One of the most severe endocrine side effects of immune checkpoint inhibitors (ICI) is hypophysitis leading to adrenal insufficiency. Recovery is rare, although it has been reported after high-dose glucocorticoid treatment. This is the first randomised study to evaluate whether hormonal recovery differs in patients treated with high-dose glucocorticoids versus glucocorticoid replacement therapy.

In this single-centre, open, randomised controlled study, patients with ICI associated hypophysitis were randomised 1:1 to high-dose glucocorticoid treatment (1 mg/kg of prednisolone for two weeks, followed by tapering until week 7 and a switch to hydrocortisone 20 mg total daily dose in week 8) or glucocorticoid replacement therapy (hydrocortisone 20 mg total daily dose) over 8 weeks. The primary outcome was the frequency of hormonal axes recovery.

Between 17th April 2019 and 16th September 2022, 18 out of the 20 randomised patients finished the trial; eight completed high-dose, 10 glucocorticoid replacement. Nine patients presented with hyponatraemia, two had typical changes on MRI, 12 had isolated adrenal insufficiency, and six had an additional hormone deficiency. None of the patients in neither group experienced a recovery in adrenal function. One patient in each group showed amelioration of hypogonadism. There was a significant, unfavourable treatment effect of high-dose treatment on HbA1c (mean treatment effect 5.16, 95% confidence interval 0.31 to 10.02, p = 0.039).

High-dose glucocorticoid treatment was not effective in restoring adrenal function and leads to adverse effects on glucose metabolism. We therefore do not recommend its use for the treatment of ICI associated hypophysitis, except for compressive symptoms.

Mucosal melanoma is a rare and aggressive subtype of melanoma, accounting for 1%-2% of new cases in the United States in 2023, and 20%-30% in China and other Asian countries. Its origin is often occult, with the lack of early clinical features, the absence of actionable driver mutations, and poor response to immunotherapy, all contributing to its poor prognosis. The rarity of this subtype leads to limited awareness and interventions. Furthermore, due to its immune evasion mechanisms, mucosal melanoma shows resistance to traditional immune checkpoint inhibitors. Consequently, new therapeutic strategies are urgently needed to improve patient outcomes. Recent clinical trials have suggested that combination immunotherapy can overcome immune evasion, reduce resistance to treatment, produce synergistic anti-tumor effects, and improve survival. Epidemiological factors and clinical characteristics play significant roles in diagnosis and prognosis, while the mutational landscape influences responses to immunotherapy. This review provides an overview of these aspects and systematically discusses current research on combination therapies and emerging immunotherapy approaches for mucosal melanoma. It also explores potential future directions for treatment, aiming to enhance therapeutic strategies for this rare cancer and improve patient outcomes.

Monoclonal antibody (mAb) therapeutics have become widely successful for treatment of any number of diseases. However, for certain hard-to-reach tissues, e.g., eye, brain, tumors, and joints, local delivery is desired and long-term controlled release is necessary to avoid frequent injections and poor patient compliance. If local and sustained exposure of mAbs (or their Fab or nanobody fragments) could be accomplished by injectable polymer long-acting release (LAR) systems, the incredible potential of mAb therapeutics could be extended to additional diseases, e.g., neovascular age-related macular degeneration (wet AMD) and glioblastoma multiforme (GBM). In prior studies, long-acting delivery of mAbs has been limited by the inability to design a delivery system prepared from a biodegradable polymer used in FDA-approved LARs that achieves long-term continuous release of structurally stable and immunoreactive mAb with a low initial burst release that is easily injectable and avoids material build-up upon repeated injection. Here, we present for the first time a long-acting delivery system capable of delivering several different mAbs for multiple indications by developing a novel process to stabilize mAbs through the combination of formulation, micronization and encapsulation conditions, and to control stabilized mAb exposure in vivo for months by formulation with an appropriate biodegradable polymer (poly(lactic-co-glycolic acid) (PLGA)), utilization of a pH- and pore-modifying agent, and development of a novel PLGA coating layer to control osmotic pressure induced by elevated levels of critical co-encapsulated stabilizers, particularly mAb-stabilizing-trehalose. The resulting implants showed long-term efficacy in animal models for both wet AMD and GBM after single local injections. Although much more work needs to be done before their clinical application to these two diseases, the injectable PLGA platform meets several important benchmarks for controlled mAb delivery and can be developed further for delivery of a wide array of mAbs and other cofactors, offering an improved therapeutic option for treating diseases amenable to local antibody therapy. One Sentence Summary: A generalizable injectable biodegradable PLGA implant platform for site-specific and long-term slow and continuous release of stabilized monoclonal antibody drugs demonstrates improved in vivo efficacy for wet AMD and glioblastoma.

Radiation therapy (RT) is a crucial modality in cancer treatment, functioning through direct DNA damage and immune stimulation. However, RT's effects extend beyond targeted cells, influencing neighboring cells through the bystander effect (ByE) and distant sites via the abscopal effect (AbE). The AbE, first described by Mole in 1953, encompasses biological reactions at sites distant from the irradiation field. While RT can enhance antitumor immune responses, it may also contribute to an immunosuppressive microenvironment. To address this limitation, combining RT with immune checkpoint inhibitors (ICIs) has gained renewed interest, aiming to amplify antitumor immune responses. Evidence of AbEs has been observed in various metastatic or advanced cutaneous cancers, including melanoma, basal cell carcinoma, cutaneous lymphoma, Merkel cell carcinoma, and cutaneous squamous cell carcinoma. Clinical studies suggest combining RT with ICIs targeting CTLA-4 and PD-1/PD-L1 may enhance AbE incidence in these cancers. This review primarily explores the current understanding of AbEs in skin cancers, briefly acknowledging the ByE focusing on combining RT with immunomodulation. It focuses on proposed mechanisms, preclinical and clinical evidence, challenges in clinical translation, and future directions for harnessing AbEs in managing advanced skin malignancies. Alternative modalities for inducing abscopal-like responses are also explored. While promising, challenges remain in consistently reproducing AbEs in clinical practice, necessitating further research to optimize treatment combinations, timing, and patient selection.

Our primary objective was to estimate the overall response rate to immune checkpoint inhibitors (ICIs) in patients with locally advanced, multiply recurrent, or metastatic conjunctival melanoma treated with ICIs. A retrospective review of all consecutive conjunctival melanoma patients who were treated with ICI between October 2017 and January 2024 was carried out. The study included 16 patients with a median age of 66 years. The indications for ICI were locally extensive conjunctival melanoma in the eye/orbital area without nodal or distant metastasis in 10 patients, local recurrence of conjunctival melanoma and simultaneous nodal or distant metastasis in four patients, and metastatic conjunctival melanoma without local recurrence in two patients. Five patients received PD-1 inhibitor monotherapy with nivolumab or pembrolizumab; the other 11 received ipilimumab (CTLA-4 inhibitor) and nivolumab for several cycles and were then continued on nivolumab monotherapy ( n = 6) or not given additional ICI therapy ( n = 3). The number of cycles of ICI ranged from 2 to 25 (median, 13). Eight patients achieved a complete response. Six patients had progressive disease. The overall rate of objective response to ICI therapy was 63% (10 of 16), and for the subset of patients with local disease only, the objective response rate was 70% (7 of 10). In 14 patients (88%), orbital exenteration or additional extensive surgery was avoided; two patients had progression despite ICI and eventually needed an orbital exenteration. Future studies should aim to correlate biomarker data with response to ICI therapy in patients with conjunctival melanoma.

In comparison to earlier treatment standards (including chemotherapy, radiation therapy, and surgery), immunotherapy has significantly improved patients' survival and quality of life. Immunotherapy is ultimately a broad term that encompasses a variety of therapeutics. Immunotherapeutic approaches have firmly established themselves as a new pillar of cancer care, ranging from neoadjuvant and adjuvant strategies to the metastatic phase in various entities. In this review article, we highlight which immunotherapies are currently standard in oncological care, with a strong focus on immune checkpoint inhibitors (ICIs), their limitations, and the commonly occurring side effects.

The tumor immune microenvironment (TIME) is often dysfunctional and complex, contributing to tumor metastasis and drug resistance. This study investigates the use of mRNA-based cancer agents as promising tools to combat and reverse refractory TIME conditions.

We optimized and engineered an mRNA cancer agent encoding double tandemly repeated sequences of the T cell costimulator Oxford 40 ligand (diOX40L). The diOX40L mRNAs were encapsulated into lipid nanoparticles (LNPs) for effective delivery. The research explored its safety and antitumor effects through a series of in vivo and in vivo experiments.

Our results demonstrate that diOX40L mRNAs efficiently express increased levels of OX40L proteins. The optimized diOX40L mRNA cancer agent generated potent immune costimulatory signals within the TIME, leading to decreased tumor growth and improved survival compared to the original sequence agent. OX40L expression in subcutaneous tumors promoted CD4+ and CD8+ T cell activation, resulting in heightened IFN-γ and IL-2 secretion and robust immune responses. Combination therapy involving PD-1 antibodies and diOX40L substantially enhanced antitumor efficacy, with increased infiltration of activated CD4+ and CD8+ T cells.

In conclusion, our findings highlight the therapeutic potential of the optimized diOX40L mRNA cancer agent in cancer treatment and its potential as an innovative alternative to protein-based therapies. The study underscores the significance of mRNA-based agents in modulating the immune microenvironment and enhancing antitumor responses.

Strategies to improve the therapeutic efficacy of cancer immunotherapy with immune checkpoint inhibitors include targeting additional immunosuppressive compartments in the tumor microenvironment (TME). Inhibitory macrophages (Mφ) can be one of the most abundant immune cells in the TME associated with poor prognosis. However, to date, selective Mφ depletion strategies as a cancer immunotherapy have not been successful in clinical trials. Macrophage Receptor with Collagenous Structure (MARCO) is one of a family of class-A scavenger receptors expressed by Mφ in the TME and is one of the most upregulated transcripts in dendritic cells (DC) following their ex vivo uptake of dead tumor cells. The clinical significance of MARCO expression in the TME is not fully understood.

The therapeutic potential of targeting MARCO by an anti-murine MARCO (ED31, clone ED31) monoclonal antibody, which inhibits ligand-binding to MARCO, was explored in combination with anti-cytotoxic T-lymphocyte associated protein 4 (anti-CTLA-4) or anti-programmed cell death protein-1 (anti-PD-1) in C57BL/6J mice bearing B16F10 or Pan02 tumors. The mechanism by which ED31 impacts the TME was investigated by flow cytometry in the different treatment arms. The contribution of Mφ was assessed by both in vivo depletion and in vitro functional assays. Chemokine production was measured by a bead-based multiplex assay.

ED31 enhanced antitumor efficacy of anti-CTLA-4, but not of anti-PD-1. Analysis of the TME revealed that adding ED31 to anti-CTLA-4 substantially increased immune cell infiltration, including mature conventional DC recruitment, that was due to a switch to M1-pattern chemokines by Mφ. Mφ depletion completely abrogated both the increase in immune cell infiltration and chemokine production, and abolished the antitumor efficacy of the combination therapy.

Targeting MARCO as an additional checkpoint in the TME can offer a strategy to improve the antitumor efficacy of anti-CTLA-4 through a mechanism involving Mφ reprogramming rather than their depletion.

Nivolumab (NIVO) + ipilimumab (IPI) combination and NIVO monotherapy have demonstrated durable clinical benefit in patients with unresectable/metastatic melanoma. This analysis describes long-term overall survival (OS) with the combination or monotherapy pooled across all major company-sponsored trials, as well as clinical factors associated with survival, in patients with immune checkpoint inhibitor (ICI) treatment-naïve unresectable/metastatic melanoma.

Data were pooled from six CheckMate studies in ICI treatment-naïve patients receiving NIVO + IPI (NIVO 1 mg/kg + IPI 3 mg/kg or NIVO 3 mg/kg + IPI 1 mg/kg) or NIVO monotherapy (3 mg/kg). OS was assessed for each treatment, as well as in select subgroups. Cox proportional multivariate analysis (MVA) and classification and regression tree (CART) analyses were performed within treatment arms.

Median follow-up for OS was 45.0 months for patients treated with NIVO + IPI (n = 839) and 35.8 months for patients treated with NIVO (n = 536). OS was longer with NIVO + IPI versus NIVO monotherapy (hazard ratio, 0.78 [95% CI, 0.67 to 0.91]), with 6-year OS rates of 52% versus 41%, respectively. Consistent benefit was observed in BRAF-mutant and BRAF-wild-type patients and those with normal and elevated lactate dehydrogenase (LDH). Numerical difference in OS was also observed across PD-L1 expression levels, although more pronounced with no/low PD-L1 expression. Clinical factors associated with decreased survival in both the MVA and CART analyses were LDH > upper limit of normal with either treatment, age ≥65 years with NIVO + IPI, and the presence of liver metastases with NIVO monotherapy.

In this large, pooled nonrandomized retrospective analysis, we observed that NIVO + IPI provides longer OS than NIVO in patients with ICI treatment-naïve advanced melanoma and identifies clinical factors that appear to be associated with survival for each treatment, which may assist with treatment decision making.

Large language models (LLMs) have emerged as transformative technologies, revolutionizing natural language understanding and generation across various domains, including medicine. In this study, we investigated the capabilities, limitations, and generalizability of Generative Pre-trained Transformer (GPT) models in analyzing unstructured patient notes from large healthcare datasets to identify immune-related adverse events (irAEs) associated with the use of immune checkpoint inhibitor (ICI) therapy.

We evaluated the performance of GPT-3.5, GPT-4, and GPT-4o models on manually annotated datasets of patients receiving ICI therapy, sampled from two electronic health record (EHR) systems and seven clinical trials. A zero-shot prompt was designed to exhaustively identify irAEs at the patient level (main analysis) and the note level (secondary analysis). The LLM-based system followed a multi-label classification approach to identify any combination of irAEs associated with individual patients or clinical notes. System evaluation was conducted for each available irAE as well as for broader categories of irAEs classified at the organ level.

Our analysis included 442 patients across three institutions. The most common irAEs manually identified in the patient datasets included pneumonitis (N=64), colitis (N=56), rash (N=32), and hepatitis (N=28). Overall, GPT models achieved high sensitivity and specificity but only moderate positive predictive values, reflecting a potential bias towards overpredicting irAE outcomes. GPT-4o achieved the highest F1 and micro-averaged F1 scores for both patient-level and note-level evaluations. Highest performance was observed in the hematological (F1 range=1.0-1.0), gastrointestinal (F1 range=0.81-0.85), and musculoskeletal and rheumatologic (F1 range=0.67-1.0) irAE categories. Error analysis uncovered substantial limitations of GPT models in handling textual causation, where adverse events should not only be accurately identified in clinical text but also causally linked to immune checkpoint inhibitors.

The GPT models demonstrated generalizable abilities in identifying irAEs across EHRs and clinical trial reports. Using GPT models to automate adverse event detection in large healthcare datasets will reduce the burden on physicians and healthcare professionals by eliminating the need for manual review. This will strengthen safety monitoring and lead to improved patient care.

Immune checkpoint inhibitors (ICIs) have led to improved outcome in patients with various types of cancer. Due to inhibition of physiological anti-inflammatory mechanisms, patients treated with ICIs may develop autoimmune inflammation of the colon, associated with morbidity, decreased quality of life (QoL), and mortality. In this review, we summarize clinical and pathophysiological aspects of immune-mediated colitis (ImC), highlighting novel treatment options. In the colon, ICIs trigger resident and circulating T cell activation and infiltration of myeloid cells. In addition, the gut microbiota critically contribute to intestinal immune dysregulation and loss of barrier function, thereby propagating local and systemic inflammation. Currently available therapies for ImC include corticosteroids, antitumor necrosis factor-α (TNF-α)- and anti-integrin α4β7 antibodies. Given that systemic immunosuppression might impair antitumor immune responses, novel therapeutic approaches are urgently needed.

Sinonasal mucosal melanoma has poor survival despite multimodality treatment. While the impact of immunotherapy (IT) on metastatic cutaneous melanoma is well-defined, there are relatively little data on sinonasal mucosal melanoma.

We sought to define immunotherapy outcomes in patients with sinonasal mucosal melanoma.

A retrospective cohort study evaluated patients treated with IT during their overall treatment strategy for SNMM. Patient demographics, treatment, and survival outcomes were recorded.

52 patients had IT treatment for SNMM from 2000 to 2022, with an average age of 69.1 ± 11.9 years. The most common treatment was surgery with radiation and IT (n = 26, 50%). Most regimens consisted of a combination of Nivolumab and Ipilimumab (n = 17, 32.7%) or pembrolizumab (n = 14, 26.9%). 44.2% of patients experienced reported complications. Overall survival at 1-, 2-, and 5 years was 86.9%, 74.1%, and 39.1%, respectively.

Approximately half of patients will have a local response following immunotherapy, but it is rare to have improvement at metastatic locations. Further research within our group will assess optimal timing and markers that are predictive of response.

Melanoma, an aggressive skin cancer, presents significant therapeutic challenges. Consequently, innovative treatment strategies beyond conventional chemotherapy, radiation, and surgery are actively explored. This review discusses the evolution of immunotherapy in advanced melanoma, highlighting PD-1/PD-L1 inhibitors, mRNA vaccines, Talimogene Laherparepvec (T-VEC), and tumor-infiltrating lymphocyte (TIL) therapies. PD-1/PD-L1 inhibitors such as pembrolizumab and nivolumab block immune checkpoints, promoting T-cell cytotoxic activity and improving overall survival in patients with advanced melanoma. T-VEC, a modified oncolytic herpes virus, promotes a systemic anti-tumor response while simultaneously lysing malignant cells. mRNA vaccines, such as Moderna's mRNA-4157/V940, take advantage of malignant-cell-specific neoantigens to amplify the adaptive immune response while protecting healthy tissue. TIL therapy is a form of therapy involving ex vivo expansion and reinfusion of the patient's tumor-specific lymphocytes and has been shown to provide durable tumor control. While these therapies have demonstrated promising clinical outcomes, challenges such as tumor resistance, high financial burden, and limited accessibility pose challenges to their widespread use. This review explores combination therapies such as PD-L1 inhibitors with mRNA vaccines, or TIL therapy, which aim to enhance treatment through synergistic approaches. Further research is required to optimize these combinations, address barriers preventing their use, and control adverse events.

Dynein cytoplasmic 2 heavy chain 1 (DYNC2H1) is reported to play a potential role in cancer immunotherapy. However, the association between DYNC2H1 mutation and the clinical benefit of immunotherapy in non-small cell lung cancer (NSCLC) and melanoma remains to be elucidated. We collected data from three public immune checkpoint inhibitor (ICI)-treated NSCLC cohorts (n = 137 in total) and seven ICI-treated melanoma cohorts (n = 418 in total) to explore the potential of DYNC2H1 mutation as a predictive biomarker. The clinical outcomes, including the objective response rate (ORR) and progression-free survival (PFS), of patients with DYNC2H1 mutations are significantly better than those of patients with wild-type DYNC2H1. Multivariate Cox regression analysis confirmed that DYNC2H1 mutation was an independent predictive factor for ICI efficacy in NSCLC and melanoma. In addition, DYNC2H1 mutation exhibited no prognostic value for NSCLC or melanoma. Tumour mutational burden (TMB) and tumour neoantigen burden (TNB) were significantly higher in patients with DYNC2H1 mutation than in those with wild-type DYNC2H1 in both NSCLC and melanoma cohort. The analysis of immune-related genes and immune cell enrichment revealed an association between DYNC2H1 mutation and increased immune infiltration, revealing a potential mechanism underlying the predictive role of DYNC2H1 mutation in immunotherapy efficacy. In conclusion, DYNC2H1 mutation serves as a predictive biomarker of ICI efficacy in NSCLC and melanoma.

Triple-negative breast cancer (TNBC), defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) expression, is acknowledged as the most aggressive form of breast cancer (BC), comprising 15%-20% of all primary cases. Despite the prevalence of TNBC, effective and well-tolerated targeted therapies remain limited, with chemotherapy continuing to be the mainstay of treatment. However, the horizon is brightened by recent advancements in immunotherapy and antibody-drug conjugates (ADCs), which have garnered the U.S. Food and Drug Administration (FDA) approval for various stages of TNBC. Poly (ADP-ribose) polymerase inhibitors (PARPi), particularly for TNBC with BRCA mutations, present a promising avenue, albeit with the challenge of resistance that must be addressed. The success of phosphoinositide-3 kinase (PI3K) pathway inhibitors in hormone receptor (HR)-positive BC suggests potential applicability in TNBC, spurring optimism within the research community. This review endeavors to offer a comprehensive synthesis of both established and cutting-edge targeted therapies for TNBC. We delve into the specifics of PARPi, androgen receptor (AR) inhibitors, Cancer stem cells (CSCs), PI3K/Protein Kinase B (AKT)/mammalian target of rapamycin (mTOR), the transforming growth factor-beta (TGF-β), Ntoch, Wnt/β-catenin, hedgehog (Hh) pathway inhibitors, Epigenetic target-mediated drug delivery, ADCs, immune checkpoint inhibitors (ICIs)and novel immunotherapeutic solutions, contextualizing TNBC within current treatment paradigms. By elucidating the mechanisms of these drugs and their prospective clinical applications, we aim to shed light on the challenges and underscore the beacon of hope that translational research and innovative therapies represent for the oncology field.

Cancer-associated cachexia can inhibit immune checkpoint inhibitor (ICI) therapy efficacy. Cachexia's effect on ICI therapy has not been studied in large cohorts of cancer patients aside from lung cancer. We studied associations between real-world routinely collected clinical cachexia markers and disability-free, hospitalization-free and overall survival of cancer patients.

A retrospective study was conducted of electronic health records (EHR) of patients with lung, renal cell, melanoma and other cancers treated with ICI therapy at Northwestern Medicine of Chicago, IL, United States, between March 2011 and January 2022. Weight, body mass index, absolute neutrophil and lymphocyte counts, albumin and C-reactive protein (CRP) measures were analysed to calculate the Fearon consensus criteria for cachexia, weight loss grading system (WLGS) score, neutrophil-lymphocyte ratio (NLR), Prognostic Nutritional Index (PNI) and modified Glasgow Prognostic Score (mGPS) at ICI therapy initiation. Kaplan-Meier and Cox proportional hazards analyses were used to determine associations between these metrics and disability-free, hospitalization-free and overall survival.

EHR analysis uncovered 3285 cancer patients on ICI therapy (54% > 65 years of age, 50.7% male, 77.7% White). At ICI therapy initiation, 1282 (39.0%) patients had cachexia (consensus criteria), 1641 (50.0%) had a WLGS score ≥ 2, 1806 (55.0%) had an NLR > 3, 1087 (33.1%) had albumin < 3.5 g/dL and 1318 (40.1%) had a PNI < 44. Missing measurements included CRP missing for 98.2% and mGPS missing for 98.6% of patients. Disability-free (n = 1373), hospitalization-free (n = 2374) and overall survival (n = 1599) events were analysed with 1-year rates of 65% (64%-67%), 35% (34%-37%) and 65% (63%-66%), respectively. Multivariate Cox model analyses showed hazard ratios (HR) for cachexia at 1.58 (95% CI 1.38-1.80), 1.47 (95% CI 1.33-1.63) and 1.97 (95% CI 1.75-2.23) for disability, hospitalization and death, respectively. HRs for WLGS ≥ 2 were 1.45 (95% CI 1.28-1.66), 1.37 (95% CI 1.24-1.51) and 1.91 (95% CI 1.69-2.17). HRs for NLR > 3 were 1.57 (95% CI 1.35-1.83), 1.40 (95% CI 1.25-1.58) and 1.95 (95% CI 1.67-2.27). HRs for albumin < 3.5 g/dL were 1.33 (95% CI 1.15-1.54), 1.67 (95% CI 1.50-1.86) and 2.09 (95% CI 1.84-2.36). HRs for PNI < 44 were 1.60 (95% CI 1.39-1.84), 1.46 (95% CI 1.31-1.63) and 2.07 (95% CI 1.80-2.37).

Fearon consensus criteria, WLGS, NLR, albumin and PNI were routinely collected at ICI initiation in regular clinical practice and predictive of worse disability-free, hospitalization-free and overall survival in cancer patients receiving ICI therapy. These routine clinical measures may aid prognostication and decision-making in cancer patients with cachexia.

Immune checkpoint inhibitor (ICI)-associated myocarditis is a rare but potentially fatal immune-related adverse event. Previously, we reported a case of ICI-associated myocarditis with elevated autoantibodies to 4E-binding protein 3 (4E-BP3). Recent studies have suggested that 4E-BP3 may play an important role in tumor development. However, its role in cardiac diseases including myocarditis is unknown. We investigated the role of 4E-BP3 in an autoimmune myocarditis mouse model. Myocarditis was induced in wild-type and 4E-BP3 knockout mice by immunization with murine α-myosin peptide. 4E-BP3 gene expression was upregulated in the heart of myocarditis mouse. We found that genetic deletion of 4E-BP3 attenuated myocardial inflammation, reduced fibrosis area, and improved cardiac function in myocarditis mice. Studies in bone marrow-chimeric mice demonstrated that immune cell-derived 4E-BP3 plays a pivotal role in the pathogenesis of myocarditis. Immune cell transfer experiments revealed that 4E-BP3 deficiency in dendritic cells and CD4+ T cells decreased disease severity in recipient mice. Furthermore, dendritic cells that were deficient in 4E-BP3 exhibited a diminished capacity to produce IL-6 and IL-1β. Naive CD4+ T cells lacking 4E-BP3 had a reduced ability to differentiate into T-helper (Th)1 and Th17 cells. These findings suggest that 4E-BP3 in dendritic cells and CD4+ T cells may be critically involved in the pathogenesis of α-myosin-specific T cell-mediated myocarditis. Thus, 4E-BP3 could be a possible therapeutic target for myocarditis.

Immunotherapy represents an emergent and heterogeneous group of anticancer treatments harnessing the human immune-surveillance system, including immune-checkpoint inhibitor monoclonal antibodies (mAbs), Chimeric Antigen Receptor T Cells (CAR-T) therapy, cancer vaccines and lymphocyte activation gene-3 (LAG-3) therapy. While remarkably effective against several malignancies, these therapies, often in combination with other cancer treatments, have showed unforeseen toxicity, including cardiovascular complications. The occurrence of immuno-mediated adverse (irAEs) events has been progressively reported in the last 10 years. These irAEs present an extended range of severity, from self-limiting to life-threatening conditions. Although recent guidelines in CardioOncology have provided important evidence in managing cancer treatments, they often encompass general approaches. However, a specific focus is required due to the particular etiology, unique risk factors, and associated side effects of immunotherapy. This review aims to deepen the understanding of the prevalence and nature of cardiovascular issues in patients undergoing immunotherapy, offering insights into strategies for risk stratification and management.

Immune checkpoint inhibitors (ICI) have improved the therapeutic arsenal in outpatient oncology care; however, data on necessity of hospitalizations associated with immune-related adverse events (irAEs) are scarce. Here, we characterized hospitalizations of patients undergoing ICI, from the prospective cohort study of the immune cooperative oncology group (ICOG) Hannover.

Between 12/2019 and 06/2022, 237 patients were included. Clinical data and characteristics of ICI were collected during a 6-month observation period after the initiation of therapy. Descriptive statistics and Kaplan-Meier statistics were administered.

During the observation period, 30/237 patients were hospitalized (HA(+)). Most common underlying tumor entities were malignant melanoma (59.5%), renal cell carcinoma (13.1%), and nonsmall-cell lung carcinoma (12.7%). HA(+) patients exhibited an increased rate of pulmonary and cerebral metastases. We observed a significantly higher hospitalization rate during dual ICI with Nivolumab and Ipilimumab (p = 0.001). The predominant irAEs for hospitalization were colitis (26.7%), followed by hypophysitis (13.3%), leading to a median hospitalization of 7 (1-34) days. Interdisciplinary consultations were frequent, especially to gastroenterology (46.7%) and neurology (26.7%). Although a trend toward a prolonged overall survival in the HA(+) subgroup was identified, no statistically significant differences were found.

The hospitalization rate of 12.6% is comparable to rates reported in previous studies. There was a disproportionate admission of patients with immune-related colitis and hypophysitis compared to the prevalence described under ICI. We observed a high need for interdisciplinary consultations in line with the heterogeneity of immune-mediated side effects. Compared to non-hospitalized patients, there was no survival disadvantage in the HA(+) cohort.

With a relatively low hospitalization rate, short length of stay, and good clinical outcome, our data support the outpatient nature of ICI. The findings underscore the importance of interdisciplinary collaboration and vigilant monitoring of irAEs to ensure timely recognition and management.

Glioblastoma (GBM), the most common and aggressive primary central nervous system (CNS) tumor in adults, continues to have a dismal prognosis. Across hundreds of clinical trials, few novel approaches have translated to clinical practice while survival has improved by only a few months over the past three decades. Randomized controlled trials of immune checkpoint inhibitors (ICIs), which have seen impressive success for advanced or metastatic extracranial solid tumors, have so far failed to demonstrate a clinical benefit for patients with GBM. This has been secondary to GBM heterogeneity, the unique immunosuppressive CNS microenvironment, immune-evasive strategies by cancer cells, and the rapid evolution of tumor on therapy. This review aims to summarize findings from major clinical trials of ICIs for GBM, review historic failures, and describe currently promising avenues of investigation. We explore the biological mechanisms driving ICI responses, focusing on the role of the tumor microenvironment, immune evasion, and molecular biomarkers. Beyond conventional monotherapy approaches targeting PD-1, PD-L1, CTLA-4, we describe emerging approaches for GBM, such as dual-agent ICIs, and combination of ICIs with oncolytic virotherapy, antigenic peptide vaccines, chimeric antigenic receptor (CAR) T-cell therapy, along with nanoparticle-based delivery systems to enhance ICI efficacy. We highlight potential strategies for improving patient selection and treatment personalization, along with real-time, longitudinal monitoring of therapeutic responses through advanced imaging and liquid biopsy techniques. Integrated radiomics, tissue, and plasma-based analyses, may potentially uncover immunotherapeutic response signatures, enabling early, adaptive therapeutic adjustments. By specifically targeting current therapeutic challenges, outcomes for GBM patients may potentially be improved.

Skin cancer is the most common new cancer among Caucasians. This cancer has different types, of which non-melanoma skin cancer is the most common type. Various factors affect this disease, one of which is viral infections, including HPV. This virus plays an important role in skin cancer, especially cSCCs. There are various options for the treatment of skin cancer, and today special attention has been paid to treatments based on therapeutic goals, immunotherapy and combination therapy. In this study, we have investigated treatments based on immunotherapy and virotherapy and the effect of HPV virus on the effectiveness of these treatments in skin cancer. Treatments based on virotherapy are performed for a long time in combination with other common treatments such as radiotherapy and chemotherapy in order to have a greater effect and lower its side effects, which include: shortness of breath, tachycardia, lowering blood pressure in the patient. Also, the most important axis of immunotherapy is to focus on PD1-PDL1, despite abundant evidence on the importance of immunotherapy, many studies investigate the use of immunotherapy inhibitors in the adjuvant and neoadjuvant setting in various cancers. Also, previous findings show conflicting evidence of the effect of HPV status on the response to immunotherapy.

Immune checkpoint inhibitors (ICIs) have revolutionized oncology, providing a groundbreaking therapeutic option for patients with various advanced-stage cancers. While these treatments can significantly extend survival, they also carry a substantial risk of immune-related adverse events, among which hypophysitis is particularly detrimental to endocrine function. This narrative review synthesizes current knowledge on the pathogenesis, clinical features, diagnosis, and management of ICI-induced hypophysitis (IH) based on an in-depth analysis of the recent literature and clinical trials. The diagnosis of IH presents unique challenges due to its overlap with systemic symptoms commonly associated with the underlying malignancy. These symptoms can include asthenia, anorexia, headache, vomiting, weight loss, hypotension, dizziness, decreased libido, and visual disturbances. Diagnostic evaluation typically combines clinical assessment, hormonal profiling, and findings from magnetic resonance imaging (MRI). Effective management of IH requires a personalized, multidisciplinary approach, focusing on hormone replacement therapy and vigilant monitoring. Long-term care depends on the severity of hypophysitis, and the specific hormonal axes involved. This review aims to enhance awareness of the critical aspects of recognizing and managing IH, underscoring the importance of early diagnosis and timely intervention to reduce its long-term effects on patient quality of life.

The treatment of cancer when associated with autoimmune diseases (AID) has been the subject of immunotherapy investigation, especially with the use of immune checkpoint inhibitors (ICI). Clinical studies have restricted the evaluation of its use in special populations such as patients with AID, leaving a gap regarding the safety of using immunotherapy.

Discuss the safety of using ICI in patients with cancer and AID, in specialized oncology units, in the cities of Bahia, Brazil.

Retrospective and quantitative cross-sectional study on immune-related adverse events (IRAE) to the use of ICI in patients with cancer and AID.

Patients (39 with cancer, and 14 with AID and cancer) were studied. Men (between 30 and 95 years old), melanoma and lung cancer and Hashimoto's thyroiditis were predominance. Pembrolizumab and Nivolumab (anti-PDL-1) were drugs most used. In general, patients using anti-PDL-1 with AID had IRAE with greater frequency and severity: Grade 1 (57%) and 3/4 grades (43%) reactions. The gastrointestinal system presented a greater IRAE in both groups, however in patients with AID more severe reactions were found (0% versus 60%). Patients with cancer and AID had higher rates of IRAE compared to patients without AID, respectively, of discontinuation (50% versus 18%) and interruption (85% versus 20%) of treatment.

IRAE increased in patients using ICI with cancer and AID. This suggests that the presence of IAD, in cancer patients, can increase the severity of IRAE. Therefore, the adoption of more appropriate therapeutic strategies is essential for better therapeutic results.

Immune checkpoint inhibition (ICI) is highly effective for the treatment of melanoma, but intrinsic resistance is present in a subgroup of patients. TGF-β pathway activity may play a role in this resistance by preventing T-cells from entering the tumor microenvironment, causing immune escape. We investigated the association of TGF-β signal transduction pathway activity with resistance to ICI treatment in advanced melanoma. Furthermore, other pathway activities were analyzed to better understand their potential role in ICI resistance.

The activity of 8 signaling pathways (TGF-β, Hedgehog, MAPK, AR, NOTCH, PI3K, JAK/STAT1-2, and NFkB) was analyzed from tumor tissue from patients with advanced melanoma. Pathway activity scores (PAS) were explored for associations with survival and response to ICI in 34 patients (19 non-responders and 15 responders). A second, independent method to investigate the predictive value of TGF-β pathway activation was conducted by determining levels of phosphorylated SMAD2.

The mean TGF-β PAS of responders vs non-responders was 53.9 vs 56.8 (P = 0.265). No significant relation with progression-free survival was detected for TGF-β activity (P = 0.078). No association between pSMAD2 staining and treatment response or survival was identified. In contrast, Hedgehog scores of responders versus non-responders were 35.7 vs 41.6 (P = 0.038). High Hedgehog PAS was the sole significant predictor of resistance to ICI (OR 0.88, P = 0.033) and worse progression-free survival (HR 1-1.1, P = 0.012).

TGF-β pathway activation showed no significant relation with treatment response to ICI or survival in patients with advanced melanoma. Hedgehog PAS was identified as a possible biomarker associated with both treatment response and survival.

Glioblastoma is a highly aggressive primary brain tumor with glioblastoma stem cells (GSCs) enforcing the intra-tumoral hierarchy. Plasma cells (PCs) are critical effectors of the B-lineage immune system, but their roles in glioblastoma remain largely unexplored. Here, we leverage single-cell RNA and B cell receptor sequencing of tumor-infiltrating B-lineage cells and reveal that PCs are aberrantly enriched in the glioblastoma-infiltrating B-lineage population, experience low level of somatic hypermutation, and are associated with poor prognosis. PCs secrete immunoglobulin G (IgG), which stimulates GSC proliferation via the IgG-FcγRIIA-AKT-mTOR axis. Disruption of IgG-FcγRIIA paracrine communication inhibits GSC proliferation and self-renewal. Glioblastoma-infiltrating PCs are recruited to GSC niches via CCL2-CCR2 chemokine program. GSCs further derive pro-proliferative signals from broadly utilized monoclonal antibody-based immune checkpoint inhibitors via FcγRIIA signaling. Our data generate an atlas of B-lineage cells in glioblastoma with a framework for combinatorial targeting of both tumor cell-intrinsic and microenvironmental dependencies.

Approximately 70% of patients receiving immune checkpoint blockade therapies develop treatment resistance. Thus, there is a need for the identification of additional immunotherapeutic targets. CD49a is a membrane protein expressed on NK cells and T cells. In this study, we found that CD49a was highly expressed on the surface of tumor-infiltrating NK cells in various mouse tumor models and that CD49a+ tumor-infiltrating NK cells were more exhausted than CD49a- tumor-infiltrating NK cells. Furthermore, CD49a or NK-specific CD49a deficiency slowed tumor growth and prolonged survival in several mouse tumor models, primarily through the essential role played by NK cells in antitumor activities. Blockade of CD49a using an mAb suppressed tumor development in mice, and combination treatment with anti-PD-L1 further enhanced antitumor efficacy. Our research reveals CD49a on NK cells as an immunotherapeutic target and highlights the potential clinical applications of CD49a-targeted therapies.

Glioblastoma multiforme (GBM) is the most common and aggressive adult glioma (16-month median survival). Its immunosuppressive microenvironment limits the efficacy of immune checkpoint inhibitors (ICIs).

To assess the effects of the ICIs antibodies anti-programmed cell death 1 (anti-PD-1) and anti-programmed cell death ligand 1 (anti-PD-L1) in treating adults with diffuse glioma.

We searched CENTRAL, MEDLINE, Embase, and clinical trials registers on 8 March 2024.

We included randomised controlled trials (RCTs) evaluating adults with diffuse glioma treated with anti-PD-1/PD-L1 compared to placebo or other therapies used alone or with other ICIs. Primary outcomes were overall survival (OS), progression-free survival (PFS), and serious adverse events (SAE). Secondary outcomes were overall response rate (ORR), quality of life (QoL), and less serious AEs.

We followed standard Cochrane methods.

We included seven RCTs evaluating anti-PD-1 treatment in recurrent (N = 4) and newly diagnosed (N = 3) grade 4 glioma participants. The analysis encompassed 1953 participants; sample sizes ranged from 35 to 716. Meta-analyses were not possible due to heterogeneity and the small number of studies. Most trials had high risk of bias. Nivolumab versus bevacizumab in people with recurrent GBM (1 trial, 369 participants) Nivolumab probably does not increase OS (hazard ratio (HR) 1.04, 95% confidence interval (CI) 0.83 to 1.30; 1.3% more, 95% CI 6.30 fewer to 7.80 more; 369 participants; moderate-certainty evidence) or PFS (HR 1.97, 95% CI 1.57 to 2.48; 16.40% more, 95% CI 12.40 more to 19.00 more; 369 participants; moderate-certainty evidence). The evidence for SAE is very uncertain (risk ratio (RR) 1.20, 95% CI 0.74 to 1.92; 347 participants). Nivolumab probably does not increase ORR (RR 0.34, 95% CI 0.18 to 0.63; 309 participants; moderate-certainty evidence), but may not increase less serious AEs (RR 1.03, 95% CI 0.96 to 1.10; 347 participants; low-certainty evidence). Nivolumab plus bevacizumab 10 mg/kg versus nivolumab plus bevacizumab 3 mg/kg in people with recurrent GBM (1 trial, 90 participants) Nivolumab plus bevacizumab 10 mg/kg may not increase OS (HR 1.39, 95% CI 0.86 to 2.25; 9.90% more, 95% CI 5.20 fewer to 18.80 more; 90 participants; low-certainty evidence). The evidence for PFS (HR 1.23, 95% CI 0.78 to 1.93; 5.80% more, 95% CI 8.20 fewer to 14.20 more; 90 participants) and SAE (RR 1.19, 95% CI 0.79 to 1.79; 90 participants) is very uncertain. Nivolumab may not increase less serious AEs (RR 1.02, 95% CI 0.96 to 1.09; low-certainty evidence; 90 participants). Pembrolizumab plus bevacizumab versus pembrolizumab in people with recurrent GBM (1 trial, 80 participants) The evidence for OS (HR 1.03, 95% CI 0.65 to 1.63; 0.30% more, 95% CI 7.60 fewer to 2.90 more; 80 participants), PFS (HR 0.97, 95% CI 0.61 to 1.54: 0.40% fewer, 95% CI 9.20 fewer to 2.80 more; 80 participants), SAE (RR 1.32, 95% CI 0.75 to 2.42; 80 participants), and ORR (RR 12.76, 95% CI 0.77 to 210.27; 80 participants) is very uncertain. Pembrolizumab plus bevacizumab may not increase less serious AEs (RR 1.04, 95% CI 0.96 to 1.13; 80 participants; low-certainty evidence). Neoadjuvant (before surgical resection) and adjuvant (after surgical resection) pembrolizumab versus adjuvant-only pembrolizumab in people with recurrent GBM (1 trial, 35 participants) The evidence for OS (HR 0.39, 95% CI 0.17 to 0.92; 25.20% fewer, 95% CI 37.10 fewer to 2.10 fewer; 35 participants), PFS (HR 0.43, 95% CI 0.20 to 0.91; 30.10% fewer, 95% CI 52.20 fewer to 3.60 fewer; 35 participants), and SAE (RR 1.00, 95% CI 0.31 to 3.28; 32 participants) is very uncertain. Nivolumab plus radiotherapy versus temozolomide plus radiotherapy in people with newly diagnosed unmethylated GBM (1 trial, 560 participants) Nivolumab plus radiotherapy probably does not increase OS (HR 1.31, 95% CI 1.09 to 1.58 months; 8.30% more, 95% CI 2.80 more to 12.90 more; 560 participants) and PFS (HR 1.38, 95% CI 1.15 to 1.65 months; 7.50% more, 95% CI 3.60 more to 10.30 more; 560 participants; moderate-certainty evidence). The evidence for SAE is very uncertain (RR 0.87, 95% CI 0.65 to 1.18; 553 participants). It may not increase ORR (RR 1.08, 95% CI 0.43 to 2.69; 560 participants; low-certainty evidence) and probably does not increase less serious AEs (RR 1.00, 95% CI 0.96 to 1.04; 560 participants; moderate-certainty evidence). The evidence for time to deterioration of QoL is very uncertain (HR 0.76, 95% CI 0.59 to 0.99; 560 participants). Nivolumab plus temozolomide plus radiotherapy versus placebo plus temozolomide plus radiotherapy in people with newly diagnosed methylated GBM (1 trial, 716 participants) Nivolumab plus temozolomide plus radiotherapy probably does not increase OS (HR 1.10, 95% CI 0.92 to 1.32; 3.50 more, 95% CI 3.80 fewer to 9.60 more; 716 participants) and PFS (HR 1.10, 95% CI 0.92 to 1.32; 3.00 more, 95% CI 3.50 fewer to 7.90 more; 716 participants), and probably increases SAE (RR 2.91, 95% CI 2.05 to 4.12; 709 participants; moderate-certainty evidence). It does not increase less serious AEs (RR 1.02, 95% CI 1.00 to 1.04; 709 participants; high-certainty evidence). Adjuvant nivolumab plus temozolomide versus temozolomide in older people with GBM (1 trial, 103 participants) Nivolumab plus temozolomide probably does not increase OS (HR 0.85, 95% CI 0.54 to 1.33; 3.10 fewer, 95% CI 15.80 fewer to 3.60 more; 103 participants; moderate-certainty evidence) and PFS (HR 0.77, 95% CI 0.49 to 1.19; 5.40 fewer, 95% CI 19.10 fewer to 2.40 more; 103 participants; moderate-certainty evidence). The evidence for SAE is very uncertain (RR 1.58, 95% CI 0.88 to 2.81; 103 participants). The evidence for QoL is very uncertain (results only reported graphically; 103 participants).

In recurrent GBM, nivolumab alone probably has no benefit. Anti-PD1 plus bevacizumab may also be ineffective based on low- to very low-certainty evidence. Neoadjuvant plus adjuvant pembrolizumab may improve OS and PFS, but this was based on only one small trial and very low-certainty evidence. In newly diagnosed GBM, nivolumab plus radiotherapy in unmethylated and plus radiotherapy plus temozolomide in methylated GBM probably has no benefit. In older participants, adjuvant nivolumab probably offers no benefit.

Previous results from this trial showed longer overall survival after treatment with nivolumab plus ipilimumab or with nivolumab monotherapy than with ipilimumab monotherapy in patients with advanced melanoma. Given that patients with advanced melanoma are living longer than 7.5 years, longer-term data were needed to address new clinically relevant questions.

We randomly assigned patients with previously untreated advanced melanoma, in a 1:1:1 ratio, to one of the following regimens: nivolumab (1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks; nivolumab (3 mg per kilogram) every 2 weeks plus placebo; or ipilimumab (3 mg per kilogram) every 3 weeks for four doses plus placebo. Treatment was continued until the occurrence of disease progression, unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to BRAF mutation status, metastasis stage, and programmed death ligand 1 expression. Here, we report the final, 10-year results of this trial, including results for overall survival and melanoma-specific survival, as well as durability of response.

With a minimum follow-up of 10 years, median overall survival was 71.9 months with nivolumab plus ipilimumab, 36.9 months with nivolumab, and 19.9 months with ipilimumab. The hazard ratio for death was 0.53 (95% confidence interval [CI], 0.44 to 0.65) for nivolumab plus ipilimumab as compared with ipilimumab and was 0.63 (95% CI, 0.52 to 0.76) for nivolumab as compared with ipilimumab. Median melanoma-specific survival was more than 120 months with nivolumab plus ipilimumab (not reached, with 37% of the patients alive at the end of the trial), 49.4 months with nivolumab, and 21.9 months with ipilimumab. Among patients who had been alive and progression-free at 3 years, 10-year melanoma-specific survival was 96% with nivolumab plus ipilimumab, 97% with nivolumab, and 88% with ipilimumab.

The final trial results showed a continued, ongoing survival benefit with nivolumab plus ipilimumab and with nivolumab monotherapy, as compared with ipilimumab monotherapy, in patients with advanced melanoma. (Funded by Bristol Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).

The immune background of breast cancer is highly heterogeneous and the immune system of the human body plays a dual role by both promoting and suppressing its progression. Innate immune cells are the first line of defense in the immune system and impart protection by identifying and interacting with foreign pathogens and cancer cells. Different innate immune cells like natural killer cells, macrophages, dendritic cells, and myeloid suppressor cells take part in hosting the cancer cells. Autophagy is another key component inside the tumor microenvironment and is linked to the disintegration and recycling of cellular components. Within the tumor microenvironment autophagy is involved with Pattern Recognition Receptors and inflammation. Various clinical studies have shown prominent results where innate immune cells and autophagy in combination are used for pathogen as well as cancer cell clearance. However, it is necessary to comprehend the complex tumor microenvironment so that different therapeutic approaches can be developed to enhance the suppressive actions of the cells toward breast cancer cells. In this review article, the complex interaction between immune cells and breast cancer cells and their role in developing effective immunotherapies to improve patient outcomes are discussed in detail.

Cancer treatment has entered the age of immunotherapy. Immune checkpoint inhibitor (ICI) therapy has shown robust therapeutic potential in clinical practice, with significant improvements in progression-free survival (PFS) and overall survival (OS). Recently, checkpoint blockade of the lymphocyte activation gene 3 (LAG3) inhibitory receptor (IR) in combination with programmed death protein 1 (PD1) inhibition has been FDA approved in patients with advanced melanoma. This has encouraged the clinical evaluation of new LAG3-directed biologics in combination with other checkpoint inhibitors. Several of these studies are evaluating bispecific antibodies that target exhausted T (TEX) cells expressing multiple IRs. This review discusses the current understanding of LAG3 in regulating antitumor immunity and the ongoing clinical testing of LAG3 inhibition in cancer.

Hepatocellular carcinoma is the sixth most common tumor and the third leading cause of cancer death worldwide. It ranks fourth in the spectrum of malignant tumor incidence and second in the order of death from major malignant tumors in China. Hepatocellular carcinoma is a complex ecosystem containing non-tumor cells (mainly immune-related cells), and its immunotherapy can stimulate the recognition of specific tumor antigens, inhibit the proliferation of cancer cells, and produce over-memory lymphocytes, which can prevent recurrence. So, immunotherapy of hepatocellular carcinoma is increasingly becoming a research hotspot in liver cancer treatment. With the intensive research in recent years, great progress has been made in immunotherapy for hepatocellular carcinoma, including immune checkpoint inhibitors, pericyte therapy, vaccination, and antiviral therapy. In addition, the study found that the therapeutic effect of combination therapy was enhanced compared to monotherapy. This review summarizes the most prominent immunotherapies currently available for the clinical treatment of patients with HCC and the main opportunities and challenges facing HCC research.

Our previous clinical investigation suggested that hypofractionated stereotactic re-irradiation (HFSRT) and PD-1 blockade may act synergistically to enhance the immune response against glioma. This subsequent trial investigated the dual blockade of CTLA4 and PD-1 in combination with HFSRT and bevacizumab.

This phase I study enrolled eligible patients with bevacizumab-naïve recurrent glioblastoma or anaplastic astrocytoma. Participants received nivolumab, ipilimumab, and bevacizumab concurrently with HFSRT (3000 cGy in 5 fractions). Subsequently, nivolumab, ipilimumab, and bevacizumab were administered for a total of 4 cycles followed by nivolumab and bevacizumab until progression. The primary end point of this study was the safety and tolerability of HFSRT in combination with nivolumab, ipilimumab, and bevacizumab in patients with recurrent HGGs. Secondary end points included 6-month survival and 9-month survival.

Twenty-six patients were treated. Treatment-related adverse events (TRAEs) of grade 3 or 4 were observed in 12 (48%) evaluable patients with no unexpected TRAEs. Six months and 9 months survival were 92% (95% CI, 82-100%) and 75% (95% CI, 60-95%), respectively. The median progression-free survival and overall survival were 7.1 months (95% CI, 5.2-12.2) and 15.6 months (95% CI, 11.3-27.0), respectively.

The combination of HFSRT with ipilimumab, nivolumab, and bevacizumab is safe. Our results underscore the potential synergies between stereotactic re-irradiation and checkpoint immunotherapy in patients with recurrent high-grade gliomas.