Evaluating the Efficacy of Immune Checkpoint Inhibitors in Elderly Patients: A Systematic Review and Meta-analysis.

In this chapter, we outline the steps for designing and conducting a rigorous systematic review and meta-analysis, focusing on the efficacy of immune checkpoint inhibitors (ICIs) in elderly patients. ICIs have improved survival rates in advanced cancers, yet their effectiveness in older populations remains unclear. We detail the essential processes involved in both systematic reviews and meta-analyses. We can evaluate the efficacy of ICIs in elderly patients with advanced cancer, examining outcomes such as overall survival and progression-free survival.

Thromboembolism during immune checkpoint inhibitor therapy: frequency and risk factors.

BACKGROUND: Thromboembolism (TE) is a well-known complication during chemotherapy in cancer patients. However, the risk of TE associated with immune checkpoint inhibitors (ICIs) is unknown. This study was performed to investigate the incidence of TE and associated risk factors in patients treated with ICIs. METHODS: We conducted a retrospective chart survey of patients receiving at least one ICI at Shinshu University Hospital between September 2014 and October 2021. Age, sex, cancer type, body mass index, medical history, laboratory data at commencement of treatment, and medication data were obtained from electronic medical records. TE events (venous thromboembolism [VTE], arterial thromboembolism [ATE]) were identified after ICI initiation. RESULTS: The study population consisted of 548 patients with a median age of 70.0 (19-89) years, 71.4% men, and a median follow-up of 15.1 months (range; 0.16-72.0 months). Nivolumab was the most commonly used ICI (45.8%), followed by pembrolizumab (23.9%), pembrolizumab plus anticancer drugs (7.8%), and nivolumab plus ipilimumab (5.1%). Thirty-eight cases of TE (6.9%) occurred (22 VTE, 16 ATE). Risk factors significantly associated with TE in multivariate logistic analysis were dyslipidemia (OR 2.44; 95% CI 1.17-5.09; p = 0.017), Khorana score ≥ 2 (HR 2.40; 95% CI 1.14-5.04; p = 0.021). Overall survival was not significantly different from patients without TE (p = 0.963). CONCLUSION: These results suggested that the frequency of TE is higher than expected and should be considered and monitored in patients treated with ICIs.

GPCRs: emerging targets for novel T cell immune checkpoint therapy.

Although immune checkpoint blockade (ICB) has become the mainstay of treatment for advanced solid organ malignancies, success in revitalizing the host anticancer immune response remains limited. G-protein coupled receptors (GPCRs) are a broad family of cell-surface proteins that have been regarded as main players in regulating the immune system, namely by mediating the activity of T lymphocytes. Among the most novel immunoregulatory GPCRs include GPR171, lysophosphatidic acid receptors (LPARs), GPR68, cannabinoid receptor 2 (CB2), and prostaglandin E receptors, many of which have shown promise in mediating antitumor response via activation of cytotoxic T cells, inhibiting immunosuppressive lymphocytes, and facilitating immune cell infiltration within the tumor microenvironment across multiple types of cancers. This paper reviews our current understanding of some of the most novel GPCRs-their expression patterns, evolving roles within the immune system and cancer, potential therapeutic applications, and perspective for future investigation.

Toripalimab in combination with chemotherapy effectively suppresses local recurrence and metastatic sarcomatoid renal cell carcinoma: A case report.

BACKGROUND: Sarcomatoid renal cell carcinoma (SRCC) is a rare variant of renal cell carcinoma associated with an unfavorable prognosis. The efficacy of conventional chemotherapy and targeted therapies are limited, whereas the emergence of immune checkpoint inhibitor has introduced new avenues for managing advanced SRCC. CASE SUMMARY: A 77-year-old female patient was referred to our hospital following the incidental detection of a right kidney tumor without specific symptoms. The tumor was successfully resected, and subsequent pathological examination confirmed SRCC. She experienced both local recurrence and distant metastasis eight months after the initial laparoscopic resection. Following six cycles of toripalimab combined with pirarubicin chemotherapy, the patient achieved a partial response. Subsequently, the patient attained an almost-complete continuous response to toripalimab monotherapy maintenance for an additional six cycles. She has not experienced disease progression for 15 months, and her overall survival has reached 24 months thus far. CONCLUSION: Combination therapy with programmed death 1 antibodies and cytotoxic agents may be a recommended first-line treatment approach for SRCC.

Absence of Survival Impact from Hepatitis During Immunotherapy in 193 Patients with Advanced Hepatocellular Carcinoma - An Observational Study from Taiwan.

Background: Hepatitis often occurs after initiating immune checkpoint inhibitor (ICI) treatment. The time and grade of hepatitis after ICI starts and the prognostic role of immune-related hepatitis in patients with advanced hepatocellular carcinoma (aHCC) remain unclear. Methods: In this real-world analysis, we enrolled aHCC patients receiving ICIs, documented the highest level of liver enzymes during/after ICIs, and analyzed the survival impact of different hepatitis patterns. Results: One hundred and ninety-three aHCC patients receiving ICIs were recruited. During ICIs, 88.6% of patients experienced aspartate transaminase (AST) elevations (Grade III/IV: 7.8%). For alanine transaminase (ALT), 81.3% had elevated levels (Grade III/IV: 3.6%), and 41.5% of patients had elevated bilirubin levels (Grade 3/4: 6.7%). The median AST, ALT, and total bilirubin values significantly increased after ICI treatment initiated (all p < 0.001) and, similarly, after excluding progressive disease (p = 0.014, p = 0.002, p < 0.001). The median time of hepatitis occurrence is from the 4.0th to 15.9th weeks. Multivariable analysis showed that patterns of liver enzyme change of AST and total bilirubin in patients receiving ICIs significantly correlate to overall survival (OS, p = 0.009 and 0.001, respectively). After ICI termination, patients with elevated bilirubin (p = 0.003) and AST (p = 0.005) would indicate poor survival, with adjustment of viral hepatitis and ICI responses. Conclusion: Hepatitis emerges between the 4th and 20th weeks post-ICI initiation. Changes in liver enzymes during ICI therapy do not directly affect OS, implying the safety of ICI use when corticosteroids are promptly administered if clinically indicated.

Exosomes from human bone marrow MSCs alleviate PD-1/PD-L1 inhibitor-induced myocardial injury in melanoma mice by regulating macrophage polarization and pyroptosis.

Myocarditis, which can be triggered by immune checkpoint inhibitor (ICI) treatment, represents a critical and severe adverse effect observed in cancer therapy. Thus, elucidating the underlying mechanism and developing effective strategies to mitigate its harmful impact is of utmost importance. The objective of this study is to investigate the potential role and regulatory mechanism of exosomes derived from human bone marrow mesenchymal stem cells (hBMSC-Exos) in providing protection against myocardial injury induced by ICIs. We observed that the administration of programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitor BMS-1 in tumor-bearing mice led to evident cardiac dysfunction and myocardial injury, which were closely associated with M1 macrophage polarization and cardiac pyroptosis. Remarkably, these adverse effects were significantly alleviated through tail-vein injection of hBMSC-Exos. Moreover, either BMS-1 or hBMSC-Exos alone demonstrated the ability to reduce tumor size, while the combination of hBMSC-Exos with BMS-1 treatment not only effectively improved the probability of tumor inhibition but also alleviated cardiac anomalies induced by BMS-1.

Alternative splicing of PBRM1 mediates resistance to PD-1 blockade therapy in renal cancer.

Alternative pre-mRNA splicing (AS) is a biological process that results in proteomic diversity. However, implications of AS alterations in cancer remain poorly understood. Herein, we performed a comprehensive AS analysis in cancer driver gene transcripts across fifteen cancer types and found global alterations in inclusion rates of the PBAF SWI/SNF chromatin remodeling complex subunit Polybromo 1 (PBRM1) exon 27 (E27) in most types of cancer tissues compared with those in normal tissues. Further analysis confirmed that PBRM1 E27 is excluded by the direct binding of RBFOX2 to intronic UGCAUG elements. In addition, the E27-included PBRM1 isoform upregulated PD-L1 expression via enhanced PBAF complex recruitment to the PD-L1 promoter. PBRM1 wild-type patients with clear cell renal cell carcinoma were resistant to PD-1 blockade therapy when they expressed low RBFOX2 mRNA levels. Overall, our study suggests targeting of RBFOX2-mediated AS of PBRM1 as a potential therapeutic strategy for immune checkpoint blockade.

Sarcopenia predicts immune-related adverse events due to anti-PD-1/PD-L1 therapy in patients with advanced lung cancer.

Introduction: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of a number of patients with advanced cancer, and while this has resulted in increased survival times, it has also led to the emergence of novel immune-related adverse events (irAEs). In individuals with advanced cancer, sarcopenia is a significant symptom of cachexia and is linked to poor nutritional status and increased mortality. The present study aimed to evaluate sarcopenia and other risk variables that can affect the emergence of irAEs in patients with lung cancer. Methods: A single-center retrospective analysis of 129 patients with advanced lung cancer treated with programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) checkpoint inhibitors was conducted from August 2020 to August 2022. Data on baseline characteristics and adverse events of participants were collected. Computed tomography was used to determine the skeletal muscle index at the third lumbar vertebra (L3-SMI) and whether sarcopenia is present. Results: The median age of all participants was 60 years old (range, 52-66 years), with men accounting for 68.9% of the total patient cohort. The present study showed that 44 (34%) participants presented with any degree of irAEs, and 79 (61.2%) patients presented with sarcopenia. There were no statistically significant differences in baseline characteristics, such as age and sex, between patients who presented with irAEs and those without irAEs. Using logistic regression analysis, individuals with sarcopenia were 2.635-times more likely to experience any grade of irAEs than those without sarcopenia. Discussion: irAEs are prevalent side effects of PD-1/PD-L1 inhibitor therapy for patients with cancer. By diagnosing and treating sarcopenia early, it is possible to lower the potential risk of irAEs in patients with advanced cancer. Furthermore, sarcopenia can be utilized as a predictor of irAEs.

Vaccination generates functional progenitor tumor-specific CD8 T cells and long-term tumor control.

BACKGROUND: Immune checkpoint blockade (ICB) therapies are an important treatment for patients with advanced cancers; however, only a subset of patients with certain types of cancer achieve durable remission. Cancer vaccines are an attractive strategy to boost patient immune responses, but less is known about whether and how immunization can induce long-term tumor immune reprogramming and arrest cancer progression. We developed a clinically relevant genetic cancer mouse model in which hepatocytes sporadically undergo oncogenic transformation. We compared how tumor-specific CD8 T cells (TST) differentiated in mice with early sporadic lesions as compared with late lesions and tested how immunotherapeutic strategies, including vaccination and ICB, impact TST function and liver cancer progression. METHODS: Mice with a germline floxed allele of the SV40 large T antigen (TAG) undergo spontaneous recombination and activation of the TAG oncogene, leading to rare early cancerous TAG-expressing lesions that inevitably progress to established liver cancer. We assessed the immunophenotype (CD44, PD1, TCF1, and TOX expression) and function (TNFα and IFNγ cytokine production) of tumor/TAG-specific CD8 T cells in mice with early and late liver lesions by flow cytometry. We vaccinated mice, either alone or in combination with ICB, to test whether these immunotherapeutic interventions could stop liver cancer progression and improve survival. RESULTS: In mice with early lesions, a subset of TST were PD1+ TCF1+ TOX- and could produce IFNγ while TST present in mice with late liver cancers were PD1+ TCF1lo/- TOX+ and unable to make effector cytokines. Strikingly, vaccination with attenuated TAG epitope-expressing Listeria monocytogenes (LMTAG) blocked liver cancer development and led to a population of TST that were PD1-heterogeneous, TCF1+ TOX- and polyfunctional cytokine producers. Vaccine-elicited TCF1+TST could self-renew and differentiate, establishing them as progenitor TST. In contrast, ICB administration did not slow cancer progression or improve LMTAG vaccine efficacy. CONCLUSION: Vaccination, but not ICB, generated a population of functional progenitor TST and halted cancer progression in a clinically relevant model of sporadic liver cancer. In patients with early cancers or at high risk of cancer recurrence, immunization may be the most effective strategy.

Small Intestine Metastasis Leads to the Diagnosis of Thoracic SMARCA4-Deficient Undifferentiated Tumor: A Case Report.

SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a rare and aggressive malignancy characterized by the loss of SMARCA4 protein expression. It typically affects middle-aged male smokers and has a poor prognosis due to its rapid progression and metastatic potential. This case report presents a 73-year-old male diagnosed with a thoracic SMARCA4-UT. Initially diagnosed with stage IVA non-small cell lung cancer, the patient underwent brain tumor resection, radiation, and chemo-immunotherapy. Treatment was halted due to immune-related adverse events. During treatment, a progressing small intestine tumor was discovered, resected, and identified as SMARCA4-UT metastasis through immunohistochemistry, leading to a revised diagnosis of SMARCA4-UT with brain and small intestine metastases. The patient received multimodal treatment, including surgery, radiation, and chemo-immunotherapy. The small intestine metastasis showed resistance to systemic therapy, necessitating surgical intervention. This case highlights the diagnostic challenges and treatment complexities of SMARCA4-UT, emphasizing the importance of comprehensive diagnostic workup and personalized treatment strategies. It demonstrates the potential efficacy of combining systemic therapy with targeted interventions for oligoprogressive disease. The patient's progression-free survival at approximately two years post-diagnosis underscores the need for further research into optimal management strategies for this rare tumor.

Delayed-Onset Immune-Related Colitis Following Pancreaticoduodenectomy in Patients With Gastric Cancer and Pancreatic Invasion Treated With Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICIs) have been approved for treating various advanced malignancies. Immune-related adverse events (irAEs) can manifest diversely and at varying times. However, postoperative diarrhea is a common complication in pancreaticoduodenectomy (PD). This case report presents a unique instance of delayed-onset irAE colitis occurring one year after PD in a patient with gastric cancer who received neoadjuvant nivolumab, a monoclonal antibody targeting human programmed death 1. A 54-year-old male developed severe diarrhea and weight loss, ultimately diagnosed with irAE colitis, which responded to steroid therapy. This report underscores the importance of extended monitoring, recognizing the potential for late-onset toxicities associated with ICIs, and differentiating from PD-related diarrhea.

Hemophagocytic lymphohistiocytosis associated with immune checkpoint inhibitor use: A review of the current knowledge and future directions.

Hemophagocytic lymphohistiocytosis (HLH) is a severe and often lethal inflammatory syndrome characterized by excessive immune activation leading to fever, cytopenias, and multiorgan involvement. Immune checkpoint inhibitors (ICIs) are central to many contemporary cancer regimens, but their use is associated with immune-related adverse events. Here, we report a case of ICI-induced HLH successfully treated with single agent dexamethasone and provide a scoping review of the literature for cases of ICI-induced HLH with a focus on treatment strategies and outcomes. Using the Medline database, we searched for cases of ICI-associated HLH, with a total of 51 cases reported between 2017 and 2023. Our results underscore the severe nature of this disease, with a 13.7 % mortality rate across 51 case reports. Treatment strategies for ICI-induced HLH were variable: steroids alone (56.9 %), steroids with etoposide (17.6 %), steroids with tociluzumab (11.8 %), among other combinations. Our literature review indicates that steroids alone may be sufficient treatment in some cases of ICI-HLH, with comparable mortality with steroids alone (n = 29) (13.8 %) to that of cases treated with both steroids and immunomodulators (n = 15, 13.3 %). Moreover, all patients treated with steroids and tocilizumab survived (n = 6), suggesting that tocilizumab may be a reasonable next line of therapy when steroid monotherapy proves inadequate. We propose an outline for investigation and treatment of this rare complication of ICI use. Finally, we discuss possible future approaches to develop evidence-based strategies for the diagnosis and management of ICI-induced HLH including the importance of integrating the role of patient community involvement.

Cancer cell-specific PD-L1 expression is a predictor of poor outcome in patients with locally advanced oral cavity squamous cell carcinoma.

BACKGROUND: Locally advanced oral cavity squamous cell carcinoma (OCSCC) presents a significant clinical challenge despite being partially responsive to standard treatment modalities. This study investigates the prognostic implications of programmed death-ligand 1 (PD-L1) expression in these tumors, focusing on its association with treatment outcomes and the immune microenvironment. METHODS: We assessed tumor-infiltrating lymphocytes (TILs) in 132 patients with OCSCC to evaluate their impact on survival. Multiplex immunohistochemistry staining for CD3, CD68, CD11c, PD-L1, and P40 was used to explore correlations with clinical outcomes in patients with early-stage (n=22) and locally advanced (n=36) OCSCC. These initial findings were validated through differential gene expression analysis, gene set enrichment, and immune cell deconvolution in a The Cancer Genome Atlas cohort of 163 locally advanced OCSCC tumors. Additionally, single-cell RNA sequencing (scRNA-seq) on a smaller cohort (n=10) further characterized the PD-L1hi or PD-L1lo cancer cells in these tumors. RESULTS: Elevated PD-L1 expression was associated with poor outcomes in patients with locally advanced OCSCC undergoing standard adjuvant therapy, irrespective of "hot" or "cold" classification based on TILs assessment. PD-L1hi tumors exhibited an active immune response phenotype, enriched with M1 macrophages, CD8+ T cells and T regulatory cells in the tumor microenvironment. Notably, the negative impact of PD-L1 expression on outcomes was primarily attributed to its expression by cancer cells, rather than immune cells. Furthermore, scRNA-seq revealed that immune interactions were not essential for PD-L1 upregulation in cancer cells, instead, complex regulatory networks were involved. Additionally, PD-L1lo locally advanced tumors exhibited more complex pathway enrichment and diverse T-cell populations compared with those in the early-stage. CONCLUSION: Our findings underscore the prognostic significance of PD-L1 expression in locally advanced OCSCC, and unveil the complex interplay between PD-L1 expression, immune responses, and molecular pathways in the tumor microenvironment. This study provides insights that may inform future therapeutic strategies, including the possibility of tailored immunotherapeutic approaches for patients with PD-L1hi locally advanced OCSCC.

Novel bispecific antibody-drug conjugate targeting PD-L1 and B7-H3 enhances antitumor efficacy and promotes immune-mediated antitumor responses.

BACKGROUND: Antibody-drug conjugates (ADCs) offer a promising approach, combining monoclonal antibodies with chemotherapeutic drugs to target cancer cells effectively while minimizing toxicity. METHODS: This study examined the therapeutic efficacy and potential mechanisms of a bispecific ADC (BsADC) in laryngeal squamous cell carcinoma. This BsADC selectively targets the immune checkpoints programmed cell death ligand-1 (PD-L1) and B7-H3, and the precise delivery of the small-molecule toxin monomethyl auristatin E. RESULTS: Our findings demonstrated that the BsADC outperformed its bispecific antibody and PD-L1 or B7-H3 ADC counterparts, particularly in terms of in vitro/in vivo tumor cytotoxicity, demonstrating remarkable immune cytotoxicity. Additionally, we observed potent activation of tumor-specific immunity and significant induction of markers of immunogenic cell death (ICD) and potential endoplasmic reticulum stress. CONCLUSION: In conclusion, this novel BsADC, through immune checkpoint inhibition and promotion of ICD, amplified durable tumor immune cytotoxicity, providing novel insights and potential avenues for future cancer treatments and overcoming resistance.

Association Between the Immune Checkpoint Inhibitor Durvalumab and Myasthenia Gravis: A Comprehensive Review.

Immune checkpoint inhibitors (ICIs), including Imfinzi (durvalumab), have revolutionized cancer treatment by stimulating the body's immune system to target cancerous cells. Although pharmaceuticals offer therapeutic benefits, several drugs have been associated with immune-related adverse events (irAEs), including the uncommon but serious condition known as myasthenia gravis (MG). This review synthesizes data from pertinent research to offer a thorough evaluation of the literature on the underlying mechanisms, clinical manifestations, and therapeutic approaches for durvalumab-induced MG. The incidence of MG in patients on durvalumab and other ICIs is typically low, with less than 1% documented, despite the potential for severe problems associated with the disease. Durvalumab disrupts immunological tolerance by stimulating autoreactive T-cells and inducing the production of autoantibodies. The clinical consequences of MG need meticulous monitoring, prompt identification, and suitable management to efficiently control the condition. Medical practitioners must carefully weigh the positive effects of ICIs against the possible hazards, emphasizing the necessity for more extensive investigation to improve patient results and establish uniform treatment protocols.

Phase I/II study of nivolumab plus lenvatinib for advanced biliary tract cancer (JCOG1808/NCCH1817, SNIPE).

BACKGROUND: Although cisplatin plus gemcitabine and other combinations have improved the survival of advanced biliary tract cancer (BTC), high unmet medical needs remain. This study aimed to assess the efficacy and safety of nivolumab plus lenvatinib in the second-line treatment for advanced BTC. PATIENTS AND METHODS: Nivolumab (240 mg) was administered biweekly. Phase I determined the recommended phase II dose of lenvatinib (20 mg or 14 mg). In phase II, the primary endpoint was the objective response rate (ORR). Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. The planned sample size was 32 patients with a power of 80%, a one-sided alpha error of 5%, threshold ORR of 10%, and expected ORR of 30%. RESULTS: In phase I, the recommended dose of lenvatinib was determined to be 20 mg in six patients, with one dose-limiting toxicity (myocarditis). In phase II, we enrolled 26 patients. ORR, DCR, and median OS and PFS were 9.4% [90% confidence interval (CI) 2.6% to 22.5%], 53.1% (95% CI 34.7% to 70.9%), and 6.4 months (95% CI 4.9-9.7 months) and 2.5 months (95% CI 1.5-4.1 months), respectively. No response was observed in patients with the usage of antibiotics. The grade 3 or 4 adverse events were hypertension (59.4%) and biliary tract infection (37.5%). Rash (28.1%) and hypothyroidism (21.9%) were observed as immune-mediated adverse events of any grade. CONCLUSIONS: Nivolumab plus lenvatinib had a manageable safety in advanced BTC, but its efficacy in the second-line treatment was limited.

Trousseau's Syndrome in Lung Cancer Patients: A Retrospective Study in a Japanese Community Hospital.

Trousseau's syndrome is a cancer-associated thromboembolism that significantly impacts patients' prognosis and quality of life (QOL). This study aimed to investigate the frequency, characteristics, and prognosis of Trousseau's syndrome in lung cancer patients at a Japanese community hospital and examine the effects of therapeutic agents on this condition. We retrospectively reviewed the electronic medical records of lung cancer patients diagnosed with thrombotic complications at the time of diagnosis in our department between August 2013 and April 2019. Patients' characteristics, thromboembolism sites, treatments, and prognosis were analyzed. Among 956 lung cancer patients, 19 (2%) had Trousseau's syndrome. The median age was 65 years, and adenocarcinoma was the most common histologic type (78.9%). The most common site of thromboembolism was the brain (84.2%). The median survival time was 84 days, and 52.6% of patients died within 90 days of diagnosis. Patients who survived longer than 90 days tended to have a higher frequency of non-adenocarcinoma histology, EGFR gene mutations, and therapeutic induction with immune checkpoint inhibitors (ICI). Trousseau's syndrome in lung cancer patients is associated with poor prognosis. Histologic type, EGFR mutation status, and treatment with ICI may influence the prognosis. Future larger-scale studies are needed to validate these potential prognostic factors and to develop personalized treatment strategies.

Curative immune checkpoint inhibitors therapy in patients with mismatch repair-deficient locally advanced rectal cancer: a real-world observational study.

BACKGROUND: Sustained clinical complete remissions were reported in all of 23 mismatch repair deficient/microsatellite instable (dMMR/MSI) locally advanced rectal cancer (LARC) patients treated with dostarlimab alone in a recent phase II study. These results led to off-label use of dostarlimab or other immune checkpoint inhibitors (ICIs) in dMMR/MSI-LARC even before regulatory approval. The present study [STAR(t)-IT-REDUCE] describes the outcome of dMMR/MSI-LARC patients treated with ICI in Italy. MATERIALS AND METHODS: Investigator-initiated, observational, retrospective-cohort, multicentric study of ICI treatment in dMMR/MSI-LARC. Patients were eligible if treated with ≥1 ICI dose from July 2022 to December 2023 (date of approval of dostarlimab for this indication in Italy). RESULTS: Seventeen dMMR/MSI-LARC patients (13 of 17 treatment-naïve) were eligible. Fourteen patients completed 6 months of treatment, two discontinued after four doses and one after five doses because of immune-related pneumonia, social constraints, or non-oncological bowel obstruction, respectively. Overall, 16 of 17 assessable patients [94.1%; 95% confidence interval (CI) 69.24% to 99.69%, 'ITT analysis'] achieved complete clinical response (cCR). Ten of 11 treatment-naïve patients completing 6 months of treatment had cCR (90.9%; 95% CI 57.12% to 99.52%, 'per-protocol analysis'). One patient with near-CR underwent rectal surgery and minimal residual intramucosal tumor was found. With a median follow-up of 9.5 months, no local relapse occurred. One patient developed unconfirmed lung metastases. Two grade 3 and no grade 4 adverse events were reported. CONCLUSION: The present STAR(t)-IT-REDUCE study documents the immunoablative and curative activity of ICI monotherapy in dMMR/MSI-LARC. Toxicity and compliance issues inherent to real-world practice are limited and do not affect achievement of initial complete tumor response but may limit response duration.

Identification of an immune-related genes signature in lung adenocarcinoma to predict survival and response to immune checkpoint inhibitors.

BACKGROUND: Although advances in immune checkpoint inhibitor (ICI) research have provided a new treatment approach for lung adenocarcinoma (LUAD) patients, their survival is still unsatisfactory, and there are issues in the era of response prediction to immunotherapy. METHODS: Using bioinformatics methods, a prognostic signature was constructed, and its predictive ability was validated both in the internal and external datasets (GSE68465). We also explored the tumor-infiltrating immune cells, mutation profiles, and immunophenoscore (IPS) in the low-and high-risk groups. RESULTS: As far as we are aware, this is the first study which introduces a novel prognostic signature model using BIRC5, CBLC, S100P, SHC3, ANOS1, VIPR1, LGR4, PGC, and IGKV4.1. According to multivariate analysis, the 9-immune-related genes (IRGs) signature provided an independent prognostic factor for the overall survival (OS). The low-risk group had better OS, and the tumor mutation burden (TMB) was significantly lower in this group. Moreover, the risk scores were negatively associated with the tumor-infiltrating immune cells, like CD8+ T cells, macrophages, dendritic cells, and NK cells. In addition, the IPS were significantly higher in the low-risk group as they had higher gene expression of immune checkpoints, suggesting that ICIs could be a promising treatment option for low-risk LUAD patients. CONCLUSION: The combination of these 9-IRGs not only could efficiently predict overall survival of LUAD patients but also show a powerful association with the expression of immune checkpoints and response to ICIs based on IPS; hoping this model paves the way for better stratification and management of patients in clinical practice.

Prognostic risk score and index including the platelet-to-lymphocyte ratio and lactate dehydrogenase in patients with metastatic or unresectable urothelial carcinoma treated with immune checkpoint inhibitors.

BACKGROUND: Avelumab and pembrolizumab are administered after platinum-based chemotherapy for the treatment of metastatic urothelial carcinoma. We explored the prognostic factors and risk scores for predicting the outcomes of metastatic or unresectable urothelial carcinoma at the start of treatment with immune checkpoint inhibitors. METHODS: This retrospective study included patients with metastatic or unresectable urothelial carcinoma treated with avelumab or pembrolizumab after platinum-based chemotherapy between January 2017 and December 2022. Prognostic factors, including patient and tumor characteristics and blood data at the initiation of immune checkpoint inhibitor therapy, were examined. RESULTS: This study included 36 and 207 patients treated with avelumab and pembrolizumab, respectively, for metastatic or unresectable urothelial carcinoma. Eastern Cooperative Oncology Group performance status, presence of visceral metastases, platelet-to-lymphocyte ratio and lactate dehydrogenase levels were independent prognostic factors for predicting overall survival. The median overall survival of patients in the risk-score model was 58.5 months (score zero), 27.9 months (one), 13.1 months (two) and 3.9 months (three or higher). The C-index for overall survival was 0.718 for the newly developed risk score compared with 0.679 for the Bellmunt score and 0.703 for the Bellmunt-C-reactive protein score. Additionally, the C-index for overall survival using the immune prognostic index derived from lactate dehydrogenase and the platelet-to-lymphocyte ratio was 0.646 compared with 0.615 for the Lung Immune Prognostic Index. CONCLUSIONS: A risk score that includes the platelet-to-lymphocyte ratio and lactate dehydrogenase may serve as a useful model for predicting prognosis following the initiation of immune checkpoint inhibitors in patients with metastatic or unresectable urothelial carcinoma.