immune scores extracted using CIBERSORTx. Outliers were identified and filtered using principal component analysis. Combat and neuroCombat were utilized for data harmonization for each data type respectively. Radiomic feature selection was performed using LASSO technique with cross validation. Support vector machine (SVM) was trained and tested with 80:20 radiomics data split and a median based binary label of immune score (low and high). Validation of the trained model was performed with hold out dataset. Data query and analysis was performed using python and R statistical software. RESULTS One hundred one patients were included in the study with 15 being on the hold out set. Trained SVM model predicted the immune score label with AUC of 0.79 and balanced accuracy of 0.76 (recall 0.75, F1 score 0.75, precision 0.75) in the test data. In the holdout set, the model predicted the immune score with AUC of 0.70 with specificity of 75% in predicting the cold immune cases. The radiomic signature that acted as the label for this model were a group of first order and second order radiomic features. CONCLUSION Radiogenomic SVM model non-invasively predicts immune status in wildtype glioblastoma microenvironment with good accuracy. This model has potential to be utilized in a prospective glioblastoma clinical trial for immunotherapy.

Decreased plasma nicotinamide and altered NAD+ metabolism in glial cells surrounding Aβ plaques in a mouse model of Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease and a leading cause of senile dementia. Amyloid-β (Aβ) accumulation triggers chronic neuroinflammation, initiating AD pathogenesis. Recent clinical trials for anti-Aβ immunotherapy underscore that blood-based biomarkers have significant advantages and applicability over conventional diagnostics and are an unmet clinical need. To further advance ongoing clinical trials and identify novel therapeutic targets for AD, developing additional plasma biomarkers closely associated with pathogenic mechanisms downstream of Aβ accumulation is critically important. To identify plasma metabolites reflective of neuroinflammation caused by Aβ pathology, we performed untargeted metabolomic analyses of the plasma by capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS) and analyzed the potential roles of the identified metabolic changes in the brain neuroinflammatory response using the female App knock-in (AppNLGF) mouse model of Aβ amyloidosis. The CE-TOFMS analysis of plasma samples from female wild-type (WT) and AppNLGF mice revealed that plasma levels of nicotinamide, a nicotinamide adenine dinucleotide (NAD+) precursor, were decreased in AppNLGF mice, and altered metabolite profiles were enriched for nicotinate/nicotinamide metabolism. In AppNLGF mouse brains, NAD+ levels were unaltered, but mRNA levels of NAD+-synthesizing nicotinate phosphoribosyltransferase (Naprt) and NAD+-degrading Cd38 genes were increased. These enzymes were induced in reactive astrocytes and microglia surrounding Aβ plaques in the cortex and hippocampus of female AppNLGF mouse brains, suggesting neuroinflammation increases NAD+ metabolism. This study suggests plasma nicotinamide could be indicative of the neuroinflammatory response and that nicotinate and nicotinamide metabolism are potential therapeutic targets for AD, by targeting both neuroinflammation and neuroprotection.

Cancer Immunotherapy Trials Network 12: Pembrolizumab in HIV-Associated Kaposi Sarcoma.

Cancer Immunotherapy Trials Network 12 demonstrated safety of pembrolizumab in treating advanced cancer in people with HIV. Here, we report results of the Kaposi sarcoma (KS) cohort. In this multicenter phase I trial, we enrolled participants with HIV-associated KS on antiretroviral therapy with CD4+ ≥50 cells/μL and HIV plasma RNA <200 copies/mL. Pembrolizumab 200 mg intravenously was administered once every 3 weeks for up to 35 cycles. The primary end point was safety, and the secondary end point was KS response by modified AIDS Clinical Trials Group Criteria. Thirty-two cisgender men enrolled with baseline median CD4+ T-cell count of 274 cells/µL. All but nine participants had received previous systemic KS therapy. Participants received a median of 11 cycles of pembrolizumab (range, 1-35). Sixty-six percent had grade ≥1 treatment-emergent adverse events, including one death from polyclonal KS herpesvirus-related B-cell lymphoproliferation. Thirty-one percent had ≥one immune-mediated AEs (imAEs) with 25% requiring systemic steroids. In 29 participants with evaluable KS, the overall response rate (ORR) was 62.1% (95% CI, 42.3 to 79.3) and did not differ by CD4+ T-cell count. ORR in the eight participants with evaluable disease without previous KS therapy was 87.5% (95% CI, 47.3 to 99.7). Median duration of response (DOR) was not reached, and the Kaplan-Meier estimate of DOR of ≥12 months was 92.3% (95% CI, 56.6 to 98.8). Median progression-free survival was 28.2 months (95% CI, 4.2 to noncalculable). Pembrolizumab yielded a high rate of durable responses in HIV-associated KS. imAEs were successfully managed with standard guidelines.

OA12.05 APOLO: Phase II Trial of Induction Chemo-Immunotherapy Plus Chemoradiotherapy and Maintenance Immunotherapy in Stage III NSCLC

OA12.05 APOLO: Phase II Trial of Induction Chemo-Immunotherapy Plus Chemoradiotherapy and Maintenance Immunotherapy in Stage III NSCLC

Role of Apolipoprotein E in Alzheimer's Disease Pathogenesis, Prognosis and Treatment.

Alzheimer's disease (AD) is an incurable and progressive neurodegenerative disease with increasing prevalence worldwide. Previous trials of anti-amyloid and anti-tau immunotherapy indicate that additional research needs to be conducted on other mechanisms to find curative or disease-modifying therapy. This review focuses on apolipoprotein E (ApoE), a critical protein in brain lipid metabolism that acts specifically in the clearance and transport of lipids and cholesterol. The ApoE4 allele confers substantial gene dose-dependent risk of developing AD and lowers the age of onset of AD, although the mechanisms of influence remain incompletely understood. The other isoforms bring different levels of AD risk. ApoE2 is protective while ApoE3 is the most common isoform and is considered neutral. An overview is presented of the latest information on the role of ApoE in AD pathogenesis with an emphasis on pathways that are involved in AD development and interactions with crucial processes in different cell types in the brain. Elucidating the key interactions of ApoE with multiple aspects of brain function can be useful for designing novel ApoE-targeted therapeutic approaches.

What do we know about the role of neoadjuvant targeted therapy in early-stage EGFR-mutant and ALK-fused non-small cell lung cancer?-a narrative review of the current literature.

The standard first-line treatment for patients with advanced non-small cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) fusions is targeted therapy using tyrosine kinase inhibitors (TKIs). However, data are still lacking on the use of TKIs as a neoadjuvant or induction approach. Therefore, this narrative review aims to summarize the current knowledge on resectable EGFR-mutant and ALK-fused NSCLC regarding available perioperative treatment regimens and off-label neoadjuvant use of targeted therapy. The relevant literature was identified by using PubMed and ClinicalTrials.gov (last search phase June 2024) and was restricted to English language. Peer-reviewed manuscripts but also conference abstracts that did not undergo peer-review were included. Patients with EGFR-mutations and ALK-fusions have typically been excluded from available phase III perioperative immunotherapy trials due to lower efficacy and higher toxicity of immunotherapy in those patients. In the adjuvant setting, recent evidence from the phase III ALINA and ADAURA trials demonstrated efficacy and safety of targeted therapy in resected ALK-fused and EGFR-mutant NSCLC. However, to date there is no approval for the use of TKIs as neoadjuvant or induction therapy in those patients. We have therefore identified a number of case series and phase II trials using targeted therapy in resectable EGFR-mutant and ALK-fused NSCLC. Current evidence suggests that targeted therapies might be effective in patients with resectable EGFR-mutant and ALK-positive NSCLC, but ongoing trials will need to provide further evidence on the safety and efficacy of perioperative TKI therapy.