PD-1 Inhibitors Research Articles

Oral Microalgae-Based Biosystem to Enhance Irreversible Electroporation Immunotherapy in Hepatocellular Carcinoma.

Irreversible electroporation (IRE) is a novel local tumor ablation technique that can potentially stimulate immune responses. However, IRE alone cannot effectively activate the immune system or prevent distant metastases. Therefore, this study utilized the biocompatibility of Chlorella vulgaris (C. vulgaris) and polydopamine (PDA) adhesive properties to encapsulate a PD-1 inhibitor (PI). The PDA coating protects the drug from degradation by stomach acid and enhances its intestinal absorption. This carrier demonstrates excellent in vivo drug release control and biodistribution, significantly increasing the oral bioavailability of PI. Combining IRE with this natural carrier significantly improves the therapeutic efficacy, which increases the local drug concentration and activates the immune system. This system demonstrates significantly improved therapeutic efficacy against local tumors compared with PI or IRE alone and significantly reduces PI-associated side effects. A convenient oral delivery system is developed using this readily available natural micro-carrier that not only improves the therapeutic effect of IRE but also mitigates its adverse effects, indicating significant potential for clinical applications. This discovery offers a new strategy for hepatocellular carcinoma treatment with the potential to improve patient outcomes.

Unveiling the role of PANoptosis-related genes in breast cancer: an integrated study by multi-omics analysis and machine learning algorithms.

The heterogeneity of breast cancer (BC) necessitates the identification of novel subtypes and prognostic models to enhance patient stratification and treatment strategies. This study aims to identify novel BC subtypes based on PANoptosis-related genes (PRGs) and construct a robust prognostic model to guide individualized treatment strategies. The transcriptome data along with clinical data of BC patients were sourced from the TCGA and GEO databases. Consensus clustering was performed on 12 PRGs to ascertain potential BC subtypes, and variances in survival, infiltration of immune cells, and functional pathways among them were examined. A prognostic model was generated through 101 combinations of machine learning algorithms and validated across multiple cohorts. The response of patients towards immunotherapy were analyzed using multiple frameworks. Consensus clustering of 12 PRGs identified two distinct BC subtypes, with subtype B exhibiting significantly lower overall survival (OS) rates compared to subtype A. Immune cell infiltration analysis revealed higher immune activity in subtype A. Functional pathway analysis revealed that subtype A exhibited a significant enrichment in immune-related pathways, while subtype B was associated with cell cycle and metabolic processes. An integrated machine learning framework integrating CoxBoost and Random Survival Forest (RSF) algorithms was developed, demonstrating high predictive performance across multiple cohorts. A nomogram combining age and risk score was constructed, showing excellent predictive performance. Immune landscape analysis revealed that the high-risk group exhibited a suppressive tumor immune microenvironment (TIME). Immunotherapy response prediction suggested that low-risk patients were more likely to benefit from PD-1 and CTLA-4 inhibitors. Our study provides a comprehensive framework for BC subtype classification and prognostic prediction, offering valuable insights for personalized treatment strategies.

Neoadjuvant immunotherapy for DNA mismatch repair proficient/microsatellite stable non-metastatic rectal cancer: a systematic review and meta-analysis

BackgroundNeoadjuvant immunotherapy (NIT) has been endorsed by clinical guidelines for the management of DNA mismatch repair deficiency/microsatellite instability-high (dMMR/MSI-H) locally advanced rectal cancer (LARC). Nonetheless, the therapeutic efficacy of NIT in mismatch repair-proficient/microsatellite stable (pMMR/MSS) non-metastatic rectal cancer (RC) remain pending matters. Therefore, a meta-analysis was carried out to assess the efficacy and safety of NIT in patients with non-metastatic pMMR/MSS RC.MethodsPubMed, Embase, Web of Science, the Cochrane Library, ClinicalTrials.gov, ASCO and ESMO were searched to obtain related studies up to July 2024. Two reviewers independently screened the included articles and extracted the pertinent data. The risk of publication bias was assessed by Begg or Egger tests and in cases of publication bias, the trim and fill method was applied. Heterogeneity was assessed using I 2 statistics.ResultsThirteen articles including 582 eligible patients were analyzed. The pooled pCR, MPR, cCR and anus preservation rate were 37%, 57%, 26% and 77% separately and the incidence of irAEs≥3 grades and TRAEs≥3 grades were 3% and 29%, respectively. Non-metastatic pMMR/MSS RC receiving the short-course radiotherapy (SCRT) in neoadjuvant setting exhibited superior pooled pCR and MPR than long-course radiotherapy (LCRT) without upregulating the incidence of adverse effects. Furthermore, patients with MSS RC underwent neoadjuvant treatment with anti-PD-1 inhibitors demonstrated higher pooled pCR, MPR, cCR compared to those receiving PD-L1 inhibitors. Additionally, yielded improved pooled MPR and anal preservation rates compared to sequential immuno-radiotherapy (63.4% vs 51.2% and 88.5% vs 69.9%), without raising the incidence of irAEs≥3 grade. Interestingly, RC patients with lymph node metastasis showed a higher pooled pCR than those without lymph node metastasis (43% vs 35%).ConclusionNIT was linked to favorable response rates and anal preservation, alongside an acceptable safety profile. Non-metastatic pMMR/MSS RC patients receiving SCRT, PD-1 inhibitors, or concurrent immuno-radiotherapy in the neoadjuvant setting exhibited enhanced outcomes. This meta-analysis provides evidence for further exploration and application of NIT in non-metastatic pMMR/MSS RC and highlights the potential for organ preservation with this approach. The relatively small sample size and the uneven quality of included studies may have had some impact on the generality of the results. Therefore, further analysis with a higher number of high-quality studies is needed to verify the conclusions.Systematic review registrationhttps://inplasy.com/, identifier: INPLASY202470110.

Abstract P022: Investigating the role of the tumor microenvironment in the rectal cancer response to preclinical radio-immunotherapy combinations

Abstract Background: Locally-advanced rectal cancer (LARC) is traditionally treated with neoadjuvant chemoradiotherapy before surgery, however, response heterogeneity necessitates the development of novel treatment combinations. Immune checkpoint blockade (ICB) with or without radiotherapy (RT) elicits clinical benefit in various solid tumors, yet ICB’s effectiveness so far is limited to colorectal tumors with microsatellite instability and the role of the tumor microenvironment (TME) is unclear. We present a novel orthotopic immunocompetent mouse model of LARC, where combinations of RT and ICB are tested to elucidate the role of TME in the response to treatment. Methods: Autochthonous murine tumor-derived organoids expressing common driver mutations (Apcfl/fl; KrasG12D/+; p53fl/fl; Tgfbr1fl/fl: ‘AKPT’) were orthotopically injected into syngeneic C57Bl/6 immunocompetent mice. Tumor response to RT-ICB was studied on timepoint and aging cohorts of mice with tumors growing in different TME settings: (a) in the rectal submucosa of wildtype mice, (b) subcutaneously in wildtype mice, and (c) in the rectal submucosa of mice lacking the iCCR locus (CCR1, CCR2, CCR3, and CCR5: ‘iCCRKO ’), which inhibits inflammatory monocyte recruitment into the TME. Radiation was delivered as 15Gy in 3# (Mon-Wed-Fri) using a Small Animal Radiation Research Platform on day 13 following tumor engraftment for the orthotopic models and on day 7 for the subcutaneous. PD-1 inhibition (PD-1i) was administered intraperitoneally (10mg/kg twice weekly) 3 days pre-RT until endpoint. Mice in the timepoint experiments were sampled 5 days following RT, while aging mice were sampled at clinical endpoint or 100 days, whichever came first. Results: RT and PD-1i offered significant survival extension and tumor control in the orthotopic wildtype setting (a). Transcriptomic characterization at 5 days revealed that untreated and irradiated tumors harbored a stroma-rich microenvironment, low in immune cells, which PD-1i partly reversed. This phenotypic ‘switch’ was also evident in an aging cohort, suggesting that RT + PD-1i have long-lasting effects on the stroma. In the subcutaneous setting (b), RT significantly increased tumor control but PD-1 blockade offered little additional advantage. Interestingly, subcutaneous AKPT tumors had significantly more CD8+ cells at baseline than orthotopic ones, highlighting the inherent immune permissiveness of the subcutaneous TME. Finally, tumors growing in the iCCRKO setting (c) were more radio-sensitive, leading to 3 instances of tumor clearance: one in the RT group and two in the RT + PD-1i. Conclusion: Our findings demonstrate the synergistic potential of RT and PD-1i to sensitize an inherently radio-resistant orthotopic mouse model of LARC. Tumor location and inflammatory monocytes emerged as key regulators of the immune response to RT-ICB, which could have important implications for LARC modeling. Importantly, we highlight that TME components can facilitate treatment resistance and give rise to targets that can be therapeutically exploited. Citation Format: Lydia Melissourgou-Syka, Michael A. Gillespie, Lily V.S. Hillson, Kathryn Gilroy, Katrina Stevenson, Susanti Susanti, Tamsin R.M. Lannagan, Eoghan Mulholland, Philip D. Dunne, Joanne Edwards, Sean M. O'Cathail, Colin W. Steele, Owen J. Sansom, Campbell S.D. Roxburgh.Investigating the role of the tumor microenvironment in the rectal cancer response to preclinical radio-immunotherapy combinations.[abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr P022

Abstract A008: Imaging response to induction PD-1 and PARP inhibition in patients with locally advanced head and neck squamous cell carcinoma

Abstract Introduction: Patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) have high risk of disease progression and death after standard concurrent chemoradiotherapy (CCRT). We are conducting a prospective trial to investigate the efficacy of combining immune checkpoint blockade (ICB) with PARP inhibition prior to and following CCRT. Here we report the feasibility of utilizing pre- and post-induction CT simulations to assess early imaging response in patients treated on trial. Methods: NCT05366166 is an ongoing multi-institution, phase II trial. Patients with HPV negative or high-risk HPV positive LA-HNSCC were eligible. All received induction pembrolizumab 400mg IV and olaparib 150mg BID for 3 weeks followed by CCRT to 70Gy with weekly cisplatin (40mg/m2) followed by one year of maintenance pembrolizumab 400mg every 6 weeks and olaparib 150mg BID. Per protocol, all patients underwent CT simulation in the radiation treatment position with intravenous contrast pre- and post-induction. Dedicated post-induction imaging by radiology was not obtained. Gross tumor volumes of the primary (GTVp) and nodal (GTVn) disease were contoured on the pre- and post-induction simulation CTs by the treating physician in RayStation (RaySearch Laboratories). Pre- and post-induction simulation CTs were evaluated by two neuroradiologists independently using the RECIST criteria (v1.1). Statistical analyses were conducted in Microsoft Excel. Results: We evaluated the first 9 patients treated on-study at our center only. Median age was 67 years (range 59-76) and 78% were male. Location of primary site was oropharynx (N=6; 4 were HPV-positive), oral cavity (N=2), and larynx (N=1). 78% were T3-T4 and 89% had N2-N3 nodal disease. The median duration from the start of induction therapy to post-induction simulation was 22 days (range 7-51). Following induction, all patients experienced symptomatic benefit and had stable disease without progression per RECIST. Comparing pre- and post-induction GTVp and GTVn, overall mean volumes were not statistically different (mean±standard deviation -- 34.0±17.9 vs 35.6±19.5 cm3 for GTVp and 38.7±51.8 vs 39.5±54.2 cm3 for GTVn, respectively). At the individual patient level, the percent volume change after induction ranged from -21.9 to +16.5% (GTVp) and -48.7 to +53.2% (GTVn). Two patients (22%) had a decrease in GTVp, while five (56%) had a decrease in GTVn. There was a positive correlation (Pearson coefficient 0.77) between the percent volume changes in GTVp and GTVn (p=0.016). No differences in response by TNM stage or HPV status were observed. Conclusion: Favorable clinical and radiographic responses to three weeks of induction pembrolizumab and olaparib suggest anti-tumor activity. Performing pre- and post-induction radiation CT simulations is necessary to ensure adequate and accurate assessment of tumor extent for radiation planning. Therefore, omitting conventional post-induction scans by radiology to assess tumor response may be feasible. Formal cost-effective analysis will be conducted. Citation Format: Xuguang S. Chen, Colette J. Shen, Benjamin Y. Huang, Valerie L. Jewells, Michael C. Repka, Travis P. Schrank, Christopher B. Sullivan, Wendell G. Yarbrough, Trevor G. Hackman, Catherine Lumley, Jeffrey M. Blumberg, Shetal A. Patel, Sumita Trivedi, Jared Weiss, Bhisham Chera, Siddharth Sheth. Imaging response to induction PD-1 and PARP inhibition in patients with locally advanced head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr A008.

Abstract B002: Pre-vaccine radiation and CTLA-4 blockade increase adjuvant effects of SARS-COV-2 mRNA vaccines

Abstract Background: We recently reported that SARS-CoV-2 mRNA vaccines stimulate massive production of interferon-⍺ (IFN-⍺) (Grippin, et al., SITC, 2024) that drives a near-doubling of median OS and three-year overall survival (OS) in patients with non-small cell lung cancer (NSCLC) and metastatic melanoma (p<0.003) (Grippin, et al., ESMO, 2024). However, design of prospective clinical trials to validate this effect is limited by insufficient understanding of the interaction of mRNA vaccines, ICIs, and local therapies. We therefore analyzed our clinical dataset to understand whether radiation and specific ICIs augment the adjuvant effects of mRNA vaccines. Methods: We utilized institutional databases to identify and extract clinical data for patients with Stage III and Stage IV non-small cell lung cancer (NSCLC) (n=2406) and metastatic melanoma (n=756) with biopsy specimens between August 2019 and August 2023. Differences in survival between groups were assessed with Gehan-Breslow-Wilcoxon tests. Results: After controlling for 34 covariates including performance status, clinical stage, steroid use, tumor proportion score (TPS) of PDL1, disease burden at presentation, cycle of therapy, mutation status, concurrent therapies, and comorbidities with multivariate Cox-proportional hazards regression, we found that receipt of a COVID mRNA vaccine within 100 days of initiation of treatment with ICI was associated with substantial survival advantage in patients with Stage III (HR 0.46, 05% CI 0.31-0.70) and Stage IV NSCLC (HR 0.46, 95% CI 0.36-0.59). Moreover, patients with Stage III disease treated with chemoradiation followed by durvalumab experienced the greatest benefits of vaccination (HR 0.17, 95% CI 0.06-0.49). Since dual agent immunotherapy was uncommon in patients with NSCLC, we then reviewed data from patients with Stage IV melanoma treated with different ICI regimens. We found that adjuvant effects of mRNA vaccines were magnified in patients who received combination therapy with dual inhibition of CTLA-4 and PD-1 (HR 0.32, 95% CI 0.17-0.60) compared to single-agent PD-1 blockade (HR 0.63, 95% CI 0.33-1.3). Conclusions: Together, this data suggests that pre-vaccine radiation therapy and combination therapy with CTLA-4 blockade enhance the adjuvant effects of mRNA vaccines. Future work will include validation of these findings in preclinical models and prospective clinical trials. Citation Format: Adam Grippin, Sage Copling, Andrew Kim, Elliana Young, Betty Kim, John Heymach, Wen Jiang, Steven H Lin. Pre-vaccine radiation and CTLA-4 blockade increase adjuvant effects of SARS-COV-2 mRNA vaccines. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B002.

Targeting NANOS1 in triple-negative breast cancer: synergistic effects of digoxin and PD-1 inhibitors in modulating the tumor immune microenvironment

IntroductionTriple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer resistant to endocrine and targeted therapies. Immune checkpoint inhibitors (ICIs) have shown significant efficacy in various cancers. Taraxacum officinale, commonly known as dandelion, has traditionally been used to treat breast-related diseases and is recognized for its beneficial composition and low side effects. FDA-approved drugs, having undergone rigorous validation for their safety, efficacy, and quality, provide a foundation for drug repurposing research. Researchers may explore FDA-approved drugs targeting the potential target NANOS1 for TOE (Taraxacum officinale extract) treatment to develop innovative therapeutic strategies. In this context, Dig (Digoxin) and AA (Algestone acetophenide) have been identified as potential drug candidates for further exploration of their therapeutic effects and application potential in targeting NANOS1.MethodsRNA sequencing (RNA-seq) was employed to identify potential targets for triple-negative breast cancer (TNBC) from TOE. Bioinformatics tools, including bc-GenExMiner v4.8, the Human Protein Atlas, and the TIMER database, were utilized for target identification. Molecular docking studies assessed FDA-approved drugs interacting with these targets, with Dig and AA selected as candidate drugs. The therapeutic efficacy of Dig and AA in combination with PD-1 inhibitors was evaluated using the 4T1 mouse model. Flow cytometry was applied to assess lymphocyte infiltration in the tumor immune microenvironment. RNA-seq analysis after target silencing by small interfering RNA (siRNA) was performed, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Validation of findings was conducted through quantitative PCR and Western blot analysis.ResultsTOE inhibited TNBC cell growth, migration, and invasion, as assessed by CCK-8 and transwell assays. RNA-seq indicated the effects may be due to NANOS1 down-regulation. Survival analysis showed lower NANOS1 expression correlated with better prognosis. Immunoinfiltration analysis indicated a negative correlation between NANOS1 levels and activated NK cells. Molecular docking identified Dig and AA as high-affinity binders of NANOS1. Animal experiments showed Dig and PD-1 inhibitor combination enhanced immunotherapy efficacy for TNBC.DiscussionThe findings from this study suggest that TOE may offer a novel therapeutic approach for TNBC by targeting NANOS1, a protein whose down-regulation is associated with improved patient outcomes. The negative correlation between NANOS1 and activated NK cells highlights the potential role of the immune system in TNBC pathogenesis and response to treatment. The identification of Dig as potential drugs targeting NANOS1 provides a new direction for drug repurposing in TNBC. The synergistic effect of Dig and PD-1 inhibition observed in animal models is promising and warrants further investigation into the role of immunotherapy in TNBC treatment. Overall, this study identifies NANOS1 as a new target for TNBC therapy and suggests a combination therapy approach that could enhance immunotherapy effectiveness and improve patient outcomes.

Nivolumab and rituximab in treatment naive follicular lymphoma: the phase II '1st FLOR' study.

Follicular lymphoma (FL) outcomes are heavily influenced by host immune activity with immune anti-tumor activity mitigated by PD-1/PD-L1 pathway engagement. Combination CD20-directed therapy plus PD-1 inhibition (PD-1i) increases T-cell tumor killing and NK-cell antibody-dependent cell cytotoxicity (ADCC). Mounting evidence supports immune-priming using PD-1i before cancer-directed agents. Our multicentre, open-label, phase II 1st FLOR study (NCT03245021) enrolled 39 previously-untreated advanced-stage FL patients to receive 4 cycles of nivolumab (240mg) then 4 cycles of 2-weekly nivolumab plus rituximab 375mg/m2 (induction) then 1 year of monthly nivolumab (480mg) plus 2 years of 2-monthly rituximab maintenance. Participants with complete response (CR) after nivolumab priming continued nivolumab monotherapy. The primary endpoint was toxicity during induction. Adverse events (AEs) ≥ grade 3 during induction occurred in 33% (n=13); most commonly elevated amylase/lipase (15%), liver enzyme derangement (11%) and infection (10%). Three patients discontinued nivolumab secondary to toxicity; two pancreatitis, one acute kidney injury. Overall response rate (ORR) was 92% (CR 59%). Median follow-up was 51 months. Median and 4-year progression-free survival (PFS) were 61 months (95%CI 2-72) and 58% (95%CI 34-97); 70% of responders remained in CR. 4-year overall survival was 95%. High baseline total metabolic tumor volume and total lesion glycolysis conferred inferior PFS (p=0.04 and p=0.02). Additionally, high baseline tumor CD8A gene expression was associated with improved PFS (p=0.03). Nivolumab priming followed by nivolumab-rituximab in treatment-naive FL is associated with favorable toxicity and high response rates potentially providing an alternative to chemotherapy. TMTV and high tumor CD8A expression are promising immunotherapy biomarkers for FL.

CXCR4 antagonist-loaded nanoparticles reprogram the tumor microenvironment and enhance immunotherapy in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer death that has limited treatment options for advanced stages. Although PD-1 inhibitors such as nivolumab and pembrolizumab have been approved for advanced HCC treatment, their effectiveness is often hampered by the immunosuppressive tumor microenvironment (TME), which is due to hypoxia-driven CXCL12/CXCR4 axis activation. In this study, we developed 807-NPs, lipid-coated tannic acid (TA) nanoparticles that encapsulate BPRCX807, a potent CXCR4 antagonist to target HCC. 807-NPs enhance the pharmacokinetics and improve the tumor availability of BPRCX807 without causing systemic toxicity. Our findings show that 807-NPs block the CXCR4/CXCL12 pathway, inhibiting Akt and mTOR activation in HCC cells and M2 macrophages and promoting their repolarization toward the antitumor M1 phenotype. In orthotopic murine HCC models, systemic administration of 807-NPs significantly remodeled the immunosuppressive TME by reprogramming tumor-associated macrophages (TAMs) toward an immunostimulatory phenotype and promoting cytotoxic T-cell infiltration into tumors. This led to suppressed primary tumor growth and metastasis, while enhancing the efficacy of cancer immunotherapies, including PD-1 blockade and whole-cancer cell vaccines, by promoting T-cell activation. Our work demonstrates the potential of using nanotechnology to deliver CXCR4 antagonists for cancer immunotherapy.

Immune suppression sustained allograft acceptance requires PD1 inhibition of CD8+ T cells

Immune suppression sustained allograft acceptance requires PD1 inhibition of CD8+ T cells

PDL1 inhibitors may be associated with a lower risk of allograft rejection than PD1 and CTLA4 inhibitors: analysis of the WHO pharmacovigilance database

BackgroundTransplant recipients face increased cancer mortality due to immunosuppressive treatments. Immune checkpoint inhibitors (ICI) have improved survival rates, but data on the use of these agents in transplant recipients is scarce. ICI may trigger allograft rejection, but the absolute risk of AR between the different ICI classes remains to be defined.MethodsVigiBase® (WHO’s pharmacovigilance database) was queried for reports of AR involving CTLA4, PD1, or PDL1 inhibitors. Disproportionality analysis compares the proportion of reports with a specific adverse drug reaction (ADR) and a given drug to the proportion of reports with the same ADR and other drugs. A lower 95% confidence interval for the Information Component (IC) >0 suggests a signal. The comparative Reporting Odds Ratios (ROR) for AR, between PD1 and PDL1 inhibitors, was calculated.ResultsWe gathered 159 AR involving an ICI, especially nivolumab (73, 45.9%), mostly affecting kidneys (87, 54.7%). Median time to onset: 28 days. Fatal outcome: 36 reports (22.6%). ICI were significantly associated with AR: IC=1.7 [1.4;1.9]. Specifically, PD1 inhibitors yielded an IC of 2.0 [1.7;2.2] (152 reports observed compared to 38 expected). By contrast, the IC of PDL1 inhibitors was negative: -2.6 [-6.4;-1.0] (1 observed, 9 expected). The comparative ROR of PD1 compared to PDL1 inhibitors was 33.7 [4.7;240.9] (p=0.0005).ConclusionsWe confirm the association between ICI treatment and AR. Notably, PDL1 inhibitors showed surprisingly low AR reports compared to CTLA4 and PD1 inhibitors. Further prospective studies are warranted to confirm whether PDL1 inhibitors indeed reduce AR risk compared to other ICI.

Knockout IL4I1 affects macrophages to improve poor efficacy of CD19 CAR-T combined with PD-1 inhibitor in relapsed/refractory diffuse large B-cell lymphoma

Chimeric antigen receptor (CAR) T-cell therapy plays a critical role in the treatment of B-cell hematologic malignancies. The combination of PD-1 inhibitors and CAR-T has shown encouraging results in treating patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). However, there are still cases where treatment is ineffective. This study aimed to investigate the role of IL4I1 in the poor efficacy of CD19 CAR-T combined with PD-1 inhibitors in R/R DLBCL and to explore potential mechanisms. Transcriptomic and metabolomic correlation analyses were performed on tumor tissue from DLBCL patients. We employed an in vitro co-culture system consisting of Pfeiffer cells, CD19 CAR-T and macrophages to investigate the underlying mechanisms. It was found that IL4I1 levels were significantly increased in the tumor tissues of R/R DLBCL patients compared to responders. Correlation analysis revealed a positive association between IL4I1 and tryptophan (Trp)-kynurenic acid (Kyn) related metabolites. In the in vitro co-culture model, the presence of IL4I1 inhibited the cytotoxicity of CAR-T cells. Depletion of IL4I1 disrupted the IDO-AHR-Kyn signaling pathway, thereby enhancing the effectiveness of PD-1 inhibitors in combination with CD19 CAR-T for DLBCL treatment. CAR-T-mediated cytotoxicity was significantly inhibited when IL4I1 was present in the in vitro co-culture model. These findings suggest that IL4I1 may be a contributing factor to poor prognosis in R/R DLBCL patients. IL4I1 expression enhances immunosuppression via the IDO-AHR-Kyn pathway, inhibiting the effectiveness of PD-1 inhibitors combined with CD19 CAR-T. Therefore, suppression of IL4I1 may represent a potential target for combination therapy in DLBCL.

Deep analysis of the trials and major challenges in the first-line treatment for patients with extensive-stage small cell lung cancer.

The median overall survival (OS) is approximately 10months when chemotherapy alone is the first-line treatment for extensive-stage small cell lung cancer (ES-SCLC). The approval of the two PD-L1 inhibitors, atezolizumab and durvalumab, marked the beginning of the immunotherapy era for ES-SCLC. Serplulimab, as the first PD-1 inhibitor to achieve success in the first-line treatment of ES-SCLC, has not only demonstrated significant improvements in patient survival outcomes but also ushered in a new era for PD-1 inhibitors in the treatment of ES-SCLC. Recently, antiangiogenic agents with chemo-immunotherapy have achieved breakthroughs in first-line ES-SCLC treatment. Improving the clinical benefits of individualized treatment for patients with ES-SCLC remains challenging. Challenges include identifying biomarkers for targeted therapy, exploring new treatments, developing new medicines, and classifying SCLC molecular subtypes. This review provides an in-depth analysis of research on first-line ES-SCLC treatment. Additionally, it discusses advances in ES-SCLC treatment.

Efficacy of radiotherapy in treating local recurrence concomitant with distant metastasis of nasopharyngeal carcinoma: a long-term retrospective multicenter study.

Patients with nasopharyngeal carcinoma (NPC) experiencing locoregional recurrence concomitant with distant metastases (rmNPC) after initial treatment represent a unique subgroup with significant management challenges. This study aimed to evaluate overall survival (OS) in rmNPC patients treated with systemic therapies with or without radiotherapy. This retrospective multicenter study included patients with locally recurrent and metastatic NPC from five hospitals. Kaplan-Meier analyses and log-rank tests were applied to assess survival outcomes based on recurrence and metastasis profiles, as well as treatment modalities. Independent prognostic factors affecting OS were identified using Cox regression models. A total of 52 patients were analyzed, with a median follow-up duration of 68.3 months (range: 7-240 months). The median OS was 23.4 months (range: 11.1-35.6 months), and the 1-, 2-, 3-, 4-, and 5-year OS rates were 61.3%, 46.5%, 31.0%, 27.9%, and 10.5%, respectively. The treatment modality did not significantly affect OS overall (P = 0.071). Median OS was 10.8 months (95% CI, 7.7-13.9) for chemotherapy alone, 24.2 months (95% CI, 8.9-39.4) for chemotherapy combined with PD-1 inhibitors, and 47.1 months (95% CI, 10.2-84.0) for chemotherapy combined with radiotherapy. In patients with oligometastasis, radiotherapy significantly improved OS (50.1 vs. 24.1 months, P = 0.021), whereas no significant OS benefit was observed for radiotherapy in polymetastatic patients (8.6 vs. 14.8 months, P = 0.168). Similarly, radiotherapy extended OS in patients with one-organ metastases (50.1 vs. 24.1 months, P = 0.026), while no significant benefit was observed in those with multiple-organ metastases (8.6 vs. 11.0 months, P = 0.831). Radiotherapy, when combined with other treatment modalities, significantly improves OS in rmNPC patients with oligometastases or one-organ metastases.

IL-21 and IL-33 May Be Effective Biomarkers to Predict the Efficacy of PD-1 Monoclonal Antibody for Advanced Cholangiocarcinoma.

Background and Objective: Treatment options for patients with advanced biliary tract cancer (BTC) are limited. The programmed cell death protein-1 (PD-1) inhibitors may have synergistic effects with chemotherapy. Therefore, the aim of our study was to provide real-world data on treatment outcomes in BTC patients receiving chemotherapy alone versus a combination of chemotherapy and PD-1 inhibitors. Additionally, we explored potential markers predictive of PD-1 inhibitor efficacy in this combined therapy. Methods: We conducted a review of patients at Changzhou First People's Hospital who received PD-1 inhibitors in combination with chemotherapy or chemotherapy alone as first-line treatment for advanced BTC. The primary endpoints of the study were progression-free survival (PFS) and overall survival (OS). Kaplan-Meier survival curves and the log-rank test were used to analyze the data. Immunohistochemistry showed the expression of interleukin-21 (IL-21), interleukin-33 (IL-33), and Eomes in the tumor tissue of patients who received PD-1 inhibitors in combination with chemotherapy. Results: The study enrolled 61 patients receiving PD-1 inhibitors combined with chemotherapy and 65 receiving chemotherapy alone. The median OS and PFS for patients receiving PD-1 inhibitors in combination with chemotherapy were 11.7 and 6.7 months, respectively. These durations were significantly longer than those for chemotherapy alone: OS of 10.3 months (95% CI: 0.16-0.21, p = 0.031) and PFS of 5.3 months (95% Confidence interval (CI) 0.25-0.32, p = 0.018). High IL-21 expression or low IL-33 expression in tumor tissue correlated with better response rates to chemotherapy combined with PD-1 inhibitors. Conclusions: Combining PD-1 inhibitors with chemotherapy shows good antitumor activity, making it an effective way to treat BTC. The expression profiles of IL-21 and IL-33 hold promise as potential markers for guiding the chemotherapy combined with immunotherapy in BTC patients.

Deep learning-based CT radiomics predicts prognosis of unresectable hepatocellular carcinoma treated with TACE-HAIC combined with PD-1 inhibitors and tyrosine kinase inhibitors

ObjectiveTo develop and validate a computed tomography (CT)-based deep learning radiomics model to predict treatment response and progression-free survival (PFS) in patients with unresectable hepatocellular carcinoma (uHCC) treated with transarterial chemoembolization (TACE)-hepatic arterial infusion chemotherapy (HAIC) combined with PD-1 inhibitors and tyrosine kinase inhibitors (TKIs).MethodsThis retrospective study included 172 patients with uHCC who underwent combination therapy of TACE-HAIC with TKIs and PD-1 inhibitors. Among them, 122 were from the Interventional Department of the Harbin Medical University Cancer Hospital, with 92 randomly assigned to the training cohort and 30 cases randomly assigned to the testing cohort. The remaining 50 cases were from the Interventional Department of the Affiliated Fourth Hospital of Harbin Medical University and were used for external validation. All patients underwent liver enhanced CT examination before treatment. Residual convolutional neural network (ResNet) technology was used to extract image features. A predictive model for treatment response of combination therapy and PFS was established based on image features and clinical features. Model effectiveness was evaluated using metrics such as the area under the receiver operating characteristic (ROC) curve (AUC), concordance index (C-index), accuracy, precision, and F1-score.ResultsAll patients had a median follow-up of 25.2 months (95% CI 24.4–26.0), with a median PFS of 14.0 months (95% CI 8.5–19.4) and a median overall survival (OS) of 26.2 months (95% CI 15.9–36.4) achieved. Objective response rate (ORR) and disease control rate (DCR) was 41.0% and 55.7%, respectively. In the treatment response prediction model, the AUC for the training cohort reached 0.96, with an accuracy of 89.5%, precision of 85.6%, and F1-score of 0.896; the AUC for the testing cohort was 0.87, with an accuracy of 80.4%, precision of 74.5%, and F1-score of 0.802. The AUC of the external validation cohort was 0.85, with accuracy of 79.1%, precision of 73.6%, and f1-score of 0.784. In the PFS prediction model, the predicted AUC for 12 months, 18 months, and 24 months-PFS in the training cohort were 0.874, 0.809, 0.801, respectively. The AUC of testing cohort were 0.762, 0.804, 0.792. The AUC of external validation cohort were 0.764, 0.796, 0.773. The C-index of the combination model, radiomics model, and clinical model were 0.75, 0.591, and 0.655, respectively. The calibration curve demonstrated that the combination model was significantly superior to both the radiomics and clinical models.ConclusionsThe study provides a CT-based radiomics model that can predict PFS for patients with uHCC treated with TACE-HAIC combined with PD-1 and TKIs.

Prognostic value of clinical complete response for patients with initially unresectable hepatocellular carcinoma after conversion with triple therapy

Introduction: Accurately predicting the outcomes of conversion therapy among patients with initially unresectable hepatocellular carcinoma (uHCC) remains a challenge. Clinical complete response (cCR) has been proposed as a predictor of prognosis. However, information on its prognostic value in these patients is limited. We aimed to explore the prognostic value of cCR in patients with uHCC following conversion therapy and identify predictors of cCR. Methods: We included 241 patients with uHCC who underwent transcatheter arterial chemoembolization combined with lenvatinib and PD-1 inhibitors (triple therapy) as first-line treatment. The prognostic value of cCR, predictive factors of cCR, and the relationship between cCR and pathological complete response (pCR) were analyzed. Results: The cCR rate of the 241 patients included was 17.4%. Patients with cCR showed better overall survival (OS) (p < 0.001) and progression-free survival (PFS) (p < 0.001) than those without. cCR was an independent risk factor for OS (hazard ratio [HR]: 0.11, 95% confidence interval [CI]: 0.03–0.42, p = 0.001) and PFS (HR: 0.29, 95% CI: 0.15–0.56, p < 0.001). Serum α-fetoprotein levels ≥400 ng/mL (odds ratio [OR]: 0.47, 95% CI: 0.22–0.95, p = 0.040) and extrahepatic metastasis (OR: 0.13, 95% CI: 0.01–0.62, p = 0.046) were independent negative predictors of cCR. A total of 107 patients (44.4%) underwent conversion surgery. Among these patients, cCR was associated with better OS (p =0.009) and recurrence-free survival (p = 0.007). cCR was significantly correlated with pCR (Φ = 0.61, p < 0.001). Albumin levels ≥35 g/L (OR: 0.12, 95% CI: 0.02–0.69, p = 0.018) and cCR (OR: 30.32, 95% CI: 9.19–128.00, p < 0.001) were independent predictors of pCR. Conclusion: cCR after triple therapy has an excellent long-term survival advantage and is significantly related to pCR. cCR may be a surrogate marker for predicting prognosis and pCR in patients with uHCC receiving triple therapy.

Efficacy and Safety of Immunotherapy Combined with Anlotinib as FirstLine Treatment in Older NSCLC Patients with PD-L1 Expression

Non-small cell lung cancer (NSCLC) predominantly affects older adults; these patients have significant comorbidities, making them unsuitable for chemotherapy. This study aimed to evaluate the efficacy and safety of immune checkpoint inhibitor (ICI) along with anlotinib combination therapy as a first-line treatment in older NSCLC patients with programmed death ligand-1(PD-L1) expression＜50%. We conducted a retrospective observational study including 73 patients with advanced NSCLC treated at Nanjing Brain Hospital. All patients were aged 75 years or older and received first-line systemic therapy with a combination of PD-1 inhibitors and anlotinib. Clinical data were obtained from electronic medical records and analyzed through Kaplan-Meier estimates and Cox proportional hazards models to assess progression-free survival (PFS), overall survival (OS), and the influence of different variables. The patients had a median age of 80 years. The median PFS was 9.8 months (95% CI: 7.9-11.7), and the median OS was 19.5 months (95% CI: 17.3-21.7). PD-L1 tumor proportion score (TPS) <1% (χ2=10.263, P=0.001) and absence of treatment-induced hypertension (χ2=12.804, P<0.001) were identified as independent risk factors for poor PFS. Advanced disease stage (χ2=11.900, P=0.001), PD-L1 TPS <1% (χ2=6.643, P=0.010), and having two or more chronic comorbidities (χ2=9.011, P=0.003) were independent risk factors for poor OS. Treatment-related hypertension was observed in 25% of patients and was associated with better PFS. ICI-anlotinib combination therapy showed promising efficacy and an acceptable safety profile in older NSCLC patients. Future studies involving larger populations are necessary to validate these findings and determine the potential of PD-L1 levels as a biomarker for treatment stratification.

Comparing PD-L1 and PD-1 inhibitors plus bevacizumab combined with hepatic arterial interventional therapies in unresetable hepatocellular carcinoma: A single-center, real-world study.

With the rise of anti-vascular endothelial growth factor antibody and programmed cell death-ligand 1 (PD-L1) regimens, particularly bevacizumab and atezolizumab, as first-line treatments for advanced hepatocellular carcinoma (HCC), there is a need to explore PD-L1 and programmed cell death 1 inhibitors in combination therapies for unresectable HCC (uHCC). Integrating systemic therapies with locoregional approaches is also emerging as a potent strategy. This study compares the outcomes of atezolizumab (PD-L1 inhibitor) and sintilimab (programmed cell death 1 inhibitor) with bevacizumab or its biosimilar, combined with hepatic arterial interventional therapies (HAIT) in uHCC patients. From January 2020 to September 2023, a retrospective analysis was conducted on 138 uHCC patients at Sun Yat-sen University Cancer Center. The cohort included 69 patients treated with atezolizumab with bevacizumab (Bev/Ate) and 69 with bevacizumab biosimilar with sintilimab (Bio/Sin), combined with HAIT. The propensity score matching was also employed to further explore the efficacy and safety. The median progression-free survival (mPFS) was 13.8 months for the Bev/Ate group and 10.0 months for the Bio/Sin group (p = 0.188). The Bev/Ate group showed significantly longer intrahepatic mPFS (HR 0.381; 95% confidence interval 0.176-0.824; p = .018) and higher overall response rates compared with the Bio/Sin group (60.87% vs. 31.88%, p = .001; 69.57% vs. 49.28%, p = .024) based on Response Evaluation Criteria in Solid Tumors v1.1 and modified Response Evaluation Criteria in Solid Tumors criteria. Treatment-related adverse events were similar between groups (p > .050). Combining atezolizumab or sintilimab with bevacizumab or its biosimilar alongside HAIT provided similar overall PFS in uHCC patients. However, the atezolizumab-bevacizumab combination with HAIT showed superior intrahepatic PFS and control rates, warranting further validation.

Machine-Learning Parsimonious Prediction Model for Diagnostic Screening of Severe Hematological Adverse Events in Cancer Patients Treated with PD-1/PD-L1 Inhibitors: Retrospective Observational Study by Using the Common Data Model.

Background/Objectives: Earlier detection of severe immune-related hematological adverse events (irHAEs) in cancer patients treated with a PD-1 or PD-L1 inhibitor is critical to improving treatment outcomes. The study aimed to develop a simple machine learning (ML) model for predicting irHAEs associated with PD-1/PD-L1 inhibitors. Methods: We utilized the Observational Medical Outcomes Partnership-Common Data Model based on electronic medical records from a tertiary (KHMC) and a secondary (KHNMC) hospital in South Korea. Severe irHAEs were defined as Grades 3-5 by the Common Terminology Criteria for Adverse Events (version 5.0). The predictive model was developed using the KHMC dataset, and then cross-validated against an independent cohort (KHNMC). The full ML models were then simplified by selecting critical features based on the feature importance values (FIVs). Results: Overall, 397 and 255 patients were included in the primary (KHMC) and cross-validation (KHNMC) cohort, respectively. Among the tested ML algorithms, random forest achieved the highest accuracy (area under the receiver operating characteristic curve [AUROC] 0.88 for both cohorts). Parsimonious models reduced to 50% FIVs of the full models showed comparable performance to the full models (AUROC 0.83-0.86, p > 0.05). The KHMC and KHNMC parsimonious models shared common predictive features including furosemide, oxygen gas, piperacillin/tazobactam, and acetylcysteine. Conclusions: Considering the simplicity and adequate predictive performance, our simplified ML models might be easily implemented in clinical practice with broad applicability. Our model might enhance early diagnostic screening of irHAEs induced by PD-1/PD-L1 inhibitors, contributing to minimizing the risk of severe irHAEs and improving the effectiveness of cancer immunotherapy.