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Objectives Materials and Methods Results Conclusion To assess the prevalence of cutaneous and oral immune‐related adverse events (irAEs) in cancer patients, risk factors for its development, and overall survival (OS).This retrospective observational study which included 748 medical records of cancer patients who received immune checkpoint inhibitors (ICIs). Demographic and clinicopathological characteristics were collected and analyzed.Most patients were male (59.4%), with stage IV cancer (65%) and received pembrolizumab (46.7%). Four hundred fourteen (55.34%) patients developed cutaneous lesions, 84 (11.2%) developed oral mucosal lesions, and 70 (9.3%) developed xerostomia. The median time for irAEs development was 11 weeks for cutaneous and oral mucosal lesions, and 21.5 weeks for xerostomia. Patients who received PD‐1 + CTLA‐4 had a higher risk for developing cutaneous irAEs (p = 0.001), while those who underwent ICI and concurrent chemotherapy had a higher risk (p = 0.008) for developing oral mucosal lesions. Patients who presented oral and cutaneous irAEs had better OS than those who did not present (p = 0.0001).Cutaneous effects affected more than half of the patients, while oral effects and xerostomia were found in around 11% and 9% of patients, respectively. Concurrent chemotherapy and PD‐1 + CTLA‐4 were more associated with oral and cutaneous irAEs, respectively. Patients who developed such irAEs had better overall survival. [ABSTRACT FROM AUTHOR]

Background: Anti-vascular endothelial growth factor monoclonal antibody (anti-VEGF) or immune checkpoint inhibitors (ICIs) combined with chemotherapy are commonly administered to cancer patients. Although cancer patients receiving anti-VEGF or ICIs have been reported to experience an increased risk of acute kidney injury (AKI), comparative studies on the AKI incidence have not been evaluated. Methods: Cancer patients receiving anti-VEGF or ICIs were retrospectively selected from the hospital information system of the First Affiliated Hospital of Wenzhou Medical University between Jan, 2020 and Dec, 2022 and were divided into two groups according to the treatment regimen: anti-VEGF group and ICIs group. The baseline characteristics were propensity-score matched. The primary outcome was sustained AKI. A comparison of cumulative incidence of sustained AKI was performed by Kaplan-Meier curves and log-rank test. Risks for outcomes were assessed using Cox proportional regression. Results: A total of 1581 cancer patients receiving anti-VEGF (n = 696) or ICIs (n = 885) were included in the primary analysis. The ICIs group had a higher cumulative incidence of sustained AKI within one year than the anti-VEGF group (26.8% vs. 17.8%, P < 0.001). Among 1392 propensity score matched patients, ICIs therapy (n = 696) was associated with an increased risk of sustained AKI events in the entire population (HR 2.0; 95%CI 1.3 to 2.5; P = 0.001) and especially in those with genitourinary cancer (HR 4.2; 95%CI 1.3 to 13.2; P = 0.015). Baseline serum albumin level (> 35 g/l) was an important risk factor for a lower incidence of sustained AKI in the anti-VEGF group (HR 0.5; 95%CI 0.3 to 0.9; P = 0.027) and the ICIs group (HR 0.3; 95%CI 0.2 to 0.5; P < 0.001). Conclusions: Among cancer patients in this real-world study, treatment with ICIs increased incidence of sustained AKI in one year. Baseline serum albumin level was an important risk factor for sustained AKI. The risk factors for sustained AKI differed between the anti-VEGF group and the ICIs group. Trial Registration: The study has been registered at ClinicalTrials.gov (NCT06119347) on 11/06/2023. [ABSTRACT FROM AUTHOR]

Anti-programmed death 1/programmed death ligand 1 (anti-PD-1/PD-L1) antibodies exert significant antitumor effects by overcoming tumor cell immune evasion and reversing T-cell exhaustion. However, the emergence of drug resistance causes most patients to respond poorly to these immune checkpoint inhibitors (ICIs). Studies have shown that insufficient T-cell infiltration, lack of PD-1 expression, deficient interferon signaling, loss of tumor antigen presentation, and abnormal lipid metabolism are all considered to be closely associated with immunotherapy resistance. To address drug resistance in tumor immunotherapy, a lot of research has concentrated on developing combination therapy strategies. Currently, ICIs such as anti-PD-1 /PD-L1 antibody combined with chemotherapy and targeted therapy have been approved for clinical treatment. In this review, we analyze the mechanisms of resistance to anti-PD-1/PD-L1 therapy in terms of the tumor microenvironment, gut microbiota, epigenetic regulation, and co-inhibitory immune checkpoint receptors. We also discuss various promising combination therapeutic strategies to address resistance to anti-PD-1/PD-L1 drugs, including combining these therapies with traditional Chinese medicine, non-coding RNAs, targeted therapy, other ICIs, and personalized cancer vaccines. Moreover, we focus on biomarkers that predict resistance to anti-PD-1/PD-L1 therapy as well as combination therapy efficacy. Finally, we suggest ways to further expand the application of immunotherapy through personalized combination strategies using biomarker systems. [ABSTRACT FROM AUTHOR]

The heterogeneity of macrophages influences the response to immune checkpoint inhibitor (ICI) therapy. However, few studies explore the impact of APOE+ macrophages on ICI therapy using single‐cell RNA sequencing (scRNA‐seq) and machine learning methods. The scRNA‐seq and bulk RNA‐seq data are Integrated to construct an M.Sig model for predicting ICI response based on the distinct molecular signatures of macrophage and machine learning algorithms. Comprehensive single‐cell analysis as well as in vivo and in vitro experiments are applied to explore the potential mechanisms of the APOE+ macrophage in affecting ICI response. The M.Sig model shows clear advantages in predicting the efficacy and prognosis of ICI therapy in pan‐cancer patients. The proportion of APOE+ macrophages is higher in ICI non‐responders of triple‐negative breast cancer compared with responders, and the interaction and longer distance between APOE+ macrophages and CD8+ exhausted T (Tex) cells affecting ICI response is confirmed by multiplex immunohistochemistry. In a 4T1 tumor‐bearing mice model, the APOE inhibitor combined with ICI treatment shows the best efficacy. The M.Sig model using real‐world immunotherapy data accurately predicts the ICI response of pan‐cancer, which may be associated with the interaction between APOE+ macrophages and CD8+ Tex cells. [ABSTRACT FROM AUTHOR]

The regulation of PD‐L1 is the key question, which largely determines the outcome of the immune checkpoint inhibitors (ICIs) based therapy. However, besides the transcription level, the protein stability of PD‐L1 is closely correlated with its function and has drawn increasing attention. In this study, EZH2 inhibition enhances PD‐L1 expression and protein stability, and the deubiquitinase ubiquitin‐specific peptidase 22 (USP22) is identified as a key mediator in this process. EZH2 inhibition transcriptionally upregulates USP22 expression, and upregulated USP22 further stabilizes PD‐L1. Importantly, a combination of EZH2 inhibitors with anti‐PD‐1 immune checkpoint blockade therapy improves the tumor microenvironment, enhances sensitivity to immunotherapy, and exerts synergistic anticancer effects. In addition, knocking down USP22 can potentially enhance the therapeutic efficacy of EZH2 inhibitors on colon cancer. These findings unveil the novel role of EZH2 inhibitors in tumor immune evasion by upregulating PD‐L1, and this drawback can be compensated by combining ICI immunotherapy. Therefore, these findings provide valuable insights into the EZH2‐USP22‐PD‐L1 regulatory axis, shedding light on the optimization of combining both immune checkpoint blockade and EZH2 inhibitor‐based epigenetic therapies to achieve more efficacies and accuracy in cancer treatment. [ABSTRACT FROM AUTHOR]

Background: Recent intravesical administration of adenoviral vectors, either as a single injection or in combination with immune checkpoint inhibitors, exemplified by cretostimogene grenadenorepvec and nadofaragene firadenovec, has demonstrated remarkable efficacy in clinical trials for non-muscle invasive bladder cancer. Despite their ability to induce an enhanced immune reaction within the lesion, the intracellular survival signaling of cancer cells has not been thoroughly addressed. Methods: An analysis of the prognostic data revealed a high probability of therapeutic efficacy with simultaneous inhibition of mTOR and STAT3. Considering the challenges of limited pharmaco-accessibility to the bladder due to its pathophysiological structure and the partially undruggable nature of target molecules, we designed a dual siRNA system targeting both mRNAs. Subsequently, this dual siRNA system was encoded into the adenovirus 5/3 (Ad 5/3) to enhance in vivo delivery efficiency. Results: Gene-targeting efficacy was assessed using cells isolated from xenografted tumors using a single-cell analysis system. Our strategy demonstrated a balanced downregulation of mTOR and STAT3 at the single-cell resolution, both in vitro and in vivo. This approach reduced tumor growth in bladder cancer xenograft and orthotopic animal experiments. In addition, increased infiltration of CD8+ T cells was observed in a humanized mouse model. We provided helpful and safe tissue distribution data for intravesical therapy of siRNAs coding adenoviruses. Conclusions: The bi-specific siRNA strategy, encapsulated in an adenovirus, could be a promising tool to augment cancer treatment efficacy and overcome conventional therapy limitations associated with "undruggability." Hence, we propose that dual targeting of mTOR and STAT3 is an advantageous strategy for intravesical therapy using adenoviruses. The current investigation introduces an innovative conceptualization of bispecific short hairpin RNA (bs_shRNA) tailored for the equilibrated modulation of dual genes within a singular cellular context. This novel bs_shRNA was loaded into the genome of an oncolytic adenovirus to augment the therapeutic efficacy of oncolytic viral interventions via the targeted inhibition of mTOR and STAT3 pathways. In addition, the administration of BSV significantly reduced the volume of bladder cancer tumors, concomitantly facilitating an enhanced recruitment of CD8+T lymphocytes in vivo. [ABSTRACT FROM AUTHOR]

Background: Basement membrane (BM) is an important component of the extracellular matrix, which plays an important role in the growth and metastasis of tumor cells. However, few biomarkers based on BM have been developed for prognostic assessment and prediction of immunotherapy in bladder cancer (BLCA). Methods: In this study, we used the BLCA public database to explore the relationship between BM-related genes (BMRGs) and prognosis. A novel molecular typing of BLCA was performed using consensus clustering. LASSO regression was used to construct a signature based on BMRGs, and its relationship with prognosis was explored using survival analysis. The pivotal BMRGs were further analyzed to assess its clinical characteristics and immune landscape. Finally, immunohistochemistry was used to detect the expression of the hub gene in BLCA patients who underwent surgery or received immune checkpoint inhibitor (ICI) immunotherapy in our hospital. Results: We comprehensively analyzed the relationship between BMRGs and BLCA, and established a prognostic-related signature which was an independent influence on the prognostic prediction of BLCA. We further screened and validated the pivotal gene-MMP14 in public database. In addition, we found that MMP14 expression in muscle invasive bladder cancer (MIBC) was significantly higher and high MMP14 expression had a poorer response to ICI treatment in our cohort. Conclusions: Our findings highlighted the satisfactory value of BMRGs and suggested that MMP14 may be a potential biomarker in predicting prognosis and response to immunotherapy in BLCA. [ABSTRACT FROM AUTHOR]

Background: Atezolizumab, one of the immune checkpoint inhibitors, has been approved as an adjuvant treatment following resection and platinum‐based chemotherapy in patients with stage II–IIIA non‐small cell lung cancer with 1% or more programmed death ligand‐1 (PD‐L1) expression. The Food and Drug Administration (FDA) has approved SP263 as a companion diagnostic assay for adjuvant treatment with atezolizumab; however, in clinical practice, the 22C3 assay is most commonly used for advanced non‐small cell lung cancer. Therefore, our study aimed to compare two PD‐L1 assays, SP263 and 22C3, to evaluate whether 22C3 could replace SP263 when deciding whether to administer adjuvant atezolizumab. Methods: We retrospectively and prospectively analyzed 98 patients who underwent surgical resection at Kanagawa Cancer Center (Japan). An immunohistochemistry assay was performed for all the cases with both SP263 and 22C3. We statistically analyzed the concordance of PD‐L1 expression between SP263 and 22C3 assays. Results: The concordance between the two assays using Cohen's kappa was κ = 0.670 (95% CI: 0.522–0.818) at the 1% cutoff and κ = 0.796 (95% CI: 0.639–0.954) at the 50% cutoff. The Spearman correlation coefficient of 0.874 (p < 0.01) indicated high concordance. PD‐L1 expression with 22C3 resulted slightly higher than that with SP263. Conclusions: This study showed a high concordance of PD‐L1 expression with the SP263 and 22C3 assays. Further studies examining the therapeutic effects of adjuvant atezolizumab are required. [ABSTRACT FROM AUTHOR]

Although cancer has long been considered a genetic disease, increasing evidence shows that epigenetic aberrations play a crucial role in affecting tumor biology and therapeutic response. The dysregulated epigenome in cancer cells reprograms the immune landscape within the tumor microenvironment, thereby hindering antitumor immunity, promoting tumor progression, and inducing immunotherapy resistance. Targeting epigenetically mediated tumor-immune crosstalk is an emerging strategy to inhibit tumor progression and circumvent the limitations of current immunotherapies, including immune checkpoint inhibitors. In this Review, we discuss the mechanisms by which epigenetic aberrations regulate tumorimmune interactions and how epigenetically targeted therapies inhibit tumor progression and synergize with immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Immune profiling has become an important tool for identifying predictive, prognostic and response biomarkers for immune checkpoint inhibitors from tumor microenvironment (TME). We aimed to build a multiplex immunofluorescence (mIF) panel to apply to formalin-fixed and paraffin-embedded tissues in mice tumors and to explore the programmed cell death protein 1/ programmed cell death 1 ligand 1 (PD-1/PD-L1) axis. Results: An automated eight-color mIF panel was evaluated to study the TME using seven antibodies, including cytokeratin 19, CD3e, CD8a, CD4, PD-1, PD-L1, F4-80 and DAPI, then was applied in six mice lung adenocarcinoma samples. Cell phenotypes were quantified by software to explore the co-localization and spatial distribution between immune cells within the TME. This mice panel was successfully optimized and applied to a small cohort of mice lung adenocarcinoma cases. Image analysis showed a sparse degree of immune cell expression pattern in this cohort. From the spatial analysis we found that T cells and macrophages expressing PD-L1 were close to the malignant cells and other immune cells. Conclusions: Comprehensive immune profiling using mIF in translational studies improves our ability to correlate the PD-1/PD-L1 axis and spatial distribution of lymphocytes and macrophages in mouse lung cancer cells to provide new cues for immunotherapy, that can be translated to human tumors for cancer intervention. [ABSTRACT FROM AUTHOR]

Background: The recent usage of immunotherapy combined with chemoradiotherapy has improved survival in advanced non-small cell lung cancer (NSCLC) patients. However, determining the most effective therapy combination remains a topic of debate. Research suggests immune checkpoint inhibitors (ICIs) post-chemoradiotherapy enhance survival, but the impact of concurrent ICIs during chemoradiotherapy on rapid disease progression is unclear. This meta-analysis aims to assess the effectiveness and safety of concurrent ICIs with radiotherapy or chemoradiotherapy in advanced non-small cell lung cancer. Methods: We searched PubMed, Embase, the Cochrane Library, and Web of Science for relevant studies, extracting data on overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs). Results: The analysis included ten studies with 490 participants. Stage III NSCLC ORR was 81.8%, while Stage IV ORR was 39.9%. One-year PFS and OS for Stage III were 68.2% and 82.6%, compared to 27.9% and 72.2% for Stage IV. Common adverse events included anemia (46.6%), nausea (47.6%), rash (36.4%), and radiation pneumonitis (36.3%). Conclusions: Our meta-analysis shows concurrent ICIs with chemoradiotherapy are effective and safe in advanced NSCLC, particularly in stage III patients at risk of progression before starting ICIs after chemoradiotherapy. The findings support further phase III trials. The review protocol was registered on PROSPERO (CRD42023493685) and is detailed on the NIHR HTA programme website. [ABSTRACT FROM AUTHOR]

Background: The standard care for resectable non-small cell lung cancer (NSCLC) involves perioperative therapy combining chemotherapy and immune checkpoint inhibitors, typically lasting 6 to 12 months. However, the optimal treatment strategies for potentially resectable squamous cell lung carcinoma (SCC) remain unclear. This Phase 2 trial aimed to assess the efficacy and safety of a condensed four-cycle perioperative treatment regimen with tislelizumab combined with chemotherapy in patients with potentially resectable stage III SCC. Methods: Patients with potentially resectable stage IIIA-IIIB (N2) SCC received intravenous tislelizumab, albumin-bound paclitaxel, and carboplatin for up to four cycles. The primary endpoints were major pathologic response (MPR) and incidence of treatment-related adverse events. Safety and potential biomarkers for efficacy prediction were also assessed. Results: Among 35 enrolled patients, 32 underwent surgery with R0 resection achieved in all cases. MPR was achieved in 24 patients and pathological complete response (pCR) in 14 patients. Radiographic objective response was observed in 31 patients. The 12-month and 24-month event-free survival rate was 85.7 and 61.0%, respectively. Four patients experienced grade 3 or 4 adverse events. Tumor tissue based next-generation sequencing revealed the potential associations between several biomarkers and pathological response, including tumor neoantigen burden score, 18-gene expression profile score, CD8 + T cells, M1/M2 macrophages ratio and interferon‐gamma expression level. Besides, circulating tumor DNA (ctDNA) dynamics and concentration were also associated with pathological response and the presence of ctDNA at postoperative month 1 was a strong predictor for disease relapse. Furthermore, metagenomic sequencing in bronchoalveolar lavage fluid demonstrated Streptococcus was the most abundant genus in the pCR group. Conclusions: A condensed four-cycle perioperative treatment regimen of tislelizumab combined with chemotherapy demonstrated promising efficacy and manageable toxicities in potentially resectable stage III SCC. Specific biomarkers showed potential for predicting treatment efficacy and the mechanism of superior antitumor response of pCR patients was preliminarily and indirectly explored. Trial registration: ClinicalTrials.gov, NCT05024266. Registered August 27, 2021. [ABSTRACT FROM AUTHOR]

Background: Pleural mesothelioma, characterized by a dismal prognosis even with multimodal therapy, has seen emerging interest in immune checkpoint inhibitors (ICIs) due to their demonstrated efficacy. Here, we present a case of epithelioid-type pleural mesothelioma with chest wall invasion treated with definitive ICI therapy, resulting in a remarkable pretreatment effect. Case presentation: A 46-year-old man was diagnosed with an abnormal chest shadow on a medical check, and a computed tomography scan showed pleural thickening at the dorsal right upper chest wall. One of the nodules was suspected to have invaded the chest wall. A needle biopsy revealed epithelioid-type pleural mesothelioma. After five cycles of nivolumab plus ipilimumab, he underwent right pleurectomy/decortication (P/D). Pathological examination revealed a significant treatment effect, showing numerous lymphocytes infiltrating the tumor nodule and viable tumor cells localized at approximately 6 mm. Conclusion: Although further accumulation of cases is required to evaluate the effectiveness and case selection, P/D after immunotherapy is a useful curative treatment option for advanced pleural mesothelioma. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) are known to facilitate tumor progression by suppressing CD8+ T cells within the tumor microenvironment (TME), thereby also hampering the effectiveness of immune checkpoint inhibitors (ICIs). While systemic depletion of Tregs can enhance antitumor immunity, it also triggers undesirable autoimmune responses. Therefore, there is a need for therapeutic agents that selectively target Tregs within the TME without affecting systemic Tregs. In this study, as shown also by others, the chemokine (C–C motif) receptor 8 (CCR8) was found to be predominantly expressed on Tregs within the TME of both humans and mice, representing a unique target for selective depletion of tumor-residing Tregs. Based on this, we developed BAY 3375968, a novel anti-human CCR8 antibody, along with respective surrogate anti-mouse CCR8 antibodies, and demonstrated their in vitro mode-of-action through induction of potent antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) activities. In vivo, anti-mouse CCR8 antibodies effectively depleted Tregs within the TME primarily via ADCP, leading to increased CD8+ T cell infiltration and subsequent tumor growth inhibition across various cancer models. This monotherapeutic efficacy was significantly enhanced in combination with ICIs. Collectively, these findings suggest that CCR8 targeting represents a promising strategy for Treg depletion in cancer therapies. BAY 3375968 is currently under investigation in a Phase I clinical trial (NCT05537740). [ABSTRACT FROM AUTHOR]

Background: Resistance to immune checkpoint inhibitors (ICIs) represents a major unmet medical need in non-small cell lung cancer (NSCLC) patients. Vascular endothelial growth factor (VEGF) inhibition may reverse a suppressive microenvironment and recover sensitivity to subsequent ICIs. Methods: This phase Ib/IIa, single-arm study, comprised dose-finding (Part A) and expansion (Part B) cohorts. Patients with ICIs-refractory NSCLC were enrolled to receive anlotinib (a multi-target tyrosine kinase inhibitor) orally (from days 1 to 14 in a 21-day cycle) and nivolumab (360 mg every 3 weeks, intravenously) on a 21-day treatment cycle. The first 21-day treatment cycle was a safety observation period (phase Ib) followed by a phase II expansion cohort. The primary objectives were recommended phase 2 dose (RP2D, part A), safety (part B), and objective response rate (ORR, part B), respectively. Results: Between November 2020 and March 2022, 34 patients were screened, and 21 eligible patients were enrolled (6 patients in Part A). The RP2D of anlotinib is 12 mg/day orally (14 days on and 7 days off) and nivolumab (360 mg every 3 weeks). Adverse events (AEs) of any cause and treatment-related AEs (TRAEs) were reported in all treated patients. Two patients (9.5%) experienced grade 3 TRAE. No grade 4 or higher AEs were observed. Serious AEs were reported in 4 patients. Six patients experienced anlotinib interruption and 4 patients experienced nivolumab interruption due to TRAEs. ORR and disease control rate (DCR) was 19.0% and 76.2%, respectively. Median PFS and OS were 7.4 months (95% CI, 4.3-NE) and 15.2 months (95% CI, 12.1-NE), respectively. Conclusion: Our study suggests that anlotinib combined with nivolumab shows manageable safety and promising efficacy signals. Further studies are warranted. Trial registration: NCT04507906 August 11, 2020. [ABSTRACT FROM AUTHOR]

PURPOSE: The choice of threshold and reliability of high tumor mutational burden (TMB) to predict outcomes and guide treatment choice for patients with metastatic melanoma receiving first-line immune checkpoint inhibitor (ICI) therapy in the real world is not well known. METHODS: Using a deidentified nationwide (US-based) melanoma clinicogenomic database, we identified a real-world cohort of patients with metastatic melanoma (N = 497) who received first-line monotherapy anti–PD-1 (n = 240) or dual anti–PD-1 and anti–CTLA-4 ICI (n = 257) and had a tissue-based comprehensive genomic profiling test TMB score. RESULTS: TMB-high (TMB-H; ≥10 mutations per megabase [muts/Mb], n = 352, 71%) was independently predictive of superior real-world progression-free survival and overall survival versus TMB-low (<10 mut/Mb, n = 145, 29%) in both mono ICI (hazard ratio [HR], 0.45 [95% CI, 0.32 to 0.63]; P <.001; HR, 0.61 [95% CI, 0.41 to 0.90]; P =.01, respectively) and dual ICI (HR, 0.67 [95% CI, 0.49 to 0.90]; P =.009; HR, 0.61 [95% CI, 0.42 to 0.88]; P =.007, respectively) patients. Dual ICI offered no significant advantage in BRAF wt patients and unexpectedly demonstrated greatest benefit in the TMB 10-19 mut/Mb group, identifying a TMB-very high (≥20 mut/Mb, n = 247, 50%) BRAF mut patient subgroup for whom mono ICI may be preferable. CONCLUSION: TMB-H predicts superior outcomes on ICI while coassessment of BRAF status and TMB may inform first-line regimen choice. Melanoma TMB predicts real-world ICI outcome but BRAF coassessment may better inform regimen choice. [ABSTRACT FROM AUTHOR]

The challenges associated with the assessment of immune checkpoint inhibitor (ICI) therapy and low immunotherapy response observed in patients with poorly immunogenic tumors are addressed. A smart‐responsive nanoprobe MZF@Gd is synthetized based on magnetic resonance tuning (MRET). The nanoprobe is designed to be targeted and cleaved by granzyme B, a marker of cytotoxic T‐cell activation. MZF@Gd consisted of superparamagnetic Mn‐ and Zn‐doped ferrite magnetic nanoparticles (MZF‐MNPs) with a magnetocaloric effect and a paramagnetic contrast agent gadolinium‐diethylenetriamine penta‐acetic acid (Gd‐DTPA). These components are connected by the granzyme B substrate peptides. The activation of the T1WI signal through MRET, following the cleavage of the probe by granzyme B, enabled the accurate evaluation of the ICI therapeutic effect. Subsequently, an active‐targeting magnetothermally responsive nanotheranostic agent FA‐P(MZF@Gd/JQ1) is fabricated. This agent incorporated the MRET probe MZF@Gd, JQ‐1 (an inhibitor of PD‐L1), the thermosensitive copolymer PCL‐b‐P(MEO2MA‐co‐OEGMA), and folic acid on the surface. Nanotheranostic agents killed tumor cells through magnetocaloric effects, stimulated antitumor immunity, and regulated the drug release, thereby achieving a synergistic effect between hyperthermia and immunotherapy. Moreover, MZF@Gd released from the agent sensitively detected the presence of granzyme B at the tumor site, thereby enabling an effective assessment of therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Background: The Accum® platform was initially designed to accumulate biomedicines in target cells by inducing endosomal-to-cytosol escape. Interestingly however, the use of unconjugated Accum® was observed to trigger cell death in a variety of cancer cell lines; a property further exploited in the development of Accum®-based anti-cancer therapies. Despite the impressive pro-killing abilities of the parent molecule, some cancer cell lines exhibited resistance. This prompted us to test additional Accum® variants, which led to the identification of the AccuTOX® molecule. Methods: A series of flow-cytometry and cell-based assays were used to assess the pro-killing properties of AccuTOX® along with its ability to trigger the production of reactive oxygen species (ROS), endosomal breaks and antigen presentation. RNA-seq was also conducted to pinpoint the most prominent processes modulated by AccuTOX® treatment in EL4 T-cell lymphoma. Finally, the therapeutic potency of intratumorally-injected AccuTOX® was evaluated in three different murine solid tumor models (EL4, E0771 and B16) both as a monotherapy or in combination with three immune-checkpoint inhibitors (ICI). Results: In total, 7 Accum® variants were screened for their ability to induce complete cell death in 3 murine (EL4, B16 and E0771) and 3 human (MBA-MD-468, A549, and H460) cancer cell lines of different origins. The selected compound (hereafter refereed to as AccuTOX®) displayed an improved killing efficiency (~ 5.5 fold compared to the parental Accum®), while retaining its ability to trigger immunogenic cell death, ROS production, and endosomal breaks. Moreover, transcriptomic analysis revealed that low dose AccuTOX® enhances H2-Kb cell surface expression as well as antigen presentation in cancer cells. The net outcome culminates in impaired T-cell lymphoma, breast cancer and melanoma growth in vivo especially when combined with anti-CD47, anti-CTLA-4 or anti-PD-1 depending on the animal model. Conclusions: AccuTOX® exhibits enhanced cancer killing properties, retains all the innate characteristics displayed by the parental Accum® molecule, and synergizes with various ICI in controlling tumor growth. These observations will certainly pave the path to continue the clinical development of this lead compound against multiple solid tumor indications. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is a major cause of cancer-related death, but despondently, the outlook and prognosis for this resistant type of tumor have remained grim for a long time. Currently, it is extremely challenging to prevent or detect it early enough for effective treatment because patients rarely exhibit symptoms and there are no reliable indicators for detection. Most patients have advanced or spreading cancer that is difficult to treat, and treatments like chemotherapy and radiotherapy can only slightly prolong their life by a few months. Immunotherapy has revolutionized the treatment of pancreatic cancer, yet its effectiveness is limited by the tumor's immunosuppressive and hard-to-reach microenvironment. First, this article explains the immunosuppressive microenvironment of pancreatic cancer and highlights a wide range of immunotherapy options, including therapies involving oncolytic viruses, modified T cells (T-cell receptor [TCR]-engineered and chimeric antigen receptor [CAR] T-cell therapy), CAR natural killer cell therapy, cytokine-induced killer cells, immune checkpoint inhibitors, immunomodulators, cancer vaccines, and strategies targeting myeloid cells in the context of contemporary knowledge and future trends. Lastly, it discusses the main challenges ahead of pancreatic cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Immune checkpoint inhibitors can rarely lead to occurrence of myositis, myocarditis, and myasthenia gravis (MG). Early recognition and multidisciplinary management are crucial for optimal outcomes. Vigilance for overlapping toxicities is essential in patients receiving combination immunotherapy. The use of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, but it is associated with immune‐related adverse events (IRAEs) affecting various organ systems. The simultaneous occurrence of MG, myocarditis, and myositis highlights the complex nature of IRAEs. Early recognition and comprehensive multidisciplinary management are crucial for optimal patient outcomes. We present a unique case report of a 76‐year‐old male patient with advanced melanoma who developed concurrent myositis, myocarditis, and MG while receiving combination immunotherapy with Nivolumab and Ipilimumab. This case underscores the significance of recognizing and addressing the "Terrible Triad" of IRAEs in patients receiving ICIs. Healthcare providers should maintain a high index of suspicion for overlapping toxicities and promptly initiate appropriate interventions. [ABSTRACT FROM AUTHOR]

Introduction: The relative efficacies of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and immune checkpoint inhibitors (ICIs) for the treatment of recurrent non-small cell lung cancer (NSCLC) after surgery remain unclear. Methods: Among 801 patients with NSCLC who underwent pulmonary resection at Kanazawa Medical University between 2017 and 2021, sixty-four patients had recurrence. We retrospectively compared the efficacies of EGFR-TKIs and ICIs in these patients with recurrent NSCLC who underwent pulmonary resection. Results: The 3-year overall survival rates after recurrence were 79.3% in patients who received EGFR-TKIs, 69.5% in patients who received ICIs, and 43.7% in patients who received cytotoxic agents. There was no significant difference in overall survival between patients treated with EGFR-TKIs and ICIs (p = 0.14) or between patients treated with ICIs and cytotoxic agents (p = 0.23), but overall survival was significantly higher in patients treated with EGFR-TKIs compared with cytotoxic agents (p < 0.01). The probabilities of a 2-year response were 88.5%, 61.6%, and 25.9% in patients treated with EGFR-TKIs, ICIs, and cytotoxic agents, respectively. There was no significant difference in response periods between patients treated with EGFR-TKIs and ICIs (p = 0.18), but the response period was significantly better in patients treated with EGFR-TKIs (p < 0.01) or ICIs (p = 0.03) compared with cytotoxic agents. Percent-predicted vital capacity (p = 0.03) and epidermal growth factor receptor gene mutation (p < 0.01) were significant factors affecting the overall response to chemotherapy in multivariate analysis. Conclusion: EGFR-TKIs and ICIs are effective for treating recurrent NSCLC after surgery. Although adjuvant chemotherapy for completely resected pathological stage II to IIIA NSCLC, atezolizumab or osimertinib, has also been recently approved as adjuvant chemotherapy, there is a risk that patients who relapse after adjuvant chemotherapy will have less choice. [ABSTRACT FROM AUTHOR]

Small cell lung cancer (SCLC) is a deadly neuroendocrine malignancy, notorious for its rapid tumor growth, early metastasis, and relatively "cold" immune environment. Only standard chemotherapies and a few immune checkpoint inhibitors have been approved for SCLC treatment, revealing an urgent need for novel therapeutic approaches. Moreover, SCLC has been recently recognized as a malignancy with high intratumoral and intertumoral heterogeneity, which explains the modest response rate in some patients and the early relapse. Molecular subtypes defined by the expression of lineage-specific transcription factors (ASCL1, NEUROD1, POU2F3, and, in some studies, YAP1) or immune-related genes display different degrees of neuroendocrine differentiation, immune cell infiltration, and response to treatment. Despite the complexity of this malignancy, a few biomarkers and targets have been identified and many promising drugs are currently undergoing clinical trials. In this review, we integrate the current progress on the genomic landscape of this shapeshifting malignancy, the characteristics and treatment vulnerabilities of each subtype, and promising drugs in clinical phases. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is widely recognized as the predominant type of primary liver malignancy. Orthotopic liver transplantation (OLT) has emerged as a highly effective treatment option for unresectable HCC. Immunotherapies as neoadjuvant options are now being actively investigated in the transplant oncology era to enhance outcomes in patients with HCC. Here, we report our experience with patients with HCC who had received Immune Checkpoint Inhibitors (ICPI) prior to curative OLT. Methods: This was a retrospective cohort that included patients with HCC who received ICPI prior to OLT at a single institution from January 2019 to August 2023. Graft rejection was assessed and reported along with the type of ICPI, malignancy treated, and the timing of ICPI in association with OLT. Results: During this cohort period, six patients with HCC underwent OLT after neoadjuvant ICPI. All patients were male with a median age of 61 (interquartile range: 59–64) years at OLT. Etiology associated with HCC was viral (N = 4) or Non-alcoholic steatohepatitis, NASH (N = 2). Tumor focality was multifocal (N = 4) and unifocal (N = 2). Lymphovascular invasion was identified in four patients. No perineural invasion was identified in any of the patients. All patients received ICPI including atezolizumab/bevacizumab (N = 4), nivolumab/ipilimumab (N = 1), and nivolumab as monotherapy (N = 1). All patients received either single or combined liver-directed/locoregional therapy, including transarterial chemoembolization (TACE), Yttrium-90 (Y90), stereotactic body radiotherapy (SBRT), and radiofrequency ablation (RFA). The median washout period was 5 months. All patients responded to ICPI and achieved a safe and successful OLT. All patients received tacrolimus plus mycophenolate as immunosuppressant (IS) therapy post-OLT and one patient received prednisone as additional IS. No patient had clinical evidence of rejection. Conclusions: This cohort emphasizes the success of tumor downstaging by ICPI for OLT when employed as the neoadjuvant therapy strategy. In addition, this study illustrated the importance of timing for the administration of ICPI before OLT. Given the lack of conclusive evidence in this therapeutic area, we believe that our study lays the groundwork for prospective trials to further examine the impact of ICPI prior to OLT. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors block the interaction between a receptor on one cell and its ligand on another cell, thus preventing the transduction of an immunosuppressive signal. While inhibition of the receptor–ligand interaction is key to the pharmacological activity of these drugs, it can be technically challenging to measure these intercellular interactions directly. Instead, target engagement (or receptor occupancy) is commonly measured, but may not always be an accurate predictor of receptor–ligand inhibition, and can be misleading when used to inform clinical dose projections for this class of drugs. In this study, a mathematical model explicitly representing the intercellular receptor–ligand interaction is used to compare dose prediction based on target engagement or receptor–ligand inhibition for two checkpoint inhibitors, atezolizumab and magrolimab. For atezolizumab, there is little difference between target engagement and receptor–ligand inhibition, but for magrolimab, the model predicts that receptor–ligand inhibition is significantly less than target engagement. The key variables explaining the difference between these two drugs are the relative concentrations of the target receptors and their ligands. Drug‐target affinity and receptor–ligand affinity can also have divergent effects on target engagement and inhibition. These results suggest that it is important to consider ligand–receptor inhibition in addition to target engagement and demonstrate the impact of using modeling for efficacious dose estimation. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors help treat malignant melanoma, but show limited use in treating malignant vaginal melanoma, an aggressive, rare gynecological malignancy. We identified two patients treated with ipilimumab and nivolumab for vaginal melanoma; both were immunonegative for programmed cell death-ligand 1 and wild-type BRAF. Case 1, a 56-year-old female who underwent radical surgery for stage 1 malignant vaginal melanoma, experienced recurrence 15 months postoperatively. She briefly responded to ipilimumab and nivolumab combination therapy before showing disease progression. Tumor shrinkage occurred with nivolumab and local radiotherapy and, 45 months postoperatively, she survives with the melanoma. Case 2, a 50-year-old female, presented with a 4-cm blackish polypoid vaginal tumor with metastatic pelvic lymph nodes. She received ipilimumab and nivolumab combination therapy for stage III unresectable malignant vaginal melanoma. The vaginal tumor shrank after the third course of treatment, and the lymphadenopathy disappeared. The patient underwent radical surgery and is currently disease-free, using nivolumab for maintenance therapy. Both patients had immune-related adverse events coinciding with periods of high therapeutic efficacy of immune checkpoint inhibitors. Neoadjuvant therapy with immune checkpoint inhibitors and radiotherapy for immune checkpoint inhibitor resensitization may effectively treat advanced or recurrent vaginal melanoma. [ABSTRACT FROM AUTHOR]

High-grade gliomas (HGGs) constitute the most common malignant primary brain tumor with a poor prognosis despite the standard multimodal therapy. In recent years, immunotherapy has changed the prognosis of many cancers, increasing the hope for HGG therapy. We conducted a comprehensive search on PubMed, Scopus, Embase, and Web of Science databases to include relevant studies. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Fifty-two papers were finally included (44 phase II and eight phase III clinical trials) and further divided into four different subgroups: 14 peptide vaccine trials, 15 dendritic cell vaccination (DCV) trials, six immune checkpoint inhibitor (ICI) trials, and 17 miscellaneous group trials that included both "active" and "passive" immunotherapies. In the last decade, immunotherapy created great hope to increase the survival of patients affected by HGGs; however, it has yielded mostly dismal results in the setting of phase III clinical trials. An in-depth analysis of these clinical results provides clues about common patterns that have led to failures at the clinical level and helps shape the perspective for the next generation of immunotherapies in neuro-oncology. [ABSTRACT FROM AUTHOR]

This study aimed to determine the accuracy and consistency of established methods of extrapolating mean survival for immuno-oncology (IO) therapies, the extent of any systematic biases in estimating long-term clinical benefit, what influences the magnitude of any bias, and the potential implications for health technology assessment. A targeted literature search was conducted to identify published long-term follow-up from clinical trials of immune-checkpoint inhibitors. Earlier published results were identified and Kaplan-Meier estimates for short- and long-term follow-up were digitized and converted to pseudo–individual patient data using an established algorithm. Six standard parametric, 5 flexible parametric, and 2 mixture-cure models (MCMs) were used to extrapolate long-term survival. Mean and restricted mean survival time (RMST) were estimated and compared between short- and long-term follow-up. Predicted RMST from extrapolation of early data underestimated observed RMST in long-term follow-up for 184 of 271 extrapolations. All models except the MCMs frequently underestimated observed RMST. Mean survival estimates increased with longer follow-up in 196 of 270 extrapolations. The increase exceeded 20% in 122 extrapolations. Log-logistic and log-normal models showed the smallest change with additional follow-up. MCM performance varied substantially with functional form. Standard and flexible parametric models frequently underestimate mean survival for IO treatments. Log-logistic and log-normal models may be the most pragmatic and parsimonious solutions for estimating IO mean survival from immature data. Flexible parametric models may be preferred when the data used in health technology assessment are more mature. MCMs fitted to immature data produce unreliable results and are not recommended. • Treatment with immune-checkpoint inhibitors can result in a proportion of patients achieving durable response, generating a long tail to the survival distribution. Conventional extrapolation methods applied to short-term data may not perform well in estimating mean survival in these circumstances. • Both standard parametric and spline-based flexible parametric models (FPMs) tend to underestimate survival benefit for immuno-oncology therapies. Performance seems to worsen as the proportion of durable responders increases. More flexible models perform better than restrictive models, but with some risk of overfitting to short-term data. Mixture-cure models fitted to early data cuts produce unreliable results and may substantially overestimate mean survival. • Log-logistic and log-normal models may be the most pragmatic and parsimonious solutions for estimating mean survival from short-term data when the proportion of durable responders is expected to be low. FPMs using odds or normal scale may be better options when the data used in health technology assessment are more mature. When the expected proportion of durable responders is high, neither standard nor FPMs are expected to perform well and methods integrating external information should be considered. [ABSTRACT FROM AUTHOR]

Summary: Immune checkpoints (ICPs) play a crucial role in regulating the immune response. In the tumor, malignant cells can hijack the immunosuppressive effects of inhibitory ICPs to promote tumor progression. Extracellular vesicles (EVs) are produced by a variety of cells and contain bioactive molecules on their surface or within their lumen. The expression of ICPs has also been detected in EVs. In vitro and in vivo studies have shown that extracellular vesicle immune checkpoints (EV ICPs) have immunomodulatory effects and are involved in tumor immunity. EV ICPs isolated from the peripheral blood of cancer patients are closely associated with the tumor progression and the prognosis of cancer patients. Blocking inhibitory ICPs has been recognized as an effective strategy in cancer treatment. However, the efficacy of immune checkpoint inhibitors (ICIs) in cancer treatment is hindered by the emergence of therapeutic resistance, which limits their widespread use. Researchers have demonstrated that EV ICPs are correlated with clinical response to ICIs therapy and were involved in therapeutic resistance. Therefore, it is essential to investigate the immunomodulatory effects, underlying mechanisms, and clinical significance of EV ICPs in cancer. This review aims to comprehensively explore these aspects. We have provided a comprehensive description of the cellular origins, immunomodulatory effects, and clinical significance of EV ICPs in cancer, based on relevant studies. Immune checkpoints (ICPs) play a crucial role in regulating the immune response. In the tumor, malignant cells can hijack the immunosuppressive effects of inhibitory ICPs to promote tumor progression. This review aims to comprehensively explore these aspects. We have provided a comprehensive description of the cellular origins, immunomodulatory effects, and clinical significance of EV ICPs in cancer, based on relevant studies. Graphical Abstract [ABSTRACT FROM AUTHOR]

Objectives The objective of this study was to determine baseline risk factors for requiring immunosuppression and having persistent arthritis in patients with immune checkpoint inhibitor–induced inflammatory arthritis (ICI–inflammatory arthritis). Methods Participants were adults with rheumatologist diagnosed ICI–inflammatory arthritis. The primary outcome was requirement of conventional synthetic (cs) or biologic (b) DMARDs; other outcomes were persistence of inflammatory arthritis >6 months after ICI cessation and requirement of CSs. Logistic regression models evaluated associations between clinical features and primary and secondary outcomes, with adjustment for potential confounders, as appropriate. Results One hundred and twenty-six patients with ICI–inflammatory arthritis were included; 53 patients (42%) required a csDMARD/bDMARD. In the univariate logistic regression analysis, higher clinical disease activity index (CDAI), tenosynovitis, longer symptom duration before first rheumatology visit and longer ICI duration were significantly associated with a higher likelihood of requiring DMARDs; in addition, there was a trend towards those treated with prior chemotherapy being less likely to need DMARDs. After adjustment, tenosynovitis, longer symptom duration and higher CDAI remained associated with requiring DMARDs, while those with prior chemotherapy were significantly less likely to require DMARDs. Combination anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein-4)/PD-1 (Programmed cell death protein-1) therapy and CS use at baseline were associated with a higher risk of persistent inflammatory arthritis. Conclusion Higher levels of disease activity, tenosynovitis and longer symptom duration prior to rheumatology referral were associated with requiring DMARDs for ICI–inflammatory arthritis, while those treated previously with chemotherapy were less likely to require additional immunosuppression. The presence of risk factors for severe disease at baseline may indicate a role for higher initial CS dose, earlier rheumatology referral, and adoption of immunosuppression beyond CSs to improve outcomes. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is a critical global health issue associated with high mortality rates, particularly in patients undergoing renal transplants and major surgeries. These individuals often receive immunosuppressants to dampen immune responses, but the impact of these drugs on AKI remains unclear. This review aims to provide a detailed understanding of the effects of different classes of immunosuppressants against AKI, elucidating their role in either exacerbating or mitigating the occurrence or progression of AKI. Several preclinical and clinical reports were analyzed to evaluate the impact of various immunosuppressants on AKI. Relevant preclinical and clinical studies were reviewed through different databases such as Scopus, PubMed, Google Scholar, and ScienceDirect, and official websites like https://clinicaltrials.gov to understand the mechanisms underlying the effects of immunosuppressants on kidney function. Specific immunosuppressants have been linked to the progression of AKI, while others demonstrate renoprotective effects. However, there is no consensus on the preferred or avoided immunosuppressants for AKI patients. This review outlines the classes of immunosuppressants commonly used and their impact on AKI, providing guidance for physicians in selecting appropriate drugs to prevent or ameliorate AKI. Understanding the effects of immunosuppressants on AKI is crucial for optimizing patient care. This review highlights the need for further research to determine the most suitable immunosuppressants for AKI patients, considering both their efficacy and potential side effects. [ABSTRACT FROM AUTHOR]

Objective To investigate the efficacy and safety of cryoablation combined with Camrelizumab monoclonal antibody in the treatment of hepatocellular carcinoma (HCC). Methods A total of 103 HCC patients who were admitted to our hospital from June 2020 to June 2023 were enrolled and randomly divided into combined treatment group with 53 patients and control group with 50 patients. The patients in the control group received percutaneous argon-helium cryoablation, and those in the combined treatment group received percutaneous argon-helium cryoablation combined with Camrelizumab monoclonal antibody. The two groups were compared in terms of short-term response, changes in T lymphocyte subsets after treatment, changes in liver function and alpha-fetoprotein (AFP) after treatment, and progression-free survival and overall survival during follow-up. The t-test was used for comparison of normally distributed continuous data between groups, and the chi-square test was used for comparison of categorical data between groups. The Kaplan-Meier method was used to plot survival curves, and the log-rank test was used for comparison of survival time between the two groups. Results The combined treatment group had significantly higher overall response rate and disease control rate than the control group (χ² =4.156 and 4.348, P=0.042 and 0.037). After treatment, the combined treatment group had significant increases in the percentages of CD3+ and CD4+ T lymphocytes and CD4+ /CD8+ ratio (P< 0.05) and a significant reduction in the percentage of CD8+ T lymphocytes (P<0.05), while the control group had no significant changes in T lymphocyte subsets after treatment (P>0.05), and compared with the control group after treatment, the combined treatment group had significantly higher percentages of CD3+ and CD4+ T lymphocytes and CD4+ /CD8+ ratio (all P<0.05) and a significantly lower percentage of CD8+ T lymphocytes (P<0.05). After treatment, both groups had significant reductions in the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and AFP (all P<0.05) and a significant increase in the level of albumin (Alb) (P>0.05), and compared with the control group after treatment, the combined treatment group had significantly lower levels of ALT, AST, and AFP (all P<0.05) and a significantly higher level of Alb (P<0.05). There were no significant differences in the incidence rates of grade Ⅲ—Ⅳ(moderate to severe) adverse reactions between the two groups (P> 0.05). Compared with the control group, the combined treatment group had significantly better median progression-free survival (21.32 months vs 15.31 months, χ² =4.689, P=0.030) and median overall survival (28.36 months vs 20.75 months, χ² =5.030, P= 0.025). Conclusion Argon-helium cryoablation combined with Camrelizumab monoclonal antibody can effectively improve short-term response, enhance immune function, and prolong survival time, with a favorable safety profile. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma is one of the most dangerous tumors of the central nervous system, and still cannot be fully overcome. We still mainly rely on standard treatments combining chemotherapy, radiotherapy, and surgery in various combinations. However, advances in technology, particularly biotechnology, are allowing the introduction of new, more precise therapies. These are more personalized, targeting a specific stage of tumor development or a particular cell population. The treatment of glioma is one of the areas in which we see more and more personalized medicine. In this article, we have tried to describe the current state of knowledge regarding the use of modern therapies in treating glioblastoma and the primary concerns. Glioblastoma is the most common malignant primary brain tumor in the adult population, with an average survival of 12.1 to 14.6 months. The standard treatment, combining surgery, radiotherapy, and chemotherapy, is not as efficient as we would like. However, the current possibilities are no longer limited to the standard therapies due to rapid advancements in biotechnology. New methods enable a more precise approach by targeting individual cells and antigens to overcome cancer. For the treatment of glioblastoma, these are gamma knife therapy, proton beam therapy, tumor-treating fields, EGFR and VEGF inhibitors, multiple RTKs inhibitors, and PI3K pathway inhibitors. In addition, the increasing understanding of the role of the immune system in tumorigenesis and the ability to identify tumor-specific antigens helped to develop immunotherapies targeting GBM and immune cells, including CAR-T, CAR-NK cells, dendritic cells, and immune checkpoint inhibitors. Each of the described methods has its advantages and disadvantages and faces problems, such as the inefficient crossing of the blood–brain barrier, various neurological and systemic side effects, and the escape mechanism of the tumor. This work aims to present the current modern treatments of glioblastoma. [ABSTRACT FROM AUTHOR]

Objective: Immune checkpoint inhibitors (ICIs), specifically targeting the programmed cell death protein-1 or its ligand (PD-1/PD-L1), have been extensively used in the treatment of a spectrum of malignancies, although the predictive biomarkers remain to be elucidated. This study aims to investigate the association between baseline circulating levels of cytokines and the creatinine/cystatin C ratio (CCR) with the treatment outcomes of ICIs in patients with advanced cancer. Methods: The pre-treatment circulating levels of 10 cytokines (PD-L1, CTLA4, CXCL10, LAG3, HGF, CCL2, MIG, GRANB, IL-18, and IL-6) were measured via automated capillary-based immunoassay platform in the serum of 65 advanced cancer patients treated with anti-PD-1/PD-L1-based systemic therapy and 10 healthy volunteers. The levels of cytokines and CCR were quantified and categorized into high and low groups based on the median value. The associations of serum cytokines and CCR with response to treatment, survival, and immune-related adverse events were assessed. Results: Elevated circulating levels of 6 cytokines (PD-L1, CXCL10, HGF, CCL2, MIG, and IL-6) were observed in cancer patients compared with that in healthy volunteers. The correlation coefficients between cytokines, CCR and nutritional risk index were also calculated. In the cancer cohort (N = 65), low circulating HGF (P = 0.023, P = 0.029), low IL-6 (P = 0.002, P < 0.001), and high CCR (P = 0.031, P = 0.008) were associated with significantly improved progression-free survival (PFS) and overall survival (OS). Multi-variable COX analyses adjusted for clinicopathological factors revealed that low HGF, low IL-6, and high CCR were independent favorable prognostic factors for PFS (P = 0.028, P = 0.010, and P = 0.015, respectively) and OS (P = 0.043, P = 0.003, and P = 0.026, respectively). Grade 2 irAEs occurred more frequently in patients with low levels of circulating CCL2 and LAG3. Conclusions: Pre-treatment circulating levels of serum IL-6, HGF, and CCR may serve as independent predictive and prognostic biomarkers in advanced cancer patients treated with ICIs-based systemic therapy. These findings might help to identify potential patients who would benefit from these therapies. [ABSTRACT FROM AUTHOR]

Introduction: It was hypothesized that use of proton beam therapy (PBT) in patients with locally advanced non–small cell lung cancer treated with concurrent chemoradiation and consolidative immune checkpoint inhibition is associated with fewer unplanned hospitalizations compared with intensity‐modulated radiotherapy (IMRT). Methods: Patients with locally advanced non–small cell lung cancer treated between October 2017 and December 2021 with concurrent chemoradiation with either IMRT or PBT ± consolidative immune checkpoint inhibition were retrospectively identified. Logistic regression was used to assess the association of radiation therapy technique with 90‐day hospitalization and grade 3 (G3+) lymphopenia. Competing risk regression was used to compare G3+ pneumonitis, G3+ esophagitis, and G3+ cardiac events. Kaplan–Meier method was used for progression‐free survival and overall survival. Inverse probability treatment weighting was applied to adjust for differences in PBT and IMRT groups. Results: Of 316 patients, 117 (37%) received PBT and 199 (63%) received IMRT. The PBT group was older (p <.001) and had higher Charlson Comorbidity Index scores (p =.02). The PBT group received a lower mean heart dose (p <.0001), left anterior descending artery V15 Gy (p =.001), mean lung dose (p =.008), and effective dose to immune circulating cells (p <.001). On inverse probability treatment weighting analysis, PBT was associated with fewer unplanned hospitalizations (adjusted odds ratio, 0.55; 95% CI, 0.38–0.81; p =.002) and less G3+ lymphopenia (adjusted odds ratio, 0.55; 95% CI, 0.37–0.81; p =.003). There was no difference in other G3+ toxicities, progression‐free survival, or overall survival. Conclusions: PBT is associated with fewer unplanned hospitalizations, lower effective dose to immune circulating cells and less G3+ lymphopenia compared with IMRT. Minimizing dose to lymphocytes may be warranted, but prospective data are needed. The use of proton beam therapy in locally advanced non–small cell lung cancer is associated with fewer 90‐day acute hospitalizations, lower effective dose to immune circulating cells, and less grade 3+ lymphopenia compared with intensity‐modulated radiation therapy. [ABSTRACT FROM AUTHOR]

Chondrosarcoma (ChS), a malignant cartilage-producing tumor, is the second most frequently diagnosed osseous sarcoma after osteosarcoma. It represents a very heterogeneous group of malignant chemo- and radiation-resistant neoplasms, accounting for approximately 20% of all bone sarcomas. The majority of ChS patients have a good prognosis after a complete surgical resection, as these tumors grow slowly and rarely metastasize. Conversely, patients with inoperable disease, due to the tumor location, size, or metastases, represent a great clinical challenge. Despite several genetic and epigenetic alterations that have been described in distinct ChS subtypes, very few therapeutic options are currently available for ChS patients. Therefore, new prognostic factors for tumor progression as well as new treatment options have to be explored, especially for patients with unresectable or metastatic disease. Recent studies have shown that a correlation between immune infiltrate composition, tumor aggressiveness, and survival does exist in ChS patients. In addition, the intra-tumor microvessel density has been proven to be associated with aggressive clinical behavior and a high metastatic potential in ChS. This review will provide an insight into the ChS microenvironment, since immunotherapy and antiangiogenic agents are emerging as interesting therapeutic options for ChS patients. [ABSTRACT FROM AUTHOR]

The treatment landscape for metastatic renal cell carcinoma (mRCC) has undergone significant transformations in recent years. The introduction of novel combination therapies involving tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors has resulted in improved oncological outcomes compared to traditional TKI monotherapy. In this evolving paradigm, the pivotal role of the multidisciplinary tumor board is underscored, particularly in shaping the therapeutic trajectory for patients eligible for locoregional interventions like cytoreductive nephrectomy and metastasectomy. In cases where systemic treatment is deemed appropriate, the absence of direct comparisons among the various combination therapies complicates the selection of a first-line approach. The clinician is faced with the challenge of making decisions based on patient-specific factors such as performance status, risk classification according to the International Metastatic Renal Cell Carcinoma Database Consortium, comorbidities, and disease characteristics, including the number and location of metastases and tumor histology. Considering these concerns, we propose, as a member of a Tuscany Interdisciplinary Uro-Oncologic Group, an algorithm to streamline the decision-making process for mRCC patients, offering guidance to clinicians in their day-to-day clinical practice. [ABSTRACT FROM AUTHOR]

Several chronic inflammatory diseases have been linked to high-salt (HS) diets. Chronic inflammation is an established causative hallmark of cancer. However, a direct role of HS diets in tumorigenesis is yet to be defined. Previous orthotopic murine breast tumor studies have shown that short-term HS diets caused inhibition of tumor growth through the activation of cytotoxic adaptive immune responses. However, there have been experimental challenges in developing a viable chronic HS-diet-based murine tumor model. To address this, we have developed a novel chronic HS diet tumor model through the sequential passaging of tumor cells in mice under HS dietary conditions. Two orthotopic murine triple-negative breast cancer models, 4T1 tumor cells injected into BALB/c mice and Py230 tumor cells injected into C57Bl/6 mice, were utilized in our study. For the HS diet cohort, prior to orthotopic injection with tumor cells, the mice were kept on a 4% NaCl diet for 2 weeks. For the regular salt (RS) diet cohort, the mice were kept on a 1% NaCl diet. Following syngeneic cancer cell injection, tumors were allowed to grow for 28 days, following which they were collected to isolate immune cell-depleted cancer cells (passage 1, P1). The tumor cells from P1 were reinjected into the next set of non-tumor-bearing mice. This procedure was repeated for three cycles (P2–P4). In P1, compared to the RS diet cohort, we observed reduced tumor kinetics in both murine tumor models on the HS diet. In contrast, by P4, there was significantly higher tumor progression in the HS diet cohort over the RS diet cohort. Flow cytometry analysis demonstrated an 8-fold increase in tumor-initiating stem cells (TISCs) from P1 to P4 of the HS diet cohort, while there were no significant change in TISC frequency with sequential passaging in the RS diet cohort. Molecular studies showed enhanced expression of TGFβR2 and CD80 on TISCs isolated from the P4 HS diet cohort. In vitro studies demonstrated that TGFβ stimulation of these TISCs increased the cellular expression of CD80 molecules. Further, the chronic HS diet selectively induced the glycolytic metabolic phenotype over the mitochondrial oxidative phosphorylation phenotype in TISCs, which is needed for the production of metabolites during tumor cell differentiation and proliferation. The infiltrating CD8 and CD4 T-lymphocytes in P4 tumors demonstrated increased expression of the immune checkpoint inhibitor (ICI) CTLA4, a known binding partner of CD80, to cause immune exhaustion and pro-tumorigenic effects. Interestingly, anti-TGFβ monoclonal antibodies (mAbs) played a synergistic role in further enhancing the anti-tumor effect of anti-CTLA4 mAb. In summary, our findings demonstrated that chronic HS diet increased the frequency of TISCs in tumors leading to blunting of cytotoxic adaptive immune responses causing tumor proliferation. Furthermore, a combination of anti-TGFβ with current ICI-based immunotherapies could exert more favorable anti-cancer clinical outcomes. [ABSTRACT FROM AUTHOR]

Background and Aim: Immune checkpoint inhibitors pose the risk of immune‐related adverse events (irAEs). Recent data suggest that irAEs may be associated with a favorable prognosis. This study aimed to investigate and analyze the association between these adverse events and the clinical benefits in patients with unresectable hepatocellular carcinoma. Methods: The study enrolled 130 patients with advanced hepatocellular carcinoma treated with atezolizumab plus bevacizumab between November 2020 and January 2023 at a single center. The relationship between irAEs and both response rate and post‐treatment outcomes was investigated. Results: Out of the 130 patients, irAEs developed in 36 (27.7%) patients. The irAE group exhibited a significantly longer progression‐free survival (PFS) than the non‐irAE group, with a median PFS of 8.9 compared with 4.6 months (P < 0.01). No difference was found in the overall survival between the irAE and non‐irAE groups. The irAE group demonstrated significantly higher disease control rate (DCR) than the non‐irAE group (97.0% vs 65.5%, P < 0.01). The analysis by irAE severity revealed that the grade 1/2 group exhibited significantly longer PFS (7.9 vs 4.6 months, P = 0.007) and higher DCR (100% vs 65.5%, P < 0.01) than the non‐irAE group. Furthermore, hypothyroidism correlated with a favorable PFS (8.9 vs 5.4 months, P = 0.02), DCR (100% vs 71.3%, P = 0.03), and overall response rate (58.3% vs 18.5%, P = 0.005). Conclusion: The presence of irAEs is associated with prolonged PFS and higher DCR. Specifically, mild irAEs (grade 1/2) and hypothyroidism displayed prolonged PFS and higher DCR. [ABSTRACT FROM AUTHOR]

Background: Few studies have reported reliable prognostic factors for immune checkpoint inhibitors (ICIs) in renal cell carcinoma (RCC). Therefore, we investigated prognostic factors in patients treated with ICIs for unresectable or metastatic RCC. Methods: We included 43 patients who received ICI treatment for RCC between January 2018 and October 2021. Blood samples were drawn before treatment, and 73 soluble factors in the plasma were analyzed using a bead-based multiplex assay. We examined factors associated with progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAE) using the Chi-squared test, Kaplan–Meier method, and the COX proportional hazards model. Results: Patients exhibited a median PFS and OS of 212 and 783 days, respectively. Significant differences in both PFS and OS were observed for MMP1 (PFS, p < 0.001; OS, p = 0.003), IL-1β (PFS, p = 0.021; OS, p = 0.008), sTNFR-1 (PFS, p = 0.017; OS, p = 0.005), and IL-6 (PFS, p = 0.004; OS, p < 0.001). Multivariate analysis revealed significant differences in PFS for MMP1 (hazard ratio [HR] 5.305, 95% confidence interval [CI], 1.648–17.082; p = 0.005) and OS for IL-6 (HR 23.876, 95% CI, 3.426–166.386; p = 0.001). Moreover, 26 patients experienced irAE, leading to ICI discontinuation or withdrawal. MMP1 was significantly associated with irAE (p = 0.039). Conclusion: MMP1 may be associated with severe irAE, and MMP1, IL-1β, sTNFR-1, and IL-6 could serve as prognostic factors in unresectable or metastatic RCC treated with ICIs. MMP1 and IL-6 were independent predictors of PFS and OS, respectively. Thus, inhibiting these soluble factors may be promising for enhancing antitumor responses in patients with RCC treated with ICIs. [ABSTRACT FROM AUTHOR]

This report describes the use of subcutaneous lidocaine infusion to manage complex pain associated with checkpoint inhibitor inflammatory arthritis. In addition, the safe administration of lidocaine in the home setting is described. A 49-year-old man with metastatic melanoma to lung, right axilla and posterior chest wall on regular pembrolizumab developed checkpoint inhibitor inflammatory arthritis. Pain associated with this was unresponsive to simple analgesia, escalating opioids and adjuvant analgesics. Lidocaine infusion was used on separate occasions (inpatient unit and home setting) to gain rapid and sustained control of inflammatory pain. Inflammatory pain responded well to 2 mg/kg/h lidocaine infusion over 4 days with sustained response between infusions of up to 6 wk. Resulting in improved mobility, functional status, and overall quality of life. Lidocaine infusion should be considered as an option for analgesic management of checkpoint inhibitor inflammatory arthritis in patients for whom usual treatment is ineffective, and as an opioid-sparing intervention. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) can provide survival benefits to cancer patients; however, they sometimes result in the development of renal immune‐related adverse events (irAEs). Tubulointerstitial nephritis (TIN) is the most representative pathological feature of renal irAEs. However, the clinicopathological entity and underlying pathogenesis of ICI‐induced TIN are unclear. Therefore, we compared the clinical and histological features of this condition with those of non‐ICI drug‐induced TIN. Age and C‐reactive protein levels were significantly higher in ICI‐induced TIN, but there were no significant differences in renal function. Immunophenotyping of ICI‐induced TIN showed massive T cell and macrophage infiltration with fewer B cells, plasma cells, neutrophils, and eosinophils. Compared with those in non‐ICI drug‐induced TIN, CD4+ cell numbers were significantly lower in ICI‐induced TIN but CD8+ cell numbers were not significantly different. However, CD8/CD3 and CD8/CD4 ratios were higher in ICI‐induced TIN. Moreover, CD25+ and FOXP3+ cells, namely regulatory T cells, were less abundant in ICI‐induced TIN. In conclusion, T cell, B cell, plasma cell, neutrophil, and eosinophil numbers proved useful for differentiating ICI‐induced and non‐ICI drug‐induced TIN. Furthermore, the predominant distribution of CD8+ cells and low accumulation of regulatory T cells might be associated with ICI‐induced TIN development. [ABSTRACT FROM AUTHOR]

Anti‐pituitary‐specific transcription factor‐1 (PIT‐1) hypophysitis, a paraneoplastic syndrome resulting from an autoimmune response against PIT‐1, typically manifests with undetectable levels of growth hormone (GH) and prolactin (PRL), and significantly low levels of serum thyroid‐stimulating hormone (TSH) at diagnosis. These hormonal levels are highly specific to this disease and serve as key diagnostic indicators. Herein, we present a detailed clinical course of a 69‐year‐old male with a history of gastric cancer and lymph node metastases who developed anti‐PIT‐1 hypophysitis after the initiation of immune checkpoint inhibitor (ICI) therapy, specifically nivolumab, oxaliplatin, and capecitabine. The patient was referred to our department owing to decreased TSH, free triiodothyronine (T3), and free thyroxine (T4) levels after two doses of nivolumab. Initially suspected as central hypothyroidism due to ICI‐related hypophysitis, further assessment confirmed the diagnosis of anti‐PIT‐1 hypophysitis. Notably, GH, PRL, and TSH levels markedly declined, leading to complete deficiencies 2 months after the first nivolumab dose—a pattern consistent with that of previous cases of anti‐PIT‐1 hypophysitis. Therefore, this report not only presents an atypical subset of ICI‐related hypophysitis but also delineates the process of hormone impairment leading to complete deficiencies in anti‐PIT‐1 hypophysitis. This case highlights the importance of vigilant monitoring for endocrine issues in patients undergoing ICI therapy, given the escalating incidence of immune‐related adverse events associated with the extensive use of ICI therapy for various cancers. [ABSTRACT FROM AUTHOR]

We previously reported that high expression of the extracellular glutathione peroxidase GPX3 is associated with poor patient outcome in ovarian serous adenocarcinomas, and that GPX3 protects ovarian cancer cells from oxidative stress in culture. Here we tested if GPX3 is necessary for tumor establishment in vivo and to identify novel downstream mediators of GPX3's pro-tumorigenic function. GPX3 was knocked-down in ID8 ovarian cancer cells by shRNA to test the role of GPX3 in tumor establishment using a syngeneic IP xenograft model. RNA sequencing analysis was carried out in OVCAR3 cells following shRNA-mediated GPX3 knock-down to identify GPX3-dependent gene expression signatures. GPX3 knock-down abrogated clonogenicity and intraperitoneal tumor development in vivo , and the effects were dependent on the level of GPX3 knock-down. RNA sequencing showed that loss of GPX3 leads to decreased gene expression patterns related to pro-tumorigenic signaling pathways. Validation studies identified GDF15 as strongly dependent on GPX3. GDF15, a member of the TGF-β growth factor family, has known oncogenic and immune modulatory activities. Similarly, GPX3 expression positively correlated with pro-tumor immune cell signatures, including regulatory T-cell and macrophage infiltration, and displayed significant correlation with PD-L1 expression. We show for the first time that tumor produced GPX3 is necessary for ovarian cancer growth in vivo and that it regulates expression of GDF15. The immune profile associated with GPX3 expression in serous ovarian tumors suggests that GPX3 may be an alternate marker of ovarian tumors susceptible to immune check-point inhibitors. • GPX3 knock-down abrogates intraperitoneal tumor development in a syngeneic IP xenograft model of ovarian cancer. • GPX3 modulates pro-tumorigenic gene expression and regulates the TGF-β family member GDF15. • GPX3 expression correlates with regulatory T-cell and macrophage signatures, and PD-L1 expression in ovarian cancer. [ABSTRACT FROM AUTHOR]

Background: The cancers of the digestive tract, including colorectal cancer (CRC), gastric cancer, and esophageal cancer, are part of the most common cancers as well as one of the most important leading causes of cancer death worldwide. Summary: Despite the emergence of immune checkpoint inhibitors (e.g., anti-CTLA-4 and anti-PD-1/PD-L1) in the past decade, offering renewed optimism in cancer treatment, only a fraction of patients derive benefit from these therapies. This limited efficacy may stem from tumor heterogeneity and the impact of metabolic reprogramming on both tumor cells and immune cells within the tumor microenvironment (TME). The metabolic reprogramming of glucose, lipids, amino acids, and other nutrients represents a pivotal hallmark of cancer, serving to generate energy, reducing equivalent and biological macromolecule, thereby fostering tumor proliferation and invasion. Significantly, the metabolic reprogramming of tumor cells can orchestrate changes within the TME, rendering patients unresponsive to immunotherapy. Key Messages: In this review, we predominantly encapsulate recent strides on metabolic reprogramming among digestive tract cancer, especially CRC, in the TME with a focus on how these alterations influence anti-tumor immunity. Additionally, we deliberate on potential strategies to address these abnormities in metabolic pathways and the viability of combined therapy within the realm of anti-cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICIs) are antineoplastic agents associated with a multitude of immune-related adverse events (irAEs). Available data from clinical trials include highly selective patient populations which may limit their applicability to real-world clinical practice. Methods: We present a retrospective cohort study of cancer patients treated with ICI therapy at the Zablocki VA Medical Center between 2014 and 2021. Information on demographics, cancer diagnosis, type of therapy, treatment duration, comorbidities, irAE type, and overall survival were collected. Results: We identified 187 patients who received at least one dose of ICI. About half the patients experienced at least one irAE, the most common categories being fatigue, pulmonary, and endocrine irAEs. Approximately half of the irAEs were diagnosed within the first three months of starting ICI therapy, and 60.38% of those who experienced irAEs discontinued ICI therapy. Patients who experienced endocrine or intestinal irAEs had a significantly longer overall survival. Conclusion: Immune-related complications due to ICI therapy are common and can frequently lead to treatment discontinuation in the real-world setting. Endocrine and intestinal irAEs may correlate with improved survival. The ICI-treated patients who received palliative radiation therapy to the bone had less irAEs, possibly due to immunogenic cell death. [ABSTRACT FROM AUTHOR]

Although nanomaterial-based nanomedicine provides many powerful tools to treat cancer, most focus on the "immunosilent" apoptosis process. In contrast, ferroptosis and immunogenic cell death, two non-apoptotic forms of programmed cell death (PCD), have been shown to enhance or alter the activity of the immune system. Therefore, there is a need to design and develop nanoplatforms that can induce multiple modes of cell death other than apoptosis to stimulate antitumor immunity and remodel the immunosuppressive tumor microenvironment for cancer therapy. In this study, a new type of multifunctional nanocomposite mainly consisting of HMME, Fe3+ and Tannic acid, denoted HFT NPs, was designed and synthesized to induce multiple modes of cell death and prime the tumor microenvironment (TME). The HFT NPs consolidate two functions into one nano-system: HMME as a sonosensitizer for the generation of reactive oxygen species (ROS) 1O 2 upon ultrasound irradiation, and Fe3+ as a GSH scavenger for the induction of ferroptosis and the production of ROS ·OH through inorganic catalytic reactions. The administration of HFT NPs and subsequent ultrasound treatment caused cell death through the consumption of GSH, the generation of ROS, ultimately inducing apoptosis, ferroptosis, and immunogenic cell death (ICD). More importantly, the combination of HFT NPs and ultrasound irradiation could reshape the TME and recruit more T cell infiltration, and its combination with immune checkpoint blockade anti-PD-1 antibody could eradicate tumors with low immunogenicity and a cold TME. This new nano-system integrates sonodynamic and chemodynamic properties to achieve outstanding therapeutic outcomes when combined with immunotherapy. Collectively, this study demonstrates that it is possible to potentiate cancer immunotherapy through the rational and innovative design of relatively simple materials. Herein, we developed a novel nanoplatform capable of inducing various modes of cell death to stimulate antitumor immunity and remodel the immunosuppressive tumor microenvironment. Briefly, we designed and synthesized a new type of multifunctional nanoplatform, HFT NPs, which consolidate two functions into one nano-system: HMME as a sonosensitizer for the generation of reactive oxygen species (ROS) 1O 2 upon ultrasound irradiation and Fe3+ as a GSH scavenger for the induction of ferroptosis and the production of ROS (·OH) through inorganic catalytic reaction. The data from in vitro and in vivo studies demonstrate that the HFT NPs administration and local ultrasound irradiation induce the occurrence of apoptosis, ferroptosis, and immunogenic cell death (ICD), and inhibit tumor growth in vivo. Notably, the combination of HFT NP treatment with immune checkpoint inhibitors, such as anti-PD-1 antibody, resulted in remarkable anticancer activity, effectively halting tumor growth. [Display omitted] [ABSTRACT FROM AUTHOR]

The success of lipid nanoparticles (LNPs) in treating COVID-19 promotes further research of mRNA vaccines for cancer vaccination. Aiming at overcoming the constraints of currently available mRNA carriers, various alternative nano-vectors have been developed for delivering tumor antigen encoding mRNA and showed versatility to induce potent anti-tumor immunity. The rationally designed nano-vaccines increase the immune activation capacity of the mRNA vaccines by promoting crucial aspects including mRNA stability, cellular uptake, endosomal escape and targeting of immune cells or organs. Herein, we summarized the research progress of various mRNA based nano-vaccines that have been reported for cancer vaccination, including LNPs, lipid enveloped hybrid nanoparticles, polymeric nanoparticles etc. Several strategies that have been reported for further enhancing the immune stimulation efficacy of mRNA nano-vaccines, including developing nano-vaccines for co-delivering adjuvants, combination of immune checkpoint inhibitors, and optimizing the injection routes for boosting immune responses, have been reviewed. The progress of mRNA nano-vaccines in clinical trials and the prospect of the mRNA vaccines for cancer vaccination are also discussed. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICI) are increasingly used in the first‐line treatment of malignant tumors. There is increasing recognition of their cardiotoxicity and, in particular, their potential to lead to myocarditis. Cardiovascular magnetic resonance (CMR) can quantify pathological changes, such as myocardial edema and fibrosis. The purpose of this systematic review and meta‐analysis was to examine the evidence for the roles of CMR in predicting prognosis in ICI‐associated myocarditis. Methods: PubMed, Cochrane Library, and Web of Science databases were searched until October 2023 for published works investigating the relationship between CMR parameters and adverse events in patients with ICI‐associated myocarditis. The analysis included studies reporting the incidence of late gadolinium enhancement (LGE), T1 values, T2 values, and CMR‐derived left ventricular ejection fraction (LVEF). Odds ratios (OR) and weighted mean differences (WMD) were combined for binary and continuous data, respectively. Newcastle‐Ottawa Scale was used to assess the methodological quality of the included studies. Results: Five cohort studies were included (average age 65–68 years; 25.4% female). Of these, four studies were included in the meta‐analysis of LGE‐related findings. Patients with major adverse cardiovascular events (MACE) had a higher incidence of LGE compared with patients without MACE (OR = 4.18, 95% CI: 1.72–10.19, p = 0.002). A meta‐analysis, incorporating data from two studies, showed that patients who developed MACE exhibited significantly higher T1 value (WMD = 36.16 ms, 95% CI: 21.43–50.89, p < 0.001) and lower LVEF (WMD = − 8.00%, 95% CI: −13.60 to −2.40, p = 0.005). Notably, T2 value (WMD = −0.23 ms, 95% CI: −1.86 to −1.39, p = 0.779) was not associated with MACE in patients with ICI‐related myocarditis. Conclusions: LGE, T1 value, and LVEF measured by CMR imaging have potential prognostic value for long‐term adverse events in patients with ICI‐related myocarditis. [ABSTRACT FROM AUTHOR]

Tumor mutational burden (TMB) is a biomarker that measures the number of somatic mutations in a tumor's genome. TMB has emerged as a predictor of response to immune checkpoint inhibitors (ICIs) in various cancer types, and several studies have shown that patients with high TMB have better outcomes when treated with programmed death-ligand 1-based therapies. Recently, the Food and Drug Administration has approved TMB as a companion diagnostic for the use of pembrolizumab in solid tumors. However, despite its potential, the use of TMB as a biomarker for immunotherapy efficacy is limited by several factors. Here we review the limitations of TMB in predicting immunotherapy outcomes in patients with cancer and discuss potential strategies to optimize its use in the clinic. • TMB has been proposed as a biomarker of ICI efficacy across cancers, but its use in the clinic remains elusive. • Technical and biological factors limit the accuracy of TMB for the prediction of ICI efficacy in patients with cancer. • Cancer-specific thresholds should be considered to identify patients who are most likely to benefit from ICI. • TMB standardization and integration with other biomarkers can improve its predictive accuracy in patients with cancer. [ABSTRACT FROM AUTHOR]