Lung cancer remains the leading cause of cancer-related mortality globally, with many patients diagnosed with advanced-stage disease. Treatment in this setting relies on systemic therapies, including chemotherapy, targeted therapy and immunotherapy. Immune-checkpoint inhibitors (ICIs), which promote or restore antitumour immunity by inhibiting immunosuppressive signalling pathways, are currently the most widely used immunotherapies in these patients. However, immune-related adverse events (irAEs) or disease progression often necessitate discontinuation of these agents, leaving many patients with limited subsequent treatment options. In this scenario, ICI rechallenge has emerged as a potential strategy. Despite this potential, evidence for ICI rechallenge after either disease progression or irAEs in patients with non-small-cell lung cancer is limited and evidence for those with small cell lung cancer seems to be non-existent. In this Review, we provide a comprehensive overview of the available data on ICI rechallenge in the context of both disease progression and irAEs, including a summary of current guidance on clinical management and detailed discussions of safety and efficacy. We also highlight important unanswered questions in an attempt to guide future research in this area.

Lung cancer is the leading cause of death worldwide. It occurs mainly in smokers, but also in 25% of cases in non-smokers. As regards metastatic stages, while immunotherapy has led to improved overall survival, smoking status may potentially influence its effectiveness. The objective of this study was to analyze its effectiveness as first-line treatment for advanced non-small cell lung cancers (NSCLC) according to patient smoking status.

This retrospective study covers all patients with stage IV NSCLC treated with first- line immunotherapy, alone or in combination, between January 2018 and 2019, in three Ile de France centers. The primary and secondary endpoints were, respectively, overall survival and progression-free survival, according to smoking status.

The analysis included 105 patients (66.7% men) of whom 38% were active smokers and 9.5% non-smokers, with adenocarcinoma in 65.7% of cases. Median OS and PFS were 17, 23.2, and 24.9 months and 4.9, 7.6, and 4 months for smokers, ex-smokers, and non-smokers respectively, without significant differences.

In this study, smoking status did not seem to modify the effectiveness of immunotherapy. Studies on a larger population are called for.

It remains unclear whether adding CTLA-4 blockade to PD-1/PD-L1 blockade improves clinical outcomes in cervical cancer (CC).

In this randomized, double-blind, placebo-controlled, phase 2 study (ClinicalTrials.gov: NCT04590599), patients with recurrent/metastatic CC (R/M CC) who experienced disease progression after or during platinum-based chemotherapy were enrolled from 37 centers across China and randomly assigned (1:1), stratified by PD-L1 expression and prior treatment lines, to receive either IBI310 plus sintilimab or placebo plus sintilimab intravenously every 3 weeks for 12 weeks, followed by sintilimab alone. The primary endpoint was the objective response rate (ORR). Pivotal secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety.

205 patients were randomized to receive IBI310-sintilimab (n = 103) or placebo-sintilimab (n = 102). The ORR difference between the IBI310-sintilimab arm (32.3%, 95% confidence interval [CI]: 23.3%-42.5%) and the placebo-sintilimab arm (23.5%, 95% CI: 15.5%-33.1%) was not significant (p = 0.17). IBI310-sintilimab and placebo-sintilimab exhibited median PFS values of 3.6 (95% CI: 2.7-6.3) and 4.2 months (95% CI: 2.8-6.2), respectively (hazard ratio [HR] = 0.91, 95% CI: 0.65-1.27; p = 0.58). The median OSs were 13.9 months (95% CI: 11.5-25.6) in the IBI310-sintilimab arm and 17.2 months (95% CI: 13.7-25.9) in the placebo-sintilimab arm (HR = 1.12, 95% CI: 0.79-1.58; p = 0.54). Adding IBI310 to sintilimab increased the incidence of grade ≥3 treatment-related adverse events (55% versus 19%).

Compared to single-agent PD-1/PD-L1 blockade, dual blockade of CTLA-4 and PD-1/PD-L1 did not significantly improve clinical outcomes in R/M CC.

This work was funded by Innovent Biologics (Suzhou).

Cancer immunotherapy has transformed oncology by harnessing the immune system to specifically target cancer cells, offering reduced systemic toxicity compared to traditional therapies. This review highlights key strategies, including adoptive cell transfer (ACT), immune checkpoint inhibitors, oncolytic viral (OV) therapy, monoclonal antibodies (mAbs), and mRNA-based vaccines. ACT reinfuses enhanced immune cells like tumor-infiltrating lymphocytes (TILs) to combat refractory cancers, while checkpoint inhibitors (eg, PD-1 and CTLA-4 blockers) restore T-cell activity. OV therapy uses engineered viruses (eg, T-VEC) to selectively lyse cancer cells, and advanced mAbs improve targeting precision. mRNA vaccines introduce tumor-specific antigens to trigger robust immune responses. Despite significant progress, challenges like immune-related side effects, high costs, and immunosuppressive tumor microenvironments persist. This review underscores the need for combination strategies and precision medicine to overcome these barriers and maximize the potential of immunotherapy in personalized cancer treatment.

No standard systemic therapy exists for recurrent/metastatic salivary gland cancer (R/M SGC). We explored the safety and activity of nivolumab and ipilimumab with palliative hypofractionated radiation (XRT) in this population.

This Phase I/II Trial enrolled R/M SGCs with evidence of progression, ECOG 0-1, no prior anti-PD-1 or CTLA4 therapy, measurable disease excluding the XRT site. Nivolumab 3 mg/kg iv Q2 weeks × 12 doses followed by 480 mg iv Q4 weeks × 8 doses and ipilimumab 1 mg/kg iv Q6 weeks × 4 doses was given. Twenty four gray XRT was given over three fractions, 2 weeks after the first dose of nivolumab. The primary endpoint was safety; secondary endpoints included RECIST 1.1 response (non-radiated lesions), progression free, and overall survival.

Between April 2019 and May 2022, 20 pts. were enrolled, the median age was 58 (range 27-77 years), 10 (50%) were male, and 12 (60%) had ECOG 0. Five (20%) Grade 3 AEs were observed in three pts.; no Grade 4 or 5 toxicities were observed. Among 19 response-evaluable patients, RECIST 1.1 PRs were observed in 4 (21%), in 2 pts. with salivary duct, 1 acinic cell, and 1 adenoid cystic, SD in 6 (31.5%) and PD in 9 (47.5%). With a median follow-up of 16 months, median OS was 25 months (95% CI: [18.7, 31]) and median PFS was 7.3 months (95% CI [2.5, 18.7]).

Nivolumab/ipilimumab and palliative XRT result in low rates of severe toxicities and modest response rates for SGC; further work is necessary to explore predictors for response.

Lynch syndrome is the most common hereditary colorectal cancer (CRC) syndrome, accounting for 3-5% of all CRC cases. Situs inversus totalis (SIT) is a rare congenital malformation with an incidence of 1 in 8,000 to 1 in 25,000. The co-occurrence of Lynch syndrome and SIT is extremely uncommon. Immune checkpoint inhibitors (ICIs) have demonstrated significant efficacy in treating microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) CRC. Tumors associated with Lynch syndrome frequently exhibit MSI-H, providing a theoretical basis for ICI use.

We report a case of bifocal colon cancer associated with Lynch syndrome and SIT. After seven cycles of sintilimab, the patient developed gastrointestinal perforation due to tumor regression, necessitating emergency surgery. The anatomical variations associated with SIT required the surgical team to adopt an alternative approach. Postoperatively, the patient continued sintilimab treatment for 2 years. In June 2024, he underwent a colostomy reversal and proximal colectomy. Pathological examination revealed a tumor regression grade (TRG) of 0, indicating complete pathological remission (pCR), with no recurrence or metastasis detected upon follow-up.

The anatomical variations associated with SIT increase the complexity of surgical procedures. Advanced imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI) are essential for assessing fine anatomical details and facilitating surgery. ICIs are an effective treatment option for Lynch syndrome-associated CRC, as demonstrated in this case. Future studies should investigate the optimal timing of immunotherapy, combination treatment strategies, and methods to mitigate immune-related toxicities. Such research will help develop comprehensive and personalized treatment plans for Lynch syndrome-associated CRC.

Cutaneous immune-related adverse events (cirAEs) represent a prevalent manifestation of adverse reactions linked to immune checkpoint inhibitors (ICIs) therapy, substantially affecting patients' quality of life. This systematic review and meta-analysis aimed to quantify the pooled incidence of cirAEs in this population and strengthen clinical awareness for early recognition and management.

A comprehensive search of PubMed, Embase, CINAHL, Cochrane Library, CBM, CNKI, and Wanfang databases was conducted from inception to December 2022. Literature that reported the incidence of cirAEs in patients with lung cancer receiving ICIs therapy was included. A meta-analysis was conducted using R software, version 4.4.1 to estimate the pooled incidence of cirAEs, and a random-effects model was used for data synthesis. Begg's rank correlation and funnel plots were used to assess publication bias.

A total of 99 articles involving 23,814 patients with lung cancer receiving ICIs therapy were included, with publication dates ranging from 2012 to 2022. The meta-analysis results reveal that the incidence of cirAEs in patients with lung cancer was 20.26% (95% confidence interval [CI (17.12-23.81)]. Significant differences were observed between all subgroups, including continent, study type, combination therapy, dual ICIs therapy, and diagnostic criteria for cirAEs for Grade 1-2 and Grade 3-4 incidences.

The incidence of cirAEs in patients with lung cancer is relatively high, particularly undergoing combined or dual ICIs therapy. To comprehensively characterize cirAEs in patients with lung cancer, large-scale multicenter studies integrating real-world pharmacovigilance data are warranted to establish precise incidence estimates and identify clinically significant risk factors.

This review's insights aroused clinical staff's attention and concern about cirAEs, potentially enhancing the quality of life of patients with cancer.

Novel approaches to tumor immunotherapy include adoptive cell immunotherapy, immune checkpoint inhibitors (ICIs), and bispecific antibodies (bsABs). bsABs are members of the antibody family that have the ability to distinguish between two distinct antigens or epitopes on a single antigen. These antibodies show better clinical results than monoclonal antibodies, suggesting that they might be a useful choice for tumor immunotherapy. Additionally, dual blockade immunotherapy targeting PD-1/PD-L1 and CTLA-4 functions at various phases of T cell activation with synergistically increasing immune responses against cancer cells, in contrast to ICI monotherapy, which sometimes displays treatment resistance and limited effectiveness. It has been shown that immune response rates and anti-tumor effects may be increased in a synergistic manner by ICI-based combination therapy. We explore the safety and effectiveness of bsABs and ICIs (especially PD1/PDL1 and CTLA-4) combination treatments in tumor immunotherapy in this study with the goal of offering evidence-based methods for clinical research and tailored tumor identification and management.

Treatment with cadonilimab and chemotherapy has shown promise as a first-line treatment for gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. However, its application in neoadjuvant settings has not yet been documented.

This multicenter, phase 2 trial (ChiCTR2200066893) was conducted at four hospitals across China. Treatment-naive patients with locally advanced G/GEJ adenocarcinoma (cT3/4, N+, M0) and who were human epidermal growth factor receptor 2 negative received 3-cycle or 4-cycle neoadjuvant treatment of cadonilimab plus FLOT (5-fluorouracil, leucovorin, oxaliplatin, and docetaxel) chemotherapy, followed by gastrectomy and 4-cycle adjuvant FLOT chemotherapy. The primary endpoint was the pathological complete response (pCR) rate. Secondary endpoints included major pathological response (MPR), overall response rate (ORR), disease control rate (DCR), R0 resection rate, downstaging rate, and safety.

Between December 23, 2022, and December 15, 2023, 32 of 38 patients completed the scheduled treatment, achieving an R0 resection rate of 100% (32/32). The pCR rate was 21.1% (8/38, 90% confidence interval [CI]: 9.7-32.4), and the MPR rate was 44.7% (17/38, 90% CI: 30.9-58.5). Radiological evaluations were available for 28 of 38 patients by blinded independent central review. The ORR was 60.7% (17/28, 90% CI: 44.7-76.7), and the DCR was 100.0% (28/28, 90% CI: 100.0-100.0). Tumor downstaging occurred in 71.9% of patients (23/32), with consistent efficacy across all populations observed in the subgroup analysis. Grade 3 adverse events occurred in 31.6% of patients without severe safety issues.

Neoadjuvant cadonilimab plus FLOT chemotherapy treatment exhibits promising efficacy with manageable toxicities in locally advanced G/GEJ adenocarcinoma, providing preliminary evidence for further investigation.

This study was funded by Akeso Biopharma.

We aimed to evaluate the efficacy and safety of cadonilimab (anti-PD-1 and CTLA-4 bispecific antibody) plus TPC chemotherapy (NAB-paclitaxel, cisplatin or lobaplatin, and capecitabine) in patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) who failed to PD-1 inhibitor-containing regimens.

In this single-arm, open-label, phase 2 study, RM-NPC patients who failed to at least one line of systemic chemotherapy and anti-PD-1 immunotherapy were enrolled and received cadonilimab plus TPC chemotherapy every 3 weeks for up to 6 cycles, followed by cadonilimab plus capecitabine every 3 weeks for a maximum of 2 years. The primary endpoint was the objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response (DoR), and safety.

Twenty-five patients were enrolled (84% male; median age 44 years (range, 24-60)), with a median follow-up of 10.2 months. The ORR was 68%, with 3 complete responses, 14 partial responses, and 6 stable diseases. The median DoR was 9.1 months (95% CI, 3.8-14.5 months). The median PFS was 10.6 months (95% CI, 5.2-16.0 months). The 12-month OS was 75.6%. Treatment was well tolerated. Grade 3 or 4 treatment-related adverse events occurred in 12 (48%) patients. Fourteen patients (56%) experienced potentially immune-related adverse events (irAEs). One patient experienced a grade 3 immune-related rash and another patient had grade 3 immune-related lipase increased. No treatment-related death occurred.

Cadonilimab in combination with TPC chemotherapy demonstrated promising antitumoral efficacy and manageable toxicities in patients with RM-NPC who failed frontline immunotherapy. Further trials are warranted to confirm and expand these findings.

This trial was registered at chictr.org.cn (ChiCTR2200067057).

Cancer remains a significant public health issue worldwide, standing as a primary contributor to global mortality, accounting for approximately 10 million fatalities in 2020 [...].

This investigator-initiated phase II trial aimed to evaluate the efficacy of cabozantinib in combination with nivolumab and ipilimumab (CaboNivoIpi) in previously treated patients with radioactive iodine-refractory differentiated thyroid cancer.

Eligible patients with radioactive iodine-refractory differentiated thyroid cancer who progressed on 1 prior line of vascular endothelial growth factor receptor-targeted therapy received a 2-week run-in of cabozantinib monotherapy followed by CaboNivoIpi for 4 cycles (cycle length = 6 weeks), followed by cabozantinib plus nivolumab (cycle length = 4 weeks) until disease progression. The primary endpoint was objective response rate (ORR) within the first 6 months of treatment. A Simon optimal 2-stage design allowed for an interim analysis after accrual of 10 evaluable patients. At least 5 responses were needed to proceed to stage 2.

Among 11 patients enrolled, the median age was 69 years. Prior vascular endothelial growth factor receptor-targeted therapies included lenvatinib, pazopanib, and sorafenib plus everolimus. Median follow-up was 7.9 months. Among 10 evaluable patients, ORR within the first 6 months of treatment was 10% (1 partial response). Median progression-free survival was 9 months (95% CI, 3.0-not reached) and median overall survival was 19.2 months (95% CI, 4.6-not reached). Grade 3/4 treatment-related adverse events (AEs) were noted in 55% (6/11) and grade 5 AEs in 18% (2/11) of patients. The most common treatment-related AE was hypertension. The study did not reach its prespecified efficacy threshold.

CaboNivoIpi had low ORRs and a high rate of grade ≥3 treatment-related AEs.

NCT03914300.

Cancer has the highest death rates due to increased immuno-oncological (IO) challenges and chemoresistance caused by gut dysbiosis, whereas administration of probiotics may reverse these responses against anticancer therapies. Recently, immunotherapeutics have extensively been focused for significant advancements in pharmacological drug discovery and clinical outcomes. Mammals have intestinal epithelial cells, mucosal immune cells, and indigenous gut microbiota which may reshape immunotherapeutics efficacy. These include use of T-cell immune checkpoint inhibitors (ICPI), genetically engineered T-cells, tumor vaccines, monoclonal antibodies (mAbs), and anti-B- and T-cell antibodies. Immunotherapeutics for cancer treatment became popular in both veterinary and human health care systems due to their strong inhibitory actions against PD-1 and CTLA-4 to check tumorigenesis. IO issues in animals also need special attention, where caninized mAbs targeting CD-20 and CD-52 have been clinically used in treating canine B-cell and T-cell lymphomas, respectively. Probiotics appeared as strong immunotherapeutics that might be shaping the epigenetics of the organisms specifically in animal breeding practices for desired features, but limited literature regarding the immunomodulatory effects in humans and animals is available. In addition, considering the important role of probiotics in humans and veterinary medicine, a new perspective on the probiotic-mediated modulation of ncRNAs (miRNAs, lncRNAs, circRNAs) is also highlighted and would be a new therapeutic tool. This review provides insight into the cellular processes and pharmacological activities for treating veterinary infectious diseases and covers small drug molecules as ncRNA-modulators in veterinary medicine.

The combination of PD-1/PD-L1 inhibitor with CTLA-4 inhibitor for advanced non-small cell lung cancer(NSCLC) is presently a significant area of research, however its clinical application remains contentious. This meta-analysis aimed to assess the efficacy and safety of first-line PD-1/PD-L1 inhibitor in combination with CTLA-4 inhibitor (CP) in the treatment of patients with advanced NSCLC.

A systemic search was conducted in four databases (PubMed, Cochrane library, Embase, and Web of Science) from their establishment until January 17, 2024, for randomized controlled trials that investigated the use of the first-line PD-1/PD-L1 inhibitor plus CTLA-4 inhibitor in patients with advanced NSCLC. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were subjected to meta-analyses.

Totally 7 eligible randomized controlled trials including 4682 people were included. Two comparative analyses were performed: CP versus chemotherapy, CP versus PD-1/PD-L1 inhibitor (P). Compared with the chemotherapy group, CP improved OS (HR: 0.84, 95% CI: 0.75-0.94, p<0.05) but not PFS (HR: 0.94, 95%CI: 0.73-1.20, p = 0.63) or ORR (OR: 1.16, 95% CI: 0.79-1.71, p = 0.45). In terms of toxicity, CP had slightly fewer any AEs compared to chemotherapy (RR: 0.94, 95% CI: 0.91-0.97; p<0.05). Compared to the P group, there was no significant difference in OS (MD: -0,25, 95% CI: -2.47-1.98, p = 0.83), PFS (MD: -0.91, 95% CI: -3.19-1.36, p = 0.43), and ORR (OR:1.05, 95% CI. 0.80-1.36, p = 0.73). Subgroup analysis revealed that CP provided superior OS compared with P in patients with PD-L1 expression < 1%.

CP was a feasible and safe first-line therapy for patients with advanced NSCLC. Specifically, CP may function as a therapeutic alternative for individuals with low or negative PD-L1 expression, resulting in enhanced long-term outcomes compared to chemotherapy or P. Further randomized controlled trials with prolonged follow-up periods are necessary to validate these results, particularly focusing on efficacy in patients with differing PD-L1 expression levels, to improve the stratified implementation of immunotherapy.

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024621116, identifier CRD42024621116.

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality, necessitating the exploration of alternate therapeutic approaches. Tumor-reactive or activated-by-cytokine killers (TRACK) are PD-L1+, highly cytolytic NK cells derived from umbilical cord blood NK cells and engineered to express soluble IL-15 (sIL15), and these cells show promise in preclinical studies against NSCLC.

We assessed safety, persistence, homing, and cytotoxic activity in 6 patients with advanced, refractory, and progressing NSCLC who received a low dose of unmatched, allogeneic, off-the-shelf sIL15_TRACK NK cells. We evaluated NK cell presence and persistence with droplet digital PCR (ddPCR), flow cytometry, and immunofluorescence staining.

sIL15_TRACK NK cells had peak measurements at 1 hour and became undetectable 4 hours after each infusion. Cognate ligands to activating NK cell receptors were found in NSCLC. sIL15_TRACK NK cells were observed in a lung tumor biopsy 7 days after the final infusion, confirming their sustainment and tumor-homing ability. They retained cytolytic function following isolation from the lung tumor. Three of 6 patients achieved disease stabilization on repeat imaging, while the others progressed.

Unmatched, allogeneic, cryopreserved, off-the-shelf sIL15_TRACK NK cells express activating receptors, home to tumor sites that express their cognate ligands, and retain cytolytic activity after infusion, underscoring their potential as a therapeutic approach in solid tumors. At low doses, the therapy was safely administered and showed preliminary evidence of activity in 3 of 6 patients with advanced and progressive NSCLC. Additional dose escalation cohorts and coadministration with atezolizumab are planned.

gov NCT05334329.

Funding was provided by CytoImmune Therapeutics and grants from the National Cancer Institute (CA266457, CA033572, and CA210087).

Brain metastasis stands as a leading contributor to mortality in lung cancer patients, yet the intricate mechanism underlying this phenomenon remains elusive. This underscores the need for robust preclinical models and effective treatment strategies. Emerging as viable in vitro models that closely replicate actual tumors, three-dimensional culture systems, particularly organoids derived from non-malignant cells or cancer organoids, have emerged as promising avenues. This review delves into the forefronts of fundamental research and clinical applications focused on lung cancer brain metastasis-derived organoids, highlighting current challenges and delineating prospects. These studies offer tremendous potential for clinical application despite being in nascent status.

Combined treatment with anti-PD-1 and anti-CTLA-4 antibodies has shown superiority over chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC), but data for older patients (aged ≥70 years) with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 or those with an ECOG performance status of 2 are scarce. We aimed to test the superiority of the PD-1 antibody nivolumab and the CTLA-4 antibody ipilimumab over platinum-based doublet chemotherapy as first-line treatment in patients with NSCLC aged 70 years or older or with an ECOG performance status of 2.

This open-label, multicentre, randomised, controlled, phase 3 trial was done at 30 hospitals and cancer centres in France. Eligible patients had stage IV histologically proven NSCLC, with no known oncogenic alterations, and were either aged 70 years or older with ECOG performance status of 0-2 or younger than 70 years with an ECOG performance status of 2. Patients were randomly assigned (1:1) centrally, using a computer-generated algorithm stratified by age (<70 vs ≥70 years), ECOG performance status (0-1 vs 2), and histology (squamous vs non-squamous) to receive nivolumab plus ipilimumab or platinum-based doublet chemotherapy (carboplatin [area under the curve ≤700 mg] plus pemetrexed [500 mg/m2 intravenous infusion every 3 weeks] or carboplatin [on day 1; area under the curve ≤700 mg] plus paclitaxel [90 mg/m2 as intravenous infusion on days 1, 5, and 15, every 4 weeks]). The primary endpoint was overall survival; secondary endpoints included progression-free survival and safety. All efficacy analyses were performed in the intention-to-treat population, which included all randomly assigned patients. Safety was analysed in the safety analysis set, which included all randomly assigned patients who received at least one dose of study treatment and who had at least one safety follow-up. The trial is registered with ClinicalTrials.gov, NCT03351361.

The trial was stopped early for futility on the basis of a pre-planned interim analysis after 33% of the expected events had occurred. Between Feb 12, 2018, and Dec 15, 2020, 217 patients were randomly assigned, of whom 216 patients were included in the final analysis, with 109 patients in the nivolumab plus ipilimumab group and 107 in the chemotherapy group; median age was 74 years (IQR 70-78). Median overall survival was 14·7 months (95% CI 8·0-19·7) in the nivolumab plus ipilimumab group and 9·9 months (7·7-12·3) in chemotherapy group (hazard ratio [HR] 0·85 [95% CI 0·62-1·16]). Among patients aged 70 years or older with an ECOG performance status of 0-1 (median age 76 years [IQR 73-79]), median overall survival was longer in the nivolumab plus ipilimumab group than the chemotherapy group: 22·6 months (95% CI 18·1-36·0) versus 11·8 months (8·9-20·5; HR 0·64 [95% CI 0·46-0·96]). Among patients with an ECOG performance status of 2 (median age 69 years [IQR 63-75]), median overall survival was 2·9 months (95% CI 1·4-4·8) in the nivolumab plus ipilimumab group versus 6·1 months (3·5-10·4) in the chemotherapy group (HR 1·32 [95% CI 0·82-2·11]). No new safety signals were reported. The most frequent grade 3 or worse adverse events were neutropenia (28 [27%] of 103 patients) in the chemotherapy group and endocrine disorders (five [5%] of 105 patients), cardiac disorders (ten [10%] patients), and gastrointestinal disorders (11 [11%] patients) in the nivolumab plus ipilimumab group.

The study showed no benefit of nivolumab plus ipilimumab combination in the overall study population. As a result of early stopping, the trial was underpowered for primary and secondary endpoints; however, the finding of better survival with nivolumab plus ipilimumab compared with platinum doublet in the subgroup of older patients with NSCLC with an ECOG performance status of 0-1 warrants further study.

Bristol-Myers Squibb.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. The discovery of specific driver mutations has revolutionized the treatment landscape of oncogene-addicted NSCLC through targeted therapies, significantly improving patient outcomes. However, immune checkpoint inhibitors (ICIs) have demonstrated limited effectiveness in this context. Emerging evidence, though, reveals significant heterogeneity among different driver mutation subgroups, suggesting that certain patient subsets may benefit from ICIs, particularly when combined with other therapeutic modalities. In this review, we comprehensively examine the current evidence on the efficacy of immunotherapy in oncogene-addicted NSCLC. By analyzing recent clinical trials and preclinical studies, along with an overview of mechanisms that may reduce immunotherapy efficacy, we explored potential strategies to address these challenges, to provide insights that could optimize immunotherapy approaches and integrate them effectively into the treatment algorithm for oncogene-addicted NSCLC.

The combination of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors and anticancer therapies has been in the spotlight in recent years. However, the risks associated with these combination therapies are not fully elucidated. The primary objective of this study was to evaluate the relative risk of organ-specific immune-related adverse events (irAEs) and common adverse events (AEs) in patients treated with PD-1/PD-L1 inhibitor-based combination therapies compared to those treated with PD-1/PD-L1 inhibitor monotherapy for solid tumors.

An electronic database search was performed using ClinicalTrials.gov, Medline, and American Society of Clinical Oncology (ASCO)/European Society for Medical Oncology (ESMO) annual meeting libraries. We included randomized controlled trials designed to assess the safety of combination therapies using PD-1/PD-L1 inhibitors and other anticancer drugs. All the selected clinical studies included solid tumors and provided information on the incidence of nonserious and serious AEs. The quality of evidence was assessed using the Cochrane risk-of-bias tool. A meta-analysis was performed using random-effect models to pool the results.

The primary analysis included 16 relevant clinical studies comprising 4232 patients, of whom 2071 and 2161 patients received PD-1/PD-L1 inhibitor--based combination therapy and PD-1/PD-L1 inhibitor monotherapy, respectively. Serious organ-specific irAEs were infrequent, even when PD-1/PD-L1 inhibitors were combined with other anticancer drugs. The incidence of serious colitis was significantly higher in the combination therapy group than in the monotherapy group. Among the common AEs associated with PD-1/PD-L1 inhibitors, the incidence of serious pyrexia/fever, nonserious pyrexia/fever, fatigue, nausea, decreased appetite, vomiting, diarrhea, dyspnea, and rash significantly increased in the combination therapy group. In the subgroup analysis based on the modes of action of concomitant anticancer drugs, the combination of PD-1/PD-L1 inhibitors and DNA synthesis inhibitors significantly increased the risk of serious colitis compared to PD-1/PD-L1 inhibitor monotherapy.

Organ-specific irAEs occur infrequently when combinations of PD-1/PD-L1 inhibitors and other anticancer drugs are used. However, the risk of serious colitis and certain AEs is higher than that associated with PD-1/PD-L1 inhibitor monotherapy. Vigilant monitoring of AEs and implementation of appropriate clinical management strategies guided by the mode of action of the combination drugs are essential.

Cancer involves tumor cells and tumor-specific immunity. The ability to accurately quantify tumor-specific immunity is limited. Most immunotherapies function by activating new effector tumor antigen-specific T cells (ETASTs) or reactivating the pre-existing ETASTs repertoire. Therefore, the amount of ETASTs can be used to characterize immunotherapy efficacy. Tumor antigens are highly heterogeneous and detecting most ETASTs is challenging. Therefore, nanoparticles loading whole-cell tumor antigens are used to activate and detect pan-clones ETASTs in the blood. The differences between ETASTs and other T cells are transformed into activated and non-activated states. By measuring markers of the activated status and cytotoxic function of ETASTs, it can distinguish ETASTs from other T cells. ETASTs in patients with lung cancer are higher than those in healthy individuals and those with benign pulmonary nodules. Therapeutic efficacy positively correlated with the number of ETASTs in the blood. ETATS levels increase only in the blood of patients who respond to immunotherapy. Single-cell sequencing studies validated these findings. This study provides a highly accurate, specific, non-invasive, and efficient biomarker for predicting immunotherapy efficacy in lung and other cancers. This method can also be applied to evaluate the efficacy of other treatments, such as radiotherapy, oncolytic viruses, and nanomedicine-based therapies.

The limited success of immune checkpoint inhibitors (ICIs) in the adjuvant setting for glioblastoma highlights the need to explore administering ICIs prior to immunosuppressive radiation. To address the feasibility and safety of this approach, we conducted a phase I study in patients with newly diagnosed Grade 3 and Grade 4 gliomas. Patients received nivolumab 300 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks until disease progression or unacceptable toxicity. Fifteen patients were treated, with four patients on dexamethasone at treatment initiation and five tumors having MGMT promoter methylated. Treatment began a median of 38 days post-surgery. The most common treatment-related adverse events (AEs) were rash, pruritus, fatigue, nausea, and anorexia. Grade 3 AEs were lipase increased (n = 2), anorexia (n = 1), pruritus (n = 1), and rash (n = 3), and one Grade 4 cerebral edema occurred. Median progression-free survival (mPFS) was 1.3 months and median overall survival (mOS) was 19.3 months (95% CI, 12.9-NA). Three patients deferred conventional radiochemotherapy for over seven months while ten eventually received it. Progressing tumors tended to exhibit higher LAG-3 levels at baseline compared to shrinking tumors. Analysis of paired pre-treatment and post-progression tissue (n = 5) showed trends of up-regulated TGF-β, ERBB2, ERBB3, and ERBB4 signaling pathways, downregulated PPAR signaling, decreased B cell proportions, and increased monocytes proportions in tumors post-treatment. We show nivolumab plus ipilimumab can be safely administered prior to standard radiotherapy for newly diagnosed gliomas and is operationally feasible. Clinicaltrials.gov NCT03425292 registered February 7, 2018.

Programmed death-1 (PD-1) checkpoint blockade has revolutionized cancer therapy, yet its clinical success is confined to a subset of patients, underscoring the urgent need to understand the molecular underpinnings of programmed cell death ligand 1 (PD-L1) expression to combat immunotherapy resistance.

Employing CRISPR/Cas9 screening, we identified key regulators of PD-L1 in non-small cell lung cancer (NSCLC) cells, focusing on the transcription factor CEBPB and its isoform liver-enriched inhibitory protein (LIP). Through chromatin immunoprecipitation (ChIP) and luciferase reporter assays, we explored the interaction between LIP and basic-helix-loop-helix E22 (BHLHE22) in controlling PD-L1 transcription. We also used immunofluorescence and NBD-CI assays to examine how N-terminal acetylation affects LIP's subcellular localization. The impact of LIP on tumor growth was assessed via subcutaneous tumorigenicity assays, while immunohistochemistry and immunofluorescence were used to analyze LIP-induced alterations in the tumor immune microenvironment.

Our research indicates that CEBPB, particularly its LIP isoform, significantly suppresses PD-L1 expression in NSCLC cells. This suppression is contingent on LIP's N-terminal acetylation by the N-terminal acetyltransferase A complex, which facilitates LIP's nuclear entry and interaction with BHLHE22. This interaction leads to the formation of a co-repressor complex at the PD-L1 promoter, effectively reducing PD-L1 expression and enhancing the tumor immune response.

Identifying CEBPB, especially the LIP isoform, as a pivotal regulator of PD-L1 expression sheds light on the mechanisms behind PD-1 blockade resistance in NSCLC. Our findings suggest that modulating LIP's function or its molecular interactions might offer a novel approach to boosting the efficacy of immunotherapies.

This study provides a comprehensive overview of the role of immunotherapy in the treatment of mismatch repair-deficient (MMRd) endometrial carcinomas. Immunotherapy has emerged as a transformative approach in the treatment of MMRd due to the high mutation rate and subsequent PD-1/PD-L1 overexpression seen in these tumors. This review analyzes the current landscape of existing randomized clinical trials, highlighting the efficacy of immune checkpoint inhibitors (ICIs) like pembrolizumab, avelumab, and dostarlimab. Additionally, the focus extends to the potential of combined therapeutic strategies, such as the integration of ICIs with targeted agents, while also exploring the application of immunotherapy in non-traditional settings beyond advanced or recurrent disease. This includes emerging roles in the adjuvant and neoadjuvant contexts to prevent recurrence and target early-stage disease. These findings underscore the importance of tailoring treatments based on the molecular characteristics of each tumor and paving the way for future advancements in the field of gynecologic oncology. Despite promising results, this article acknowledges the necessity of further research to refine patient selection criteria and explore combination strategies that can overcome resistance mechanisms.

Cancer is the result of the interactions between tumor cells and tumor-specific immune responses. The current biomarkers detect tumor cells' properties, but accurate measurement of tumor-specific immunity is lacking. Most immunotherapies work by activating new effector tumor antigen-specific T cells (ETASTs) or reactivating pre-existing ETASTs' repertoire. The responses to immunotherapy depend on the increase of ETASTs. The amount of ETASTs, especially in blood, is critical for therapeutic efficacy. Distinguishing ETASTs from other T cells by their structural characteristics is difficult. Therefore, nanoparticles loading whole tumor antigens are utilized to activate broad clones ETASTs pre-existing in peripheral blood, followed by detecting them. Thus, the differences between ETASTs and other T cells are transformed to the differences between activated states and unactivated states. By measuring the markers of activated states and cytotoxic functions, we can distinguish ETASTs from other T cells. Nanoparticles loading mixed multiple allogeneic tumor tissue lysates or mixed multiple tumor cell lines can be utilized as universal nanoparticles to replace nanoparticles loading personalized tumor tissue. ETASTs (TATAN-activated CD8+IFN-γ+) in esophageal cancer patients are more than those in healthy people. Measurement of the ETASTs in the blood of esophageal cancer patients before and after ongoing therapy showed that ETATSs increased in the blood of patients who were responsive to immunotherapy but did not increase in the blood of nonresponders. These illustrated that therapeutic efficacy was positively correlated with the level of ETASTs in PBMC. Altogether, this study provides us a highly accurate and specific biomarker for predicting the therapeutic efficacy of cancer immunotherapy and potentially other therapies, such as radiotherapy.

Up to 40% of patients with non-small cell lung cancer (NSCLC) develop central nervous system (CNS) metastases. Current treatments for this subgroup of patients with advanced NSCLC include local therapies (surgery, stereotactic radiosurgery, and, less frequently, whole-brain radiotherapy), targeted therapies for oncogene-addicted NSCLC (small molecules, such as tyrosine kinase inhibitors, and antibody-drug conjugates), and immune checkpoint inhibitors (as monotherapy or combination therapy), with multiple new drugs in development. However, confirming the intracranial activity of these treatments has proven to be challenging, given that most lung cancer clinical trials exclude patients with untreated and/or progressing CNS metastases, or do not include prespecified CNS-related endpoints. Here we review progress in the treatment of patients with CNS metastases originating from NSCLC, examining local treatment options, systemic therapies, and multimodal therapeutic strategies. We also consider challenges regarding assessment of treatment response and provide thoughts around future directions for managing CNS disease in patients with advanced NSCLC.

For patients with advanced non-small cell lung cancer (NSCLC) who have received frontline immunochemotherapy, subsequent treatment options are limited. As the first dual programmed cell death-1 (PD-1)/cytotoxic T lymphocyte-associated antigen-4 bispecific antibody approved globally, cadonilimab demonstrated potential antitumor activity in advanced NSCLC patients resistant to anti-PD-1/PD-L1 antibodies.

We retrospectively collected efficacy and safety data from advanced NSCLC patients treated with cadonilimab-based regimens in later therapy lines.

A total of 41 advanced NSCLC patients refractory to anti-PD-1/PD-L1 therapy were enrolled. More than half of the patients received cadonilimab-based regimen as a fourth or later line of treatment. At the data cutoff date, treatment efficacy could be evaluated in 23 patients. One patient (4.3%) achieved partial response, eight patients (34.8%) experienced stable disease, and 14 patients (60.9%) progressed. The objective response rate and disease control rate were 4.3% and 39.1%, respectively. The median progression-free survival for all evaluated patients was 108.0 days. Due to the short follow-up period, the median overall survival has not yet been reached. Treatment-related adverse events (TRAEs) and immune-related AEs occurred in 63.4% and 22% patients, respectively. The most common TRAEs included gamma-glutamyl transferase elevation (17.1%), coughing (14.6%), and fatigue (12.2%). Five patients (12.2%) experienced grade ≥3 TRAEs.

In this heavily pretreated cohort of advanced NSCLC patients, cadonilimab-based regimens showed moderate antitumor efficacy with a generally tolerable and manageable safety profile. However, more evidence is needed to support the administration of cadonilimab in NSCLC patients refractory to previous anti-PD-1/PD-L1 therapy.

Immunotherapy has made significant strides in cancer treatment, particularly through immune checkpoint blockade (ICB), which has shown notable clinical benefits across various tumor types. Despite the transformative impact of ICB treatment in cancer therapy, only a minority of patients exhibit a positive response to it. In patients with solid tumors, those who respond well to ICB treatment typically demonstrate an active immune profile referred to as the "hot" (immune-inflamed) phenotype. On the other hand, non-responsive patients may exhibit a distinct "cold" (immune-desert) phenotype, differing from the features of "hot" tumors. Additionally, there is a more nuanced "excluded" immune phenotype, positioned between the "cold" and "hot" categories, known as the immune "excluded" type. Effective differentiation between "cold" and "hot" tumors, and understanding tumor intrinsic factors, immune characteristics, TME, and external factors are critical for predicting tumor response and treatment results. It is widely accepted that ICB therapy exerts a more profound effect on "hot" tumors, with limited efficacy against "cold" or "altered" tumors, necessitating combinations with other therapeutic modalities to enhance immune cell infiltration into tumor tissue and convert "cold" or "altered" tumors into "hot" ones. Therefore, aligning with the traits of "cold" and "hot" tumors, this review systematically delineates the respective immune characteristics, influencing factors, and extensively discusses varied treatment approaches and drug targets based on "cold" and "hot" tumors to assess clinical efficacy.

Although immunotherapy is expanding treatment options for cancer patients, the prognosis of advanced cancer remains poor, and these patients must contend with both cancers and cancer-related thrombotic events. In particular, immune checkpoint inhibitors are associated with an increased risk of atherosclerotic thrombotic events. Given the fundamental role of platelets in atherothrombosis, co-administration of antiplatelet agents is always indicated. Platelets are also involved in all steps of cancer progression. Classical antithrombotic drugs can cause inevitable hemorrhagic side effects due to blocking integrin β3 bidirectional signaling, which regulates simultaneously thrombosis and hemostasis. Meanwhile, many promising new targets are emerging with minimal bleeding risk and desirable anti-tumor effects. This review will focus on the issue of thrombosis during immune checkpoint inhibitor treatment and the role of platelet activation in cancer progression as well as explore the mechanisms by which novel antiplatelet therapies may exert both antithrombotic and antitumor effects without excessive bleeding risk.