Anti-programmed Death Research Articles

First-in-human phase Ib trial of M9241 (NHS-IL12) plus avelumab in patients with advanced solid tumors, including dose expansion in patients with advanced urothelial carcinoma

BackgroundIn preclinical studies, combining M9241 (a novel immunocytokine containing interleukin (IL)-12 heterodimers) with avelumab (anti-programmed death ligand 1 antibody) resulted in additive or synergistic antitumor effects. We report dose-escalation and...

Pembrolizumab-associated expansion of radiation-induced morphoea responsive to dupilumab: a case report.

Radiation-induced morphea (RIM) is a rare but distinctive inflammatory complication of therapeutic radiation.1 It most commonly presents as painful sclerosis of the epidermis and dermis limited to the irradiated field. Morphea has also been reported as an immune-related adverse event (irAE) induced by anti-programmed death-1 (PD-1) immune checkpoint inhibitors (ICIs).2,3 We report a patient who first received local radiation therapy to the thorax for lung adenocarcinoma that was complicated by RIM. The patient's morphea then progressed widely beyond the irradiated field in the setting of pembrolizumab therapy. Histopathology and imaging confirmed morphea extending beyond the irradiated field and with deeper muscular and fascial involvement. Pain and edema progressed through multiple lines of toxicity-directed therapy, but ultimately responded significantly to dupilumab. Response was confirmed clinically and radiographically, and the patient was able to resume ICI therapy. This case report highlights the ability of ICIs to induce progression of pre-existing RIM and supports the consideration of dupilumab in refractory cases.

Intracellular Adhesion Molecule-1 Improves Responsiveness to Immune Checkpoint Inhibitor by Activating CD8+ T Cells.

Immune checkpoint inhibitor (ICI) clinically benefits cancer treatment. However, the ICI responses are only achieved in a subset of patients, and the underlying mechanisms of the limited response remain unclear. 160 patients with non-small cell lung cancer treated with anti-programmed cell death protein-1(anti-PD-1) or anti-programmed death ligand-1 (anti-PD-L1)are analyzed to understand the early determinants of response to ICI. It is observed that high levels of intracellular adhesion molecule-1 (ICAM-1) in tumors and plasma of patients are associated with prolonged survival. Further reverse translational studies using murine syngeneic tumor models reveal that soluble ICAM-1 (sICAM-1) is a key molecule that increases the efficacy of anti-PD-1 via activation of cytotoxic T cells. Moreover, chemokine (CXC motif) ligand 13 (CXCL13) in tumors and plasma is correlated with the level of ICAM-1 and ICI efficacy, suggesting that CXCL13 might be involved in the ICAM-1-mediated anti-tumor pathway. Using sICAM-1 alone and in combination with anti-PD-1 enhances anti-tumor efficacy in anti-PD-1-responsive tumors in murine models. Notably, combinatorial therapy with sICAM-1 and anti-PD-1 converts anti-PD-1-resistant tumors to responsive ones in a preclinical study. These findings provide a new immunotherapeutic strategy for treating cancers using ICAM-1.

Combination immunotherapy of glioblastoma with dendritic cell cancer vaccines, anti-PD-1 and poly I:C

Glioblastoma (GBM) is a lethal cancer with limited therapeutic options. Dendritic cell (DC)-based cancer vaccines provide a promising approach for GBM treatment. Clinical studies suggest that other immunotherapeutic agents may be combined with DC vaccines to further enhance antitumor activity. Here, we report a GBM case with combination immunotherapy consisting of DC vaccines, anti-programmed death-1 (anti-PD-1) and poly I:C as well as the chemotherapeutic agent cyclophosphamide that was integrated with standard chemoradiation therapy, and the patient remained disease-free for 69 months. The patient received DC vaccines loaded with multiple forms of tumor antigens, including mRNA-tumor associated antigens (TAA), mRNA-neoantigens, and hypochlorous acid (HOCl)-oxidized tumor lysates. Furthermore, mRNA-TAAs were modified with a novel TriVac technology that fuses TAAs with a destabilization domain and inserts TAAs into full-length lysosomal associated membrane protein-1 to enhance major histocompatibility complex (MHC) class I and II antigen presentation. The treatment consisted of 42 DC cancer vaccine infusions, 26 anti-PD-1 antibody nivolumab administrations and 126 poly I:C injections for DC infusions. The patient also received 28 doses of cyclophosphamide for depletion of regulatory T cells. No immunotherapy-related adverse events were observed during the treatment. Robust antitumor CD4+ and CD8+ T-cell responses were detected. The patient remains free of disease progression. This is the first case report on the combination of the above three agents to treat glioblastoma patients. Our results suggest that integrated combination immunotherapy is safe and feasible for long-term treatment in this patient. A large-scale trial to validate these findings is warranted.

Mortality associated with the development of acute liver failure after a single dose of nivolumab

Immune-related adverse events (irAEs) caused by immune checkpoint inhibitors are reported in all organs; however, the frequency of liver injury is low compared to irAEs in other organs. We describe a case of fulminant hepatitis after administration of the first dose of nivolumab for the management of esophageal cancer. A man in his 80s was treated with nivolumab as a second-line therapy after his overall health worsened during preoperative chemotherapy for esophageal cancer. He was admitted to the hospital as an emergency case 30days later with complaints of vomiting, following which acute liver failure was diagnosed. The patient developed hepatic encephalopathy on the third day after admission and died on the seventh day. The pathological results showed sub-extensive spread hepatocellular necrosis throughout the liver, and immunostaining confirmed the presence of CD8-positive cells, which is consistent with irAEs. Immune checkpoint inhibitors have proven to be effective for the treatment of malignant tumors, and although fatalities due to acute liver failure are extremely rare, such cases have been reported previously. Among the immune checkpoint inhibitors, anti-programmed death-1 receptor is associated with less hepatotoxicity. However, even a single dose of this treatment can cause acute liver failure, which could be fatal.

1219 Identification of epidermal adhesion abnormalities in vitiligo lesions induced by anti-programmed death 1 blockade using single-cell RNA-sequence

1219 Identification of epidermal adhesion abnormalities in vitiligo lesions induced by anti-programmed death 1 blockade using single-cell RNA-sequence

Liposomal ATM siRNA delivery for enhancing triple-negaitive breast cancer immune checkpoint blockade therapy.

Triple-negative breast cancer (TNBC), which accounts for 10%-20% of breast cancer cases, is characterized by a higher metastasis rate, higher recurrence risk, and worse prognosis. Traditional treatments such as chemotherapy, surgery, and radiotherapy have limited therapeutic effects. Although immune checkpoint blockade (ICB) therapy represented by anti-programmed death 1 (aPD-1) antibody has made further progress in treating TNBC, its therapeutic effect is still not optimistic. Ataxia telangiectasia mutated (ATM) is a critical factor in the DNA damage response (DDR) pathway, which is associated with the development of tumors. Recent studies have found that it can regulate the tumor immune microenvironment, affecting ICB responsiveness. Inhibition of ATM could enhance ICB therapy by promoting mitochondrial DNA cytoplasmic leakage and activating the innate immune signaling pathway. To explore the effect of ATM siRNA(siATM) on the ICB responsiveness of TNBC, we designed and synthesized nanoparticles using 1,2-dioleoyl-glycero-3-phosphatidylcholine (DOPC) liposomes to deliver siATM. In vitro and in vivo experiments demonstrated that DOPC/siATM could enhance the ability of siRNA to enter tumor cells and effectively inhibit the expression of ATM protein. Our study found that nanoparticles carrying siATM could activate cytotoxic T lymphocytes and regulate the immunosuppressive tumor microenvironment (ITM) by activating the cGAS-STING pathway. Its combination with aPD-1 may be a potential way to improve the efficacy of TNBC.

Abstract 6404: Clinical scenario of immune checkpoint inhibitor treatment in metastatic nasopharyngeal carcinoma

Abstract Advanced in local treatment technology and early detection methodology, distant metastasis became a critical issue in Nasopharyngeal carcinoma (NPC). Recently, cancer immunotherapy especially immune checkpoint inhibitors (ICIs) including anti-programmed death-1 (PD-1) and PD-1 ligand (PD-L1) monoclonal antibodies (Mabs) had a rapid progress in cancer patient management. We try to clarify the clinical scenario of immune-related parameters in metastatic NPC. We had check 81 metastatic tissue PD-L1 expression without ICI treatment from the tissue bank of CGMH, Linkou, during 2005~2019. Using anti-PD-L1 antibody, 22C3 Dako, tumor proportional score (TPS) was positive in 43.2% (35/81) checked tissue and combine positive score (CPS) was positive in 58.0% (47/81) tissue respectively. For overall survival (OS) combined with PD-L1 expression in metastatic tissue analysis, positive CPS but not TPS correlated with longer survival with statistical significance (TPS: >0% vs =0%, median survival, 24m vs 22.5m, p=0.615186; CPS: >0% vs =0%, median survival, 28m vs 16m, p=0.003709). Retrospectively analysis of metastatic NPC treatment of combination of chemotherapy, ICIs, and local treatment in our institute in the past 6 years, total 40 patients was enrolled with median overall survival of 34.1 months. Objective response rate by RECIST criteria for immunotherapy-based regimen was 75% (CR:40%; PR:35%) and disease control rate was 85%. According to response by RECIST criteria, median overall survival were 34.1 months vs. 16.7 months respectively for responders and non-responders. With pre-treated NLR as cutoff value of 1.6, difference of median overall survival between two groups (responder vs nonresponder) was statistically significant (p=0.021). We also found that lower median post-treatment NLR in responders than in non-responders (1.4 vs. 3.2, p=0.013). Using rapid lymphocyte amplification protocol via IL-2 stimulation, the PBMC from most of the patient received ICIs treatment can be amplified 1~10 folds and positively correlated with total lymphocyte count. Through flowcytometry analysis, we found these amplified PBMC was lymphocyte dominant and rich in CD8+. We also found these amplified PBMC can kill the NPC EBV-positive cell line and xenograft in vitro and in vivo. These results demonstrated that combination of chemotherapy, ICIs, and local treatment will benefit metastatic NPC patients. Citation Format: Cheng-Lung Hsu, Yung-Chia Kuo. Clinical scenario of immune checkpoint inhibitor treatment in metastatic nasopharyngeal carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6404.

Abstract 5138: Systemic agonist anti-CD40 treatment delivers precise melanoma immunotherapy within established autoimmune landscapes

Abstract The overlapping signatures of type 1 interferons (IFN) and IFN-gamma (IFNg) has proven challenging in human autoimmunity and cancer immunotherapy, particularly for resistance to anti-programmed death 1 (anti-PD1) monotherapy. By contrast, agonist abs targeting of CD40 (anti-CD40) antibodies (abs) has clinically elicit anti-tumor immunity with limited autoimmune complications. Here, we explore the relationships between anti-PD1 or agonist CD40 responses in melanoma tumors from type 1 IFN alpha receptor (IFNAR)-sufficient and type 1 IFNAR-deficient lupus-prone mice that overexpress IFNg. To address this, RNA-sequencing (RNA-seq) data on tumors treated with either anti-PD1 or agonist anti-CD40 was evaluated for tumor objective responses compared to untreated controls. Cellular and canonical pathway identification from RNA-seq data were interrogated from the IPA library for significantly differential expressed genes (DEG). Variance patterns of the anti-PD1 and anti-CD40 monotherapies identified known resistance and response pathways highly concordant with IFN co-expression patterns in the RNA-sequencing data, respectively. IPA biomarker analysis for uniquely regulated genes showed that anti-PD1 induced only 59 DEG; while anti-CD40 induced 494 DEG including Il-27, and PR/SET Domain 1 (PRDM1), a transcription factor regulated by IL-27. Specifically, signatures of MDSC development (irf8, il10); and adaptive resistance (pdcd1, pdcd1lg2, and TNFRSF5/CD40)) were negatively associated with response to anti-P1 monotherapy. By contrast, signatures of IFN activation (stat1, Ifng, and Ifngr1), chemotaxis (Cxcl10, Il12b and Il-27), attractants (Sema3g and Sema4a), and antigen presentation MHC II (h2-Aa, h2-Ab1, and ciita) were associated positively with response to agonist anti-CD40 monotherapy. Importantly, anti-CD40 alone delivered anti-tumor immune responses in type 1 IFN receptor-deficient lupus-prone mice that overexpress IFNg (Ifnar-/-ARE-/-) mice suggesting synergy with therapies blocking type 1 IFN signaling. Thus, these findings indicate that the rational use of CD40 agonists abs provide a better therapeutic platform to deliver precise anti-melanoma responses in complex autoimmune landscapes. Citation Format: Julio C. Valencia, Michael Sanford, Howard A. Young. Systemic agonist anti-CD40 treatment delivers precise melanoma immunotherapy within established autoimmune landscapes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5138.

Abstract 6327: Intratumoral administration of ultra high-concentration nitric oxide (UNO) is more efficacious than anti-PD1 therapy in 4T1 tumor-bearing mice

Abstract Background: For the majority of metastatic triple-negative breast cancer (mTNBC) patients, chemotherapy is the standard first-line treatment, however, outcomes in this population are poor. A monoclonal antibody against the immune checkpoint inhibitor anti-programmed death 1 (PD-1) also has antitumor activity in patients with mTNBC. Previously, we reported that delivering ultra-high concentrations of nitric oxide (UNO) to mouse colon tumors stimulated innate and adaptive immune responses leading to the rejection of secondarily-induced tumors. Moreover, adding an anti-PD-1 antibody to UNO treatment resulted in primary tumor regression in 53% of the mice, the rejection of a distant tumors in all mice, and prolonged survival compared to control and anti-PD-1 arms. In this in vivo study, we investigated the ability of UNO to improve the efficacy of anti-PD-1 antibody treatment in the aggressive mouse breast cancer model, 4T1. Methods: We tested two treatment protocols: 4T1 mice tumors were treated with either a single dose of UNO and anti-PD-1 or a repeated dose of UNO and anti-PD-1. In the single dose design, 4T1 tumors were treated with a single administration of UNO combined with Anti-PD1 administration starting one day after UNO treatment (n=9-10 mice per group). In the repeated dosing design, 4T1 tumors were treated with UNO twice combined with Anti-PD-1 administration starting on the first UNO treatment day (n=8 mice per group). • UNO treatment regimen: 50,000 ppm, 10 minutes, flow rate ~0.2 liters per minute • Anti-PD1 treatment regimen: 10 mg/kg antibody was administered every 3 days for a total of 5 treatments. Results (UNO Single Dose): The primary tumors of 4T1 tumor-bearing mice were 13.2% smaller in the combined single-dose UNO group compared to anti-PD-1 alone 15 days post-UNO treatment. Results (UNO Repeated Dosing): The primary tumors of 4T1 tumor-bearing mice were 25.2% smaller in the combined repeated dose UNO group compared to the anti-PD-1 alone group 16 days after the first UNO treatment. Conclusion: Treating 4T1 tumors with single and repeated doses of UNO improved outcomes compared to anti-PD-1 alone. This suggests that local short-term treatment with UNO can serve as a treatment option for cancer patients with tumors that are not amenable to immune checkpoint inhibitor treatment. Citation Format: Yana Epshtein, Matan Goldshtein, Selena Chaisson, Jedidiah Monson, Matt Johnson, Amir Avniel, Steve Lisi, Hila Confino. Intratumoral administration of ultra high-concentration nitric oxide (UNO) is more efficacious than anti-PD1 therapy in 4T1 tumor-bearing mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6327.

MP33-07 ANTI-PROGRAMMED DEATH RECEPTOR 1 PLUS ANTI-EPIDERMAL GROWTH FACTOR RECEPTOR ANTIBODIES AND COMBINATION CHEMOTHERAPY FOR RELAPSED LOCALLY ADVANCED AND/OR METASTATIC PENILE SQUAMOUS CELL CARCINOMA

You have accessJournal of UrologyCME1 Apr 2023MP33-07 ANTI-PROGRAMMED DEATH RECEPTOR 1 PLUS ANTI-EPIDERMAL GROWTH FACTOR RECEPTOR ANTIBODIES AND COMBINATION CHEMOTHERAPY FOR RELAPSED LOCALLY ADVANCED AND/OR METASTATIC PENILE SQUAMOUS CELL CARCINOMA Longbin Xiong, Lichao Wei, Ting Xue, Ru Yan, Tingyu Liu, Lijuan Jiang, Huali Ma, Yanxia Shi, Xin An, Yijun Zhang, Shengjie Guo, Kai Yao, Fangjian Zhou, and Hui Han Longbin XiongLongbin Xiong More articles by this author , Lichao WeiLichao Wei More articles by this author , Ting XueTing Xue More articles by this author , Ru YanRu Yan More articles by this author , Tingyu LiuTingyu Liu More articles by this author , Lijuan JiangLijuan Jiang More articles by this author , Huali MaHuali Ma More articles by this author , Yanxia ShiYanxia Shi More articles by this author , Xin AnXin An More articles by this author , Yijun ZhangYijun Zhang More articles by this author , Shengjie GuoShengjie Guo More articles by this author , Kai YaoKai Yao More articles by this author , Fangjian ZhouFangjian Zhou More articles by this author , and Hui HanHui Han More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003266.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Relapsed locally advanced and/or metastatic penile cancer has an extremely poor prognosis with a need for effective therapy. This study retrospectively estimated the efficacy and tolerability of anti-programmed death receptor-1 (PD1) plus anti-epidermal growth factor receptor (EGFR) antibodies and combination chemotherapy in relapsed locally advanced and/or metastatic penile squamous cell carcinoma. METHODS: A retrospective review of 30 relapsed locally advanced and/or metastatic (T4/N2-3/M1) penile squamous cell carcinoma received anti-PD1 plus anti-EGFR antibodies and cisplatin-based chemotherapy in Sun Yat-sen University Cancer Center from Jan 2018 to Aug 2022. Of 15 were chemotherapy-pretreated patients, and the remaining 15 were chemotherapy-naïve patients. Clinical responses were assessed using the Response Evaluation Criteria in Solid Tumours (RECIST v1.1) in 27 evaluable patients. Adverse events (AEs) were graded according to Common Terminology Criteria for Adverse Events (CTCAE v5.0). Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. RESULTS: Partial responses were observed in 63% (17/27) patients, and 14 were chemotherapy-naïve patients. The objective response rate (ORR) was 100% (14/14) and 23% (3/13) in chemotherapy-naïve and chemotherapy-pretreated patients, respectively. Fourteen patients subsequently received consolidated surgery. Eight patients achieved pathological complete response, and six were chemotherapy-naïve patients. The median follow-up time was 11.4 (range: 2.3-36.2) months. The median PFS and OS were 15.6 (1.0-32.6) and 20.9 (10.5-30.3) months in chemotherapy-pretreated patients, respectively. However, these were not reached in overall cohort and chemotherapy-naïve patients. 2-year PFS (OS) was 53% (62%) in overall cohort, whereas 75% (79%) and 35% (47%) in chemotherapy-naïve and chemotherapy-pretreated patients, respectively. Treatment-related AEs were experienced by all patients, with 60% (18/30) experiencing a grade 3 or 4 AEs. The most common grade 3-4 treatment-related AEs were lymphopenia (40%), anemia (23%), and neutropenia (13%). CONCLUSIONS: Anti-PD1 antibody plus anti-EGFR antibody and cisplatin-based combination chemotherapy were effective, well-tolerated, and satisfying long-term survival outcome for relapsed locally advanced and/or metastatic penile squamous cell carcinoma. However, prolonged follow-up and large prospective clinical trials are needed to validate the findings on this important issue. Source of Funding: This study was supported by the National Natural Science Foundation of China (No. 81772755). © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e452 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Longbin Xiong More articles by this author Lichao Wei More articles by this author Ting Xue More articles by this author Ru Yan More articles by this author Tingyu Liu More articles by this author Lijuan Jiang More articles by this author Huali Ma More articles by this author Yanxia Shi More articles by this author Xin An More articles by this author Yijun Zhang More articles by this author Shengjie Guo More articles by this author Kai Yao More articles by this author Fangjian Zhou More articles by this author Hui Han More articles by this author Expand All Advertisement PDF downloadLoading ...

MYC activation impairs cell-intrinsic IFNγ signaling and confers resistance to anti-PD1/PD-L1 therapy in lung cancer

Elucidating the adaptive mechanisms that prevent host immune response in cancer will help predict efficacy of anti-programmed death-1 (PD1)/L1 therapies. Here, we study the cell-intrinsic response of lung cancer (LC) to interferon-γ (IFNγ), a cytokine that promotes immunoresponse and modulates programmed death-ligand 1 (PD-L1) levels. We report complete refractoriness to IFNγ in a subset of LCs as a result of JAK2 or IFNGR1 inactivation. A submaximal response affects another subset that shows constitutive low levels of IFNγ-stimulated genes (IγSGs) coupled with decreased H3K27ac (histone 3 acetylation at lysine 27) deposition and promoter hypermethylation and reduced IFN regulatory factor 1 (IRF1) recruitment to the DNA on IFNγ stimulation. Most of these are neuroendocrine small cell LCs (SCLCs) with oncogenic MYC/MYCL1/MYCN. The oncogenic activation of MYC in SCLC cells downregulates JAK2 and impairs IγSGs stimulation by IFNγ. MYC amplification tends to associate with a worse response to anti-PD1/L1 therapies. Hence alterations affecting the JAK/STAT pathway and MYC activation prevent stimulation by IFNγ and may predict anti-PD1/L1 efficacy in LC.

Current Strategy to Treat Immunogenic Gastrointestinal Cancers: Perspectives for a New Era.

Since pembrolizumab, an anti-programmed death-1 (PD-1) antibody, showed a dramatic response to immunogenic cancers with microsatellite instability-high (MSI-H) and/or deficient mismatch repair (dMMR) in the pilot clinical trial KEYNOTE-016, subsequent studies have confirmed durable responses of anti-PD-1 inhibitors for MSI-H/dMMR solid tumors. As immunotherapy is described as a "game changer," the therapeutic landscape for MSI-H/dMMR solid tumors including gastrointestinal cancers has changed considerably in the last decade. An MSI/MMR status has been established as the predictive biomarker for immune checkpoint blockades, playing an indispensable role in the clinical practice of patients with MSI-H/dMMR tumors. Immunotherapy is also now investigated for locally advanced MSI-H/dMMR gastrointestinal cancers. Despite this great success, a few populations with MSI-H/dMMR gastrointestinal cancers do not respond to immunotherapy, possibly due to the existence of intrinsic or acquired resistance mechanisms. Clarifying the underlying mechanisms of resistance remains a future task, whereas attempts to overcome resistance and improve the efficacy of immunotherapy are currently ongoing. Herein, we review recent clinical trials with special attention to MSI-H/dMMR gastrointestinal cancers together with basic/translational findings, which provide their rationale, and discuss perspectives for the further therapeutic development of treatment in this field.

The impact of immunosuppressive agents on immune checkpoint inhibitor efficacy in patients with advanced melanoma: A real-world, multicenter, retrospective study.

Immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs) are often managed via immunosuppressive agents (ISAs); however, their impact on ICI efficacy is not well studied. The impact of the use of ISAs on ICI efficacy in patients with advanced melanoma was therefore investigated. This is a real-world, multicenter, retrospective cohort study of patients with advanced melanoma who received ICIs (n=370). Overall survival (OS) and time to treatment failure (TTF) from the time of ICI initiation were compared among patients in subgroups of interest by unadjusted and 12-week landmark sensitivity-adjusted analyses. The association of irAEs and their management with OS and TTF were evaluated using univariate and multivariable Cox proportional hazards regression models. Overall, irAEs of any grade and of grade ≥3 occurred in 57% and 23% of patients, respectively. Thirty-seven percent of patients received steroids, and 3% received other ISAs. Median OS was longest among patients receiving both (not reached [NR]), shorter among those receiving only systemic steroids (SSs) (84.2months; 95% CI, 40.2 months to NR), and shortest among those who did not experience irAEs (10.3months; 95% CI, 6-20.1 months) (p<.001). Longer OS was significantly associated with the occurrence of irAEs and the use of SSs with or without ISAs upon multivariable-adjusted analysis (p<.001). Similar results were noted with anti-programmed death 1 (PD-1) monotherapy and combination anti-PD-1plusanti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) therapy, and with 12-week landmark sensitivity analysis (p=.01). These findings in patients with melanoma who were treated with ICIs suggest that the use of SSs or ISAs for the management of irAEs is not associated with inferior disease outcomes, which supports the use of these agents when necessary.

Prognostic value of inflammatory markers and clinical features for survival in advanced or metastatic esophageal squamous cell carcinoma patients receiving anti-programmed death 1 treatment.

This study aims to assess the prognostic value of inflammatory markers and clinical features in advanced or metastatic esophageal squamous cell carcinoma (ESCC) patients receiving anti-programmed death 1 (PD-1) treatment. Based on receiver operating characteristic curve (ROC) analysis, Youden's indexes were applied to determine the cut-off values for inflammatory markers, including neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocye ratio (dNLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII). Wilcoxon test was conducted to evaluate the changes in above inflammatory markers. Kaplan-Meier method was utilized to estimate progression-free survival (PFS) and overall survival (OS), and the Log-rank test was used to compare the different survival between groups. Univariate and multivariate Cox regression analyses were performed to assess the prognostic value of inflammatory markers and clinical features. 162 advanced or metastatic ESCC patients receiving anti-PD-1 treatment were enrolled in this retrospective study. The cut-off values of NLR, dNLR, MLR, PLR, and SII were 4.748, 2.214, 0.309, 250.505, and 887.895, respectively. NLR, dNLR, PLR, and SII declined significantly among the partial response (PR) (P<0.001, P<0.001, P=0.036, P<0.001), objective response rate (ORR) (P<0.001, P<0.001, P=0.036, P<0.001), and disease control rate (DCR) (P<0.001, P<0.001, P=0.038, P<0.001) groups, respectively. Significant increases were found in NLR (P<0.001), dNLR (P<0.001), MLR (P=0.001), and SII (P=0.024) when anti-PD-1 treatment failed. Multivariate Cox regression analysis indicated that NLR (P<0.001, P=0.002), lymph node metastasis (P=0.013, P=0.001), Eastern Cooperative Oncology Group Performance Status (ECOG PS) (P=0.008, P=0.002), and treatment lines (P=0.037, P=0.048) were significant prognostic indicators of PFS and OS. Additionally, SII (P=0.016) was also significantly related to OS in ESCC patients. The risk score model showed that low risk patients prolonged PFS and OS than those with middle or high risk (P<0.001, P<0.001). Inflammatory markers can reflect short-term outcomes of anti-PD-1 treatment for ESCC patients. NLR, lymph node metastases, ECOG PS, and treatment lines are significant prognostic indicators for PFS and OS. And the risk score model constructed based on the above factors has favourable prognostic predictive value.

Novel multivalent S100A8 inhibitory peptides attenuate tumor progression and metastasis by inhibiting the TLR4-dependent pathway

The tumor-elicited inflammation is closely related to tumor microenvironment during tumor progression. S100A8, an endogenous ligand of Toll-like receptor 4 (TLR4), is known as a key molecule in the tumor microenvironment and premetastatic niche formation. We firstly generated a novel multivalent S100A8 competitive inhibitory peptide (divalent peptide3A5) against TLR4/MD-2, using the alanine scanning. Divalent peptide3A5 suppressed S100A8-mediated interleukin-8 and vascular endothelial growth factor production in human colorectal tumor SW480 cells. Using SW480-transplanted xenograft models, divalent peptide3A5 suppressed tumor progression in a dose-dependent manner. We demonstrated that combination therapy with divalent peptide3A5 and bevacizumab synergistically suppressed tumor growth in SW480 xenograft models. Using syngeneic mouse models, we found that divalent peptide3A5 improved the efficacy of anti-programmed death (PD)1 antibody, and lung metastasis. In addition, by using multivalent peptide library screening based on peptide3A5, we then isolated two more candidates; divalent ILVIK, and tetravalent ILVIK. Of note, multivalent ILVIK, but not monovalent ILVIK showed competitive inhibitory activity against TLR4/MD-2 complex, and anti-tumoral activity in SW480 xenograft models. As most tumor cells including SW480 cells also express TLR4, S100A8 inhibitory peptides would target both the tumor microenvironment and tumor cells. Thus, multivalent S100A8 inhibitory peptides would provide new pharmaceutical options for aggressive cancers.

Single-cell characterization of anti-LAG-3 and anti-PD-1 combination treatment in patients with melanoma.

BackgroundRelatlimab plus nivolumab (anti-lymphocyte-activation gene 3 plus anti-programmed death 1 [anti-LAG-3+anti-PD-1]) has been approved by the FDA as a first-line therapy for stage III/IV melanoma, but its detailed effect on the immune system is unknown.MethodsWe evaluated blood samples from 40 immunotherapy-naive or prior immunotherapy-refractory patients with metastatic melanoma treated with anti-LAG-3+anti-PD-1 in a phase I trial using single-cell RNA and T cell receptor sequencing (scRNA+TCRαβ-Seq) combined with other multiomics profiling.ResultsThe highest LAG3 expression was noted in NK cells, Tregs, and CD8+ T cells, and these cell populations underwent the most significant changes during the treatment. Adaptive NK cells were enriched in responders and underwent profound transcriptomic changes during the therapy, resulting in an active phenotype. LAG3+ Tregs expanded, but based on the transcriptome profile, became metabolically silent during the treatment. Last, higher baseline TCR clonality was observed in responding patients, and their expanding CD8+ T cell clones gained a more cytotoxic and NK-like phenotype.ConclusionAnti-LAG-3+anti-PD-1 therapy has profound effects on NK cells and Tregs in addition to CD8+ T cells.Trial registrationClinicalTrials.gov (NCT01968109)FundingCancer Foundation Finland, Sigrid Juselius Foundation, Signe and Ane Gyllenberg Foundation, Relander Foundation, State funding for university-level health research in Finland, a Helsinki Institute of Life Sciences Fellow grant, Academy of Finland (grant numbers 314442, 311081, 335432, and 335436), and an investigator-initiated research grant from BMS.

Neoantigen-targeted CD8+ T cell responses with PD-1 blockade therapy.

Neoantigens are peptides derived from non-synonymous mutations presented by human leukocyte antigens (HLAs), which are recognized by antitumour T cells1-14. The large HLA allele diversity and limiting clinical samples have restricted the study of the landscape of neoantigen-targeted T cell responses in patients over their treatment course. Here we applied recently developed technologies15-17 to capture neoantigen-specific T cells from blood and tumours from patients with metastatic melanoma with or without response to anti-programmed death receptor1 (PD-1) immunotherapy. We generated personalized libraries of neoantigen-HLA capture reagents to single-cell isolate the T cells and clone their T cell receptors (neoTCRs). Multiple T cells with different neoTCR sequences (T cell clonotypes) recognized a limited number of mutations in samples from seven patients with long-lasting clinical responses. These neoTCR clonotypes were recurrently detected over time in the blood and tumour. Samples from four patients with no response to anti-PD-1 also demonstrated neoantigen-specific T cell responses in the blood and tumour to a restricted number of mutations with lower TCR polyclonality and were not recurrently detected in sequential samples. Reconstitution of the neoTCRs in donor T cells using non-viral CRISPR-Cas9 gene editing demonstrated specific recognition and cytotoxicity to patient-matched melanoma cell lines. Thus, effective anti-PD-1 immunotherapy is associated with the presence of polyclonal CD8+ T cells in the tumour and blood specific for a limited number of immunodominant mutations, which are recurrently recognized over time.

Comparison of survival benefit between salvage surgery after conversion therapy versus surgery alone for hepatocellular carcinoma with portal vein tumor thrombosis: a propensity score analysis

BackgroundSalvage surgery after conversion therapy with a combination of tyrosine kinase inhibitor and anti-programmed death-1 antibody has shown improved survival benefits in patients with hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT). We aimed to compare the survival benefits in a retrospective cohort of patients with HCC with PVTT who underwent salvage surgery after conversion therapy and surgery alone. MethodsFrom January 2015 to October 2021, we selected patients diagnosed with HCC with PVTT who underwent liver resection at Chinese PLA General Hospital. The primary endpoint in the comparison of survival benefits between conversion therapy and surgery-alone groups was recurrence-free survival. Propensity score matching was applied to reduce any potential bias in the study. ResultsThe 6-, 12-, and 24-month recurrence-free survival rates in the conversion and surgery alone groups were 80.3% vs 36.5%, 65.4% vs 29.4%, and 56% vs 21%, respectively. On multivariable Cox regression analyses, conversion therapy significantly reduced HCC-related mortality and HCC recurrence rates compared with surgery alone. ConclusionsFor patients with HCC with PVTT, surgery after conversion therapy is in relationship with increased survival in comparison with surgery alone.

Raddeanin A Enhances Mitochondrial DNA-cGAS/STING Axis-Mediated Antitumor Immunity by Targeting Transactive Responsive DNA-Binding Protein 43.

Immune checkpoint therapies (ICT) have achieved unprecedented efficacy in multiple cancer treatments, but are still limited by low clinical response rates. Identification of immunogenic cell death (ICD)-inducing drugs that can induce tumor cell immunogenicity and reprogram the tumor microenvironment is an attractive approach to enhance antitumor immunity. In the present study, Raddeanin A (RA), an oleanane class triterpenoid saponin isolated from Anemone raddeana Regel, is uncovered as a potent ICD inducer through an ICD reporter assay combined with a T cell activation assay. RA significantly increases high-mobility group box 1 release in tumor cells and promotes dendritic cell (DC) maturation and CD8+ T cell activation for tumor control. Mechanistically, RA directly binds to transactive responsive DNA-binding protein 43 (TDP-43) and induces TDP-43 localization to mitochondria and mtDNA leakage, leading to cyclic GMP-AMP synthase/stimulator of interferon gene-dependent upregulation of nuclear factor κB and type I interferon signaling, thereby potentiating the DC-mediated antigen cross-presentation and T cell activation. Moreover, combining RA with anti-programmed death 1 antibody effectively enhances the efficacy of ICT in animals. These findings highlight the importance of TDP-43 in ICD drug-induced antitumor immunity and reveal a potential chemo-immunotherapeutic role of RA in enhancing the efficacy of cancer immunotherapy.