Efficacy Of Immune Checkpoint Inhibitors Research Articles

The characteristics of the tumor immune microenvironment in colorectal cancer with different MSI status and current therapeutic strategies.

Colorectal cancer (CRC) remains a significant cause of cancer-related mortality worldwide. Despite advancements in surgery, chemotherapy, and radiotherapy, the effectiveness of these conventional treatments is limited, particularly in advanced cases. Therefore, transition to novel treatment is urgently needed. Immunotherapy, especially immune checkpoint inhibitors (ICIs), has shown promise in improving outcomes for CRC patients. Notably, patients with deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) tumors often benefit from ICIs, while the majority of CRC cases, which exhibit proficient mismatch repair (pMMR) or microsatellite-stable (MSS) status, generally show resistance to this approach. It is assumed that the MSI phenotype cause some changes in the tumor microenvironment (TME), thus triggering antitumor immunity and leading to response to immunotherapy. Understanding these differences in the TME relative to MSI status is essential for developing more effective therapeutic strategies. This review provides an overview of the TME components in CRC and explores current approaches aimed at enhancing ICI efficacy in MSS CRC.

Circulating Tumor Cell-Free DNA as Prognostic Biomarker in Non-Small Cell Lung Cancer Patients Undergoing Immunotherapy: The CORELAB Experience.

The expression level of Programmed Death-Ligand 1 (PD-L1) determined by the immunohistochemical method is currently approved to test the potential efficacy of immune-checkpoint inhibitors and to candidate patients with Non-Small Cell Lung Cancer (NSCLC) for treatment with immunotherapeutic drugs. As part of the CORELAB (New prediCtivebiOmaRkers of activity and Efficacy of immune checkpoint inhibitors in advanced non-small cell Lung cArcinoma) project, aimed at identifying new predictive and prognostic biomarkers in NSCLC patients receiving immunotherapeutic drugs, we investigated the role of circulating tumor DNA (ctDNA) molecular characterization as an additional predictive biomarker. We analyzed plasma ctDNA by targeted Next Generation Sequencing in a subset of 50 patients at different time points. ctDNA content was inversely correlated with the clinical outcome both at a baseline and after 2 months of treatment. OS was significantly higher in patients with ≥50% ctDNA reduction. TP53 and KRAS were the most frequently mutated genes, and patients with KRAS and/or TP53 mutations showed worse outcomes than patients without detectable variants or with mutations in other genes. Fewer common variants were found in BRAF, EGFR, MAP2K1, MET, NRAS, and PIK3CA genes. Our data demonstrated that molecular characterization of ctDNA and also its quantitative evaluation could serve as a dynamic, real-time prognostic, and predictive biomarker, enabling regular molecular monitoring of therapy efficacy in support of other medical examinations.

Immunotherapy in Recurrent Ovarian Cancer.

It remains challenging to treat recurrent ovarian cancer effectively as traditional interventions like chemotherapy and surgery have limited long-term efficacy, highlighting an urgent need for innovative approaches. Immunotherapy offers potential advantages in modulating the immune response against tumor cells and has emerged as a promising strategy in ovarian cancer management. This review discusses various immunotherapy modalities, including active and passive immune strategies, for recurrent ovarian cancer. We systematically reviewed recent immunotherapy advances for recurrent ovarian cancer, including the efficacy and mechanisms of single and dual immune checkpoint inhibitors, checkpoint inhibitor combinations with chemotherapy or radiotherapy, anti-angiogenic agents, PARP inhibitors, antibody-drug conjugates (ADC), tumor vaccines, and adoptive cell therapies (ACT). Additionally, we assessed emerging research on biomarkers predictive of immunotherapy responsiveness in ovarian cancer. The findings indicate that immunotherapy, particularly combinations involving immune checkpoint inhibitors and other agents, demonstrates promising efficacy in recurrent ovarian cancer, with some therapies showing enhanced benefits in specific subtypes. The immune microenvironment in platinum-sensitive and -resistant cases exhibits distinct immunological profiles, influencing therapy outcomes. Several potential biomarkers have been identified, potentially aiding in patient stratification and treatment optimization. Immunotherapy significantly advances recurrent ovarian cancer treatment, with various combinations potentially improving outcomes. Further research on predictive biomarkers and immune microenvironment characteristics is crucial for personalizing immunotherapy approaches and enhancing their efficacy in managing recurrent ovarian cancer.

Efficacy of immune checkpoint inhibitors in renal cell carcinoma venous tumour thrombus shrinkage (UroCCR 128)

PurposeSurgery remains the cornerstone of localized renal cell carcinoma (RCC) care. Pembrolizumab has recently been recommended as a standard of care for RCC patients who are at high risk of recurrence. Data regarding the efficacy of ICIs either alone or in combination with ICIs or VEGF TKIs for VTT shrinkage are scarce.MethodsIn the framework of the French kidney cancer research network UroCCR (NCT 03293563), we performed a retrospective multicentric European study to evaluate VTT shrinkage in patients treated with ICIs with metastatic or locally advanced renal cell carcinoma (RCC). The primary endpoint was the objective response rate (ORR) of patients with VTT to ICI-based therapy. Radiological assessment was performed by a treating physician according to the RECISTv1.1 criteria.ResultsWe included 44 patients. The median age was 69 years (range 37–88). All patients was intermediate or poor IMDC risk group. Twenty-three patients were treated with anti-PD-1 in combination with anti-CTLA-4 therapy, 13 patients with ICI monotherapy, and 8 patients with ICIs in combination with antiangiogenic TKI. At baseline, the median VTT diameter was 22 mm (range 7–93). After a median duration of treatment of 5.8 months (range 1.8–39.1), the ORR was 38% (n = 17), including 4 complete responses (CRs) and 13 partial responses (PRs). Ten patients had stable disease (SD), and 17 had progressive disease (PD) as the best response of the VTT.ConclusionThese data highlight the potential efficacy of ICIs to shrink the VTT even if they seem to have little impact on the extent of VTT.

Chronological Effects of Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer.

Circadian rhythm is a physiological process that oscillates in a 24 h cycle. It has a complex connection with the function of the human immune system and even with the development of tumours. Previous studies demonstrated the time-dependent effects of chemotherapy and radiotherapy; however, there are few studies on the timing effects of immunotherapy. Here, we explored the differences in the efficacy of immune checkpoint inhibitors (ICIs) administered at different circadian rhythm times in non-small cell lung cancer (NSCLC). C57BL/6N lung Lewis cancer mice models were constructed. Then, mice were intraperitoneally injected with saline or anti-PD-1 antibody at 7 AM or 7 PM, The expression of PD-L1 was detected by flow cytometry, and the expressions of clock gene BMAL1 and PER2 were detected by polymerase chain reaction (PCR) after treatment. A retrospective analysis was conducted on patients with NSCLC who received ICIs in our department from June 2020 to December 2022. Animal experiments showed that mice treated with ICIs in the morning showed slower tumour growth and smaller tumour volumes than those in the afternoon, accompanied by increased expression of BMAL1 and PER2 and suppression of PD-L1 expression. Retrospective analysis showed that patients who received ICIs in the afternoon (after 12:00) had significantly longer progression-free survival than those in the morning (before 12:00) (median was 16.5 months versus 9.8 months, respectively, p = 0.031, hazard ratio = 1.87). These findings suggest that immunotherapy may have time dependence, offering a novel therapeutic strategy.

High‑intensity focused ultrasound thermal ablation boosts the efficacy of immune checkpoint inhibitors in advanced cancers with liver metastases: A single‑center retrospective cohort study.

High-intensity focused ultrasound thermal ablation (HIFU) is a novel non-invasive technique in the treatment of liver metastases (LIM) that allows focal destruction and is not affected by dose limits. This retrospective study aimed to explore the efficacy of HIFU in improving survival and the safety of the method in newly diagnosed patients with cancer with LIM who received first-line immune checkpoint inhibitor (ICI) therapy. Between January 2018 and December 2023, data from 438 newly diagnosed patients with cancer and LIM who were treated at Mianyang Central Hospital (Mianyang, China) were reviewed. A total of 94 patients were enrolled in this study, of whom 28 were diagnosed with lung carcinoma, 36 with gastric carcinoma, 11 with esophageal carcinoma, 7 with cholangiocarcinoma and 12 with other malignancies. The patients were divided into groups depending on whether they underwent HIFU. Progression-free survival (PFS), overall survival (OS) and adverse events (AEs) were compared. Clinicopathological features were analyzed using the chi-squared test. Of the 94 patients, 28 received ICI + HIFU as first-line treatment. After a median follow-up of 13.8 months, the median PFS and OS in the HIFU group were 2.38 times [10.95 vs. 4.60 months, 95% confidence interval (CI): 1.087-3.106, P<0.0001] and 1.84 times (19.6 vs. 10.67 months, 95% CI: 1.087-3.106, P=0.0418), respectively, higher than in the group without HIFU. All-cause AEs and immune-mediated AEs were similar between the groups with and without HIFU. However, the incidence of grade 1-2 immune-mediated AEs, troponin elevation, hepatotoxicity and renal dysfunction were more common in the current patients with LIM than those reported previously for the entire population. No immune-mediated AEs of grade ≥3 occurred in either group. HIFU prolonged the PFS and OS of first-line ICI in newly diagnosed patients with advanced cancer with LIM, with manageable safety and tolerability. The efficacy of HIFU in patients with LIM who plan to undergo ICI treatment warrants further prospective clinical investigation.

Concomitant medication effects on patients with lung cancer taking immune checkpoint inhibitors a review.

In the past decade, a variety of immune checkpoint inhibitors (ICIs) are currently approved for lung cancer in the world. As a new therapeutic approach, ICIs have shown significant clinical benefits in the first-line or second-line treatment for advanced lung cancer, improving the survival and quality of life of patients. Patients need to take multiple drugs in the meantime due to their own disease or side effects during treatment. In view of drug interactions, concomitant medications have a positive or negative impact on the prognosis of lung cancer patients. In this review, we reviewed the effects of multiple drugs on the prognosis of patients with lung cancer taking ICIs. Several studies indicate that antibiotics, proton pump inhibitors (PPIs), corticosteroids, and opioid analgesics can decrease the efficacy of ICIs. Aspirin and bone-targeting drugs can enhance the efficacy of ICIs and improve the survival rate. The effects of metformin (MET), renin-angiotensin-aldosterone system inhibitors (RASI), nonsteroidal anti-inflammatory drug (NSAIDS) (except aspirin), and statins on ICIs are controversial. Future research should further explore the effects of these concomitant medications on ICIs and develop personalized prescriptions based on the specific needs of patients.

Concurrent versus sequential immunotherapy with chemoradiotherapy for unresectable stage III non-small-cell lung cancer: a retrospective study.

Immunotherapy combined with chemoradiotherapy has demonstrated promising efficacy in stage III non-small-cell lung cancer (NSCLC). However, the optimal timing for immunotherapy intervention during radiotherapy remains unclear. This study aimed to compare the efficacy and safety of immune checkpoint inhibitors (ICIs) administered concurrently or sequentially with chemoradiotherapy in unresectable stage III NSCLC. A retrospective analysis of 98 patients with unresectable stage III NSCLC, treated between January 1, 2019, and June 30, 2023, was conducted. Patients were grouped based on concurrent or sequential administration of ICIs with chemoradiotherapy. Median progression-free survival (mPFS), median overall survival (mOS), 1 and 2-year PFS rates, 2 and 3-year OS rates, objective remission rate (ORR), and disease control rate (DCR) were evaluated. Survival analysis was performed using the Kaplan-Meier method. Univariate and multivariate analyses were conducted using the log-rank test and Cox proportional hazards model. Treatment-related adverse effects were assessed and graded. A total of 98 patients with unresectable stage III NSCLC treated with chemoradiotherapy and ICIs were included. The mPFS and mOS were 19.0 (14.2-23.8) months and 31.5 (24.3-38.7) months, 12.8 (9.5-16.1) months and 28.5 (19.3-37.7) months in the concurrent and sequential ICI groups, respectively, and mPFS showed a significant difference (P=0.047). The estimated 1 and 2-year PFS rates were 79.6% (95% confidence interval [CI]: 67.6-91.6) and 40.4% (95% CI: 15.8-49.2) for the concurrent group, compared to 51.0% (95% CI: 35.9-66.1) and 31.6% (95% CI: 14.5-48.7) for the sequential group. The estimated 2 and 3-year OS rates were 65.7% (95% confidence interval [CI]: 48.6-82.8) and 40.0% (95% CI: 16.1-63.9) for the concurrent group, compared to 54.6% (95% CI: 35.8-73.4) and 28.7% (95% CI: 4.8-52.6) for the sequential group. The Eastern Cooperative Oncology Group Performance Status Scale (ECOG) score and tumor differentiation were identified as independent factors associated with PFS and OS. Distant metastasis occurred in 13.8% and 25.5% of patients in the concurrent and sequential ICI groups, respectively (P=0.049). The incidence of any grade of pneumonitis was 43.1% and 38.3% in two groups, with grade 3 or higher in 7.8% and 8.5% of patients, respectively. Hematologic toxicity of any grade was observed in 29.4% and 34.0% of the two groups, with grade 3 or higher toxicity identified in 3.9% and 2.1% of patients, respectively. Concurrent immunotherapy combined with chemoradiotherapy demonstrated superior efficacy than sequential immunotherapy, with good safety and tolerability in patients with unresectable stage III NSCLC.

Fertility-sparing treatment outcomes using immune checkpoint inhibitors in endometrial cancer patients with Lynch syndrome.

To evaluate the efficacy of immune checkpoint inhibitors (ICIs) for fertility-sparing treatment in Lynch syndrome-associated endometrial cancer (LS-EC). Four LS-EC cases received programmed cell death protein 1 (PD-1) inhibitors for fertility preservation at the Obstetrics and Gynecology Hospital of Fudan University from 2017 to 2023. The clinical data and long-term outcomes were retrospectively reviewed. Case 1, carrying germline MLH1 mutation, was diagnosed with Stage IIAmMMRd (International Federation of Gynecology and Obstetrics 2023) endometrial cancer (EC) at 38 years old. She received PD-1 inhibitor treatment and achieved a pathological complete response (CR) at 42 weeks. Case 2, carrying MLH1 mutation, underwent colorectal cancer surgery at 22 years and was diagnosed with EC and synchronous ovarian cancer at 39 years. After 24-week PD-1 treatment, CR of EC and ovarian cancer was achieved. Case 3, carrying MSH2 mutation, was diagnosed with endometrial atypical hyperplasia (EAH) at 35 years. After receiving 7-month progestin, she had the progressed disease with Stage IA2mMMRd EC and colon cancer was found soon after. She received PD-1 treatment for 18 weeks and achieved a CR of EC. She conceived naturally with full term delivery. Case 4, carrying MSH2 mutation, had a recurrence of Stage IBmMMRd EC 15 months after CR from EAH treated with progestin at 40 years. She received PD-1 treatment for 18 weeks and achieved CR. No recurrence was found in all cases after 3-41 months of follow-up after CR. ICIs might be an effective choice for LS-EC patients desiring fertility preservation.

Efficacy of immune checkpoint inhibitors in pulmonary sarcomatoid carcinoma and predictive potential of mutated TP53

Efficacy of immune checkpoint inhibitors in pulmonary sarcomatoid carcinoma and predictive potential of mutated TP53

Immune Checkpoint Inhibitors +/- Chemotherapy for Patients With NSCLC and Brain Metastases: A Systematic Review and Network Meta-Analysis.

Multiple studies have demonstrated the intracranial efficacy of immune checkpoint inhibitors (ICI) +/- chemotherapy. The efficacy of chemoimmunotherapy compared to ICI alonein patients with metastatic NSCLC and brain metastases (BM) remains unknown. A systematic review and network meta-analysis were performed to evaluate ICI efficacy and the influence of additional chemotherapy on survival outcomes in treatment-naïve metastatic NSCLC with BM. Randomized phase II/III studies with at least one treatment arm with an ICI were eligible. Overall survival (OS) and progression-free survival (PFS) in patients with and without BM were assessed. Ten studies were included, totaling 6560 patients, 770 with BM. Pairwise meta-analysis revealed that patients with BM treated with ICI +/- chemotherapy had improved PFS (hazard ratio [HR] 0.49; 95% CI 0.40-0.60) and OS (HR 0.55; 95% CI 0.44-0.68) versus chemotherapy alone. Patients without BM treated with ICI +/- chemotherapy also had improved PFS and OS compared to chemotherapy alone. In the network meta-analysis of patients with BM, chemoimmunotherapy demonstrated improved PFS compared to ICI alone (HR 0.64; 95% CI 0.43-0.96; p = 0.03). No significant difference was observed in OS. In the population of patients without BM, no significant differences in PFS or OS were observed between chemoimmunotherapy versus ICI alone. This meta-analysis confirms that ICIs with or without chemotherapy are superior to chemotherapy alone for the first-line management of metastatic NSCLC with and without BM. This network meta-analysis suggests combination chemoimmunotherapy offers PFS benefit over ICI monotherapy in BM patients, warranting direct comparisons in clinical trials. PROSPERO: CRD42024501345.

Radiomics signature for dynamic monitoring of tumor inflamed microenvironment and immunotherapy response prediction

BackgroundThe efficacy of immune checkpoint inhibitors (ICIs) depends on the tumor immune microenvironment (TIME), with a preference for a T cell-inflamed TIME. However, challenges in tissue-based assessments via biopsies have...

RECQL4 affects MHC class II-mediated signalling and favours an immune-evasive signature that limits response to immune checkpoint inhibitor therapy in patients with malignant melanoma.

Cancer immunotherapy has transformed metastatic cancer treatment, yet challenges persist regarding therapeutic efficacy. RECQL4, a RecQ-like helicase, plays a central role in DNA replication and repair as part of the DNA damage response, a pathway implicated in enhancing efficacy of immune checkpoint inhibitor (ICI) therapies. However, its role in patient response to ICI remains unclear. We analysed whole exome and bulk RNA sequencing data from a pan-cancer cohort of 25775 patients and cutaneous melanoma cohorts (untreated: n=471, anti-progressive disease [PD]-1 treated: n=212). RECQL4 copy number variations and expression levels were assessed for patient outcomes. We performed gene set enrichment analysis to identify RECQL4-dependent signalling pathways and explored the association between RECQL4 levels and immunoscores. We evaluated the interplay of ICI response and RECQL4 expression in melanoma cohorts of 95 responders and 85 non-responders prior to and after ICI-targeted therapy and tested the prognostic power of RECQL4. Finally, we generated genetically engineered RECQL4 variants and conducted comprehensive multi-omic profiling, employing techniques such as liquid chromatography with tandem mass spectrometry, to elucidate mechanistic insights. We identified RECQL4 as a critical negative regulator of poor prognosis and response to ICI therapy, but also demonstrated its suitability as an independent biomarker in melanoma. High tumour purity and limited signatures of tumour immunogenicity associated with response to anti-PD-1 correlated with high RECQL4 activity. We found alterations in the secretion profile of immune regulatory factors and immune-related pathways robustly suppressed in tumours with high RECQL4 levels, underscoring its crucial role in fostering immune evasion. Mechanistically, we identified RECQL4-mediated regulation of major histocompatibility complex class II molecule expression and uncovered class II major histocompatibility complex transactivator as a mediator bridging this regulation. Our findings unraveled the pivotal role of RECQL4 in immune modulation and its potential as both a predictive biomarker and therapeutic target for optimising immunotherapeutic strategies across various cancer types. High RECQL4 expression limits survival and can act as an independent prognostic factor in melanoma patients. RECQL4 has the potential to act as a negative feedback mediator of immune checkpoint-targeted therapy by limiting signatures associated with therapeutic efficacy. RECQL4 favours an immune-evasive phenotype by downregulating major histocompatibility complex class II molecules.

A responsive cocktail nano-strategy breaking the immune excluded state enhances immunotherapy for triple negative breast cancer.

The exclusion of immune cells from the tumor can limit the effectiveness of immunotherapy in triple negative breast cancer (TNBC). The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway plays a crucial role in priming adaptive anti-tumor immunity through the production of type I interferons (IFNs), facilitating the maturation of dendritic cells (DCs) and the function of T cells. Although the increased expression of programmed death-ligand 1 (PD-L1) upon STING activation is favorable for amplifying the efficacy of immune checkpoint inhibitors (ICIs) and realizing combination therapy, the penetration barrier remains a major obstacle. Herein, we fabricated a smart-responsive nanosystem (B&V@ZB-MCL) by integrating the extracellular matrix (ECM)-degrading drug losartan with a STING agonist (Vadimezan, abbreviated to Vad) and a PD-L1 inhibitor (BMS-1). Losartan was first released in the acidic tumor microenvironment to overcome the physical barrier, enhancing the penetration of immunotherapeutic components. Under the triggering of 1O2 generated by a photosensitizer (Ce6), the reactive oxygen species (ROS)-sensitive degradation of the nanocore ensured the site-directed release of Vad and BMS-1. The released Vad and damaged tumor DNA activated immune responses through the cGAS-STING pathway, while the elevated expression level of PD-L1 promoted the anti-tumor effect of BMS-1. Significant degradation of collagen fibers, restoration of immune effector cells, and lower tumor volume were observed in this integrated triple drug sequential therapy, which provides a promising prospect for TNBC treatment.

Oral administration of Bifidobacterium longum and Bifidobacterium infantis ameliorates cefcapene pivoxil-induced attenuation of anti-programmed cell death protein-1 antibody action in mice.

Gut bacteria play pivotal roles in the antitumor effects of immune checkpoint inhibitors (ICIs). However, antimicrobial therapy, often necessary for infections in cancer patients, can reduce the efficacy of ICIs. The potential of probiotics to restore ICI efficacy remains uncertain. This study evaluated the effects of Bifidobacterium longum and Bifidobacterium infantis (BLBI) in a CT-26 subcutaneous tumor mouse model treated with anti-programmed cell death protein 1 antibody (αPD-1) and cefcapene pivoxil (CFPN-PI). BALB/c mice received daily oral gavage of CFPN-PI for 5 days before tumor inoculation, followed by weekly αPD-1 administration and tumor growth monitoring. BLBI was administered via ad libitum feeding, mixed in powdered feed. Gut microbiota composition and fecal short-chain fatty acid concentrations were assessed, along with gene expression and immune cell populations in the tumor microenvironment, using quantitative RT-PCR and flow cytometry, respectively. CFPN-PI alone increased tumor growth and attenuated the antitumor effect of αPD-1. In contrast, BLBI inhibited CFPN-PI-induced tumor growth and improved the efficacy of αPD-1. Probiotic treatment increased the stool propionic acid concentration and the number of tumor-infiltrating conventional type 1 dendritic cells. Relative decreases in Bacteroides and Lachnospiraceae _NK4A136_group species and relative increases in Muribaculaceae and Unclassified_f_Oscillospiraceae species correlated with an improved αPD-1 response. These results suggest that probiotic administration may be a new therapeutic strategy to rescue the attenuated efficacy of ICIs in patients with cancer who require antimicrobial therapy.

Mutation in CDC42 Gene Set as a Response Biomarker for Immune Checkpoint Inhibitor Therapy.

Immune checkpoint inhibitors (ICIs) have achieved great success; however, a subset of patients exhibits no response. Consequently, there is a critical need for reliable predictive biomarkers. Our focus is on CDC42, which stimulates multiple signaling pathways promoting tumor growth. We hypothesize that an impaired function of CDC42 may serve as an indicator of a patient's response to ICI therapy. We consider CDC42 and its downstream binding and effector proteins as a gene set, as mutations in these components could lead to defective CDC42 function. To elucidate the biomarker function of mutations within the CDC42 gene set, we curated a comprehensive discovery dataset that included seven ICI treatment cohorts. And we curated two ICI treatment cohorts for validation. We explored the mechanism based on The Cancer Genome Atlas database. We also examined whether combining a CDC42 inhibitor with ICI could enhance ICI's efficacy. Mutations in the CDC42 gene set were associated with improved overall survival and progression-free survival. Furthermore, our analysis of immune response landscapes among different statuses of the CDC42 gene set supports its role as a biomarker. Animal experiments also revealed that the combination of the CDC42 inhibitor (ML141) with anti-PD-1 blockade can additively reduce tumor growth. Our study suggests that the CDC42 gene set mutations could potentially serve as a novel biomarker for the clinical response to ICI treatment. This finding also provides insights into the potential of combining ICI and CDC42 inhibitor use for more efficient patient treatment.

Efficacy and safety of immune checkpoint inhibitors combined with iodine-125 seed implantation in driver gene-negative non-small cell lung cancer: a retrospective cohort study

Efficacy and safety of immune checkpoint inhibitors combined with iodine-125 seed implantation in driver gene-negative non-small cell lung cancer: a retrospective cohort study

Gene copy deletion of STK11, KEAP1, and SMARCA4: clinicopathologic features and association with outcomes to immunotherapy +/- chemotherapy in nonsquamous non-small cell lung cancer.

Mutations in STK11, KEAP1, and SMARCA4 predispose to inferior immune checkpoint inhibitor (ICI) efficacy in non-small cell lung cancer (NSCLC), particularly among KRAS-mutant cases. However, the frequency, clinicopathologic features, and clinical impact of deletions in these genes are poorly characterized. Clinicopathologic correlates of STK11, KEAP1, and SMARCA4 deletion were analyzed in nonsquamous NSCLCs at Dana-Farber Cancer Institute (DFCI). mRNA and LKB1 protein levels were assessed via The Cancer Genome Atlas. Clinical outcomes were analyzed in patients who received ICI+/-chemotherapy at DFCI and Memorial Sloan Kettering Cancer Center (MSKCC). Analyses of each deletion excluded cases with mutations in that gene. Among 3,194 nonsquamous NSCLCs, 14.7% had STK11 deletion (STK11DEL), 13.5% KEAP1 deletion (KEAP1DEL), and 13.7% SMARCA4 deletion (SMARCA4DEL). These deletions correlated with lower PD-L1 expression and higher disease stage, tumor mutational burden, and aneuploidy. STK11DEL, KEAP1DEL, and SMARCA4DEL each correlated with lower corresponding mRNA expression, and STK11DEL with lower LKB1 protein expression. Among 767 patients treated with chemoimmunotherapy, these deletions associated with worse objective response rates (STK11 31% vs. 45%, P=0.005; KEAP1 33% vs. 45%, P=0.03; SMARCA4 29% vs. 45%, P=0.0007), progression free survival (STK11 HR 1.5, P=0.0001; KEAP1 HR 1.4, P=0.002; SMARCA4 HR 1.6, P<0.0001), and overall survival (STK11 HR 1.7, P<0.0001; KEAP1 HR 1.5, P=0.003; SMARCA4 HR 1.7, P<0.0001). The effect of these deletions on chemoimmunotherapy outcomes was comparable to the effect of mutations in these genes. Among 1,267 patients treated with ICI alone, these deletions did not impact outcomes in the MSKCC cohort, but generally associated with worse outcomes in the DFCI cohort among KRAS-mutant cases. STK11, KEAP1, and SMARCA4 deletions correlate with distinct clinicopathologic features, reduced PD-L1, and poor chemoimmunotherapy efficacy in NSCLC.

Gut microbiome and immune checkpoint inhibitor toxicity.

Multiple studies have suggested that gut microbiome may influence immune checkpoint inhibitor (ICI) efficacy, but its association with immune-related adverse events (irAEs) is less well studied. In this prospective cohort study, we assessed whether gut microbiome composition at start, or changes during ICI, are associated with severe irAEs. Stool samples of cancer patients treated with anti-PD-1 ± anti-CTLA-4 were analyzed using 16S rRNA gene sequencing and metagenomic shotgun sequencing. Differences in alpha and beta diversity between patients with and without severe irAE were assessed, as well as differential relative abundance (RA) of taxa, MetaCyc pathways, and seven prespecified literature-based bacterial groups including pathobionts and Ruminococcaceae. We analyzed 497 samples of 195 patients before and soon after starting ICI, at severe irAE onset and after starting immunosuppression. Mean RA of the pathobionts group was significantly higher in patients who developed a severe irAE (8.2 %) compared to those who did not (4.8 %; odds ratio 1.40; 95 %CI 1.07-1.87) at baseline, and also early during ICI treatment and at severe irAE onset. A significantly stronger decrease in RA of Ruminococcaceae after starting ICI was observed in patients who developed a severe irAE compared to those who did not. RAs of Ruminococcaceae, the genus Ruminococcus, and the species R. bromii and R. callidus were significantly lower at severe irAE onset compared to other time points. Gut microbiome dysbiosis signaled by higher RA of pathobionts and decrease in RA of Ruminococcaceae may predispose to severe irAEs.

Immunotherapy against glioblastoma using backpack-activated neutrophils.

Immune checkpoint inhibitors (ICIs) represent new therapeutic candidates against glioblastoma multiforme (GBM); however, their efficacy is clinically limited due to both local and systemic immunosuppressive environments. Hence, therapeutic approaches that stimulate local and systemic immune environments can improve the efficacy of ICIs. Here, we report an adoptive cell therapy employing neutrophils (NE) that are activated via surface attachment of drug-free disk-shaped backpacks, termed Cyto-Adhesive Micro-Patches (CAMPs) for treating GBM. CAMP-adhered neutrophils (NE/CAMPs) significantly improved the efficacy of an anti-PD1 antibody (aPD-1) in a subcutaneous murine GBM model (GL261). A combination of NE/CAMPs and aPD-1 completely regressed subcutaneous GL261 tumors in mice. The efficacy of NE/CAMPs against GBM was also tested in an orthotopic GL261 model. Neutrophil's ability to migrate into the brain was not affected by CAMP attachment, and intracerebral NE/CAMP accumulation was observed in mice-bearing orthotopic GBM. The combination treatment of NE/CAMPs and aPD-1 activated systemic immune responses mediated by T cells and showed improved therapeutic responses compared with aPD-1 alone in the orthotopic GBM model. These results suggest that immunomodulation with NE/CAMPs offers a potential approach for the treatment of GBM by combination with ICIs.