Immune Checkpoint Inhibitors Research Articles

Comparing PD-L1 with PD-1 antibodies combined with lenvatinib and hepatic arterial infusion chemotherapy for unresectable hepatocellular carcinoma

BackgroundA combination of hepatic arterial infusion chemotherapy (HAIC), lenvatinib, and immune checkpoint inhibitors (ICIs) yields a high tumor response rate and survival benefit in unresectable hepatocellular carcinoma (uHCC). However, the selection criteria for different ICIs remain unclear. This study aims to compare the efficacy and safety of PD-1/PD-L1 antibodies combined with HAIC and lenvatinib.MethodsThis retrospective study included 184 patients with uHCC treated with HAIC+lenvatinib+PD-1/PD-L1 antibody from June 2019 to January 2022. We utilized propensity score matching (PSM) to select and match 60 patients treated with HAIC + durvalumab + lenvatinib (HDL) against 60 patients treated with HAIC + PD-1 antibodies + lenvatinib (HPL) to compare the efficacy and safety profiles of these two groups.ResultsAfter PSM, the baseline characteristics were well-balanced between the HDL and HPL groups. The overall survival (p = 0.293) and progression-free survival (p = 0.146) showed no significant difference. The objective response rate (ORR) was higher in the HDL group compared to the HPL group according to modified RECIST (74.1% vs. 53.6%, p = 0.022) and RECIST 1.1 (60.3% vs. 41.1%, p = 0.040), respectively. The incidence of grade 3 or 4 adverse events (AEs) was 10.0% and 18.3% (p = 0.191) in the HDL and HPL groups, respectively.ConclusionsPD-L1 antibody appears to be a preferable companion in the combination therapy of HAIC + ICIs + lenvatinib compared to PD-1 antibody, showing higher ORR and relatively lower incidence of severe AEs. Further prospective studies involving a larger patient population are warranted.

The Good (Tumor Killing) and the Bad (Cardiovascular Complications) of Immunologic Checkpoint Inhibitors.

This review details the significant advancement in knowledge of Immune-checkpoint inhibitor (ICI) and its potential deleterious cardiac immune-related adverse effects (irAE). We explore their mechanisms on the cardiac tissue, providing guidance on risk factors, clinical presentations, diagnostic strategies along with treatment. Recent findings have provided insights of cardiac irAEs that exist beyond the previously well-known ICI-induced myocarditis. We have a better understanding of the wide variety of cardiac irAEs pathologies both early and late onset. Moreover, there is more data on mechanisms of cardiotoxicity and patient and therapy-related risk factors, supporting closer routine cardiac monitoring with biomarkers and imaging for prevention and early detection. Diagnosing cardiac irAEs is a challenge given its broad clinical presentation. A high-level of suspicion in addition to early work-up is crucial to prevent serious cardiac events. A multi-disciplinary team including Cardiologists and Oncologists is essential for closely monitor patients' cardiac status on ICI therapy. There is a need of updated guidelines to establish clear recommendations in patients on ICIs.

Cancer Therapy-Induced Encephalitis

Encephalitis associated with cancer therapies is a rare but serious complication that can significantly impact patients’ quality of life and it requires prompt identification and management. Over the past two decades, immunotherapy—particularly immune checkpoint inhibitors—has become a cornerstone of cancer treatment, with up to half of metastatic cancer patients in economically developed countries now receiving these therapies. The widespread adoption of immunotherapy has led to improved survival rates and long-term remissions, even in patients with advanced metastatic disease. However, as immune modulators, these therapies can trigger a range of immune-related adverse events, including a variety of novel neurological toxicities. Among these, encephalitis is of particular concern due to its potential severity, which can compromise treatment outcomes. This review aims to provide a comprehensive overview of the literature on this condition, highlighting optimal diagnostic strategies and management approaches to mitigate the risk of significant morbidity, while also comparing encephalitis induced by immunotherapy with that caused by traditional chemotherapies and targeted oncologic treatments.

Tumor Biology Hides Novel Therapeutic Approaches to Diffuse Large B-Cell Lymphoma: A Narrative Review

Diffuse large B-cell lymphoma (DLBCL) is a malignancy of immense biological and clinical heterogeneity. Based on the transcriptomic or genomic approach, several different classification schemes have evolved over the years to subdivide DLBCL into clinically (prognostically) relevant subsets, but each leaves unclassified samples. Herein, we outline the DLBCL tumor biology behind the actual and potential drug targets and address the challenges and drawbacks coupled with their (potential) use. Therapeutic modalities are discussed, including small-molecule inhibitors, naked antibodies, antibody–drug conjugates, chimeric antigen receptors, bispecific antibodies and T-cell engagers, and immune checkpoint inhibitors. Candidate drugs explored in ongoing clinical trials are coupled with diverse toxicity issues and refractoriness to drugs. According to the literature on DLBCL, the promise for new therapeutic targets lies in epigenetic alterations, B-cell receptor and NF-κB pathways. Herein, we present putative targets hiding in lipid pathways, ferroptosis, and the gut microbiome that could be used in addition to immuno-chemotherapy to improve the general health status of DLBCL patients, thus increasing the chance of being cured. It may be time to devote more effort to exploring DLBCL metabolism to discover novel druggable targets. We also performed a bibliometric and knowledge-map analysis of the literature on DLBCL published from 2014–2023.

The Double-Edged Sword of Immunotherapy—Durvalumab-Induced Polyendocrinopathy—Case Report

Introduction: Immunotherapy is one of the greatest advancements in oncological patient care. The broader the treatment application, the more common the adverse events associated with the therapy. Immune checkpoint inhibitors (ICI) are currently used in numerous malignancies. These drugs influence the immune cells’ interactions, which translates to interruption of immune evasion and increased anti-tumor activity. However, the disruption of immunological signaling pathways often leads to adverse events, such as endocrinological insufficiencies, among which thyroid is the most common. Moreover, the co-appearance of several insufficiencies has been previously described. Case report: A 73-year-old female treated with durvalumab due to non-small cell lung carcinoma was admitted to the emergency unit due to symptoms of ketoacidosis. She had a history of well-controlled type 2 diabetes mellitus and autoimmune thyroiditis. Laboratory results showed increased anti-GAD antibodies, while the low C-peptide level indicated type 1 diabetes mellitus. Moreover, over the course of longer observation, the patient presented with abrupt aggravation of her autoimmune thyroiditis. Conclusions: The new onset of endocrinological insufficiencies is a rare adverse event of immunotherapy. Clinicians must pay particular attention to any signs indicating these life-threatening conditions. In case of the appearance of any endocrinological adverse event, the close cooperation of oncologists and endocrinologists is required to enhance patients’ quality of life.

Stereotactic Radiotherapy Plus Nivolumab in Patients with Locally Advanced Pancreatic Cancer: Results from Phase 1/2 Clinical CA209-9KH Trial.

The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) highlights the urgent need for novel therapeutic strategies. Immune checkpoint inhibitors (ICIs) seem to be ineffective in most PDAC studies. Therefore, we conducted an open-label, multicenter phase 1/2 study (CA209-9KH) to evaluate the safety of stereotactic radiotherapy (SRT) and sequential ICI therapy in PDAC, as well as to validate the efficacy of this regimen as a potential activator of antitumor immunity. Patients aged ≥ 18years with unresectable non-metastatic PDAC following four FOLFIRINOX induction cycles were included. Treatment comprised SRT (4 × 8Gy) and sequential nivolumab administration until disease progression or unacceptable toxicity. The primary endpoints were safety and toxicity assessment. Secondary endpoints included progression-free survival (PFS), overall survival (OS), biomarker evaluation, and quality of life (QoL) analysis. Twenty-two patients were screened, with 15 enrolled. Eleven (median) nivolumab cycles were administered. SRT demonstrated low and clinically nonsignificant toxicity, whereas nivolumab toxicity aligned with prior safety profiles, without grade 4-5 events observed. Three patients discontinued therapy owing to toxicity. Median PFS and OS were 8.1 and 13.0months, respectively, with 12-month PFS and OS rates of 0% and 66.7%, respectively, and a 24-month OS rate of 8.9%. Biomarker levels correlated with clinical or radiological disease control. Patient-reported QoL remained acceptable, deteriorating with disease progression. SRT and nivolumab therapy exhibited manageable toxicity profiles consistent with previous findings; however, long-term treatment responses were not achieved with this regimen in locally advanced PDAC. Another strategy to trigger antitumor immunity in PDAC needs to be sought. EudraCT: 2017-003404-52; ClinicalTrials.gov: NCT04098432.

Acute-Onset Type 1 Diabetes Mellitus and Pancreatic Atrophy Caused by an Immune Checkpoint Inhibitor

Acute-Onset Type 1 Diabetes Mellitus and Pancreatic Atrophy Caused by an Immune Checkpoint Inhibitor

Impact of select actionable genomic alterations on efficacy of neoadjuvant immunotherapy in resectable non-small cell lung cancer

BackgroundNeoadjuvant immune checkpoint inhibitors (ICIs) have improved survival outcomes compared with chemotherapy in resectable non-small cell lung cancer (NSCLC). However, the impact of actionable genomic alterations (AGAs) on the efficacy...

Antibiotic-induced loss of gut microbiome metabolic output correlates with clinical responses to CAR-T cell therapy

Antibiotic-induced microbiome dysbiosis is widespread in oncology, adversely affecting outcomes and side effects of various cancer treatments, including immune checkpoint inhibitors and chimeric antigen receptor T (CAR-T) cell therapies. In this study, we observed that prior exposure to broad-spectrum ABX with extended anaerobic coverage like piperacillin-tazobactam and meropenem was associated with worsened anti-CD19 CAR-T therapy survival outcomes in large B-cell lymphoma patients (n=422), compared to other ABX classes. In a discovery subset of these patients (n=67), we found that the use of these ABX was in turn associated with substantial dysbiosis of gut microbiome function, resulting in significant alterations of the gut and blood metabolome, including microbial effectors such as short-chain fatty acids (SCFAs) and other anionic metabolites, findings that were largely reproduced in an external validation cohort (n=58). Broader evaluation of circulating microbial metabolites revealed reductions in indole and cresol derivatives, as well as trimethylamine N-oxide, in patients who received ABX treatment (discovery n=40, validation n=28). These findings were recapitulated in an immune-competent CAR-T mouse model, where meropenem-induced dysbiosis led to a systemic dysmetabolome and decreased murine anti-CD19 CAR-T efficacy. Furthermore, we demonstrate that SCFAs can enhance the metabolic fitness of CAR-T cells, leading to improved tumor killing capacity. Together, these results suggest that broad-spectrum ABX deplete metabolically active commensals whose metabolites are essential for enhancing CAR-T efficacy, shedding light on the intricate relationship between ABX exposure, microbiome function and their impact on CAR-T cell efficacy. This highlights the potential for modulating the microbiome to augment CAR-T immunotherapy.

Investigating tumor immunogenicity in breast cancer: deciphering the tumor immune response to enhance therapeutic approaches

The interplay between immune cells and malignant cells represents an essential chapter in the eradication of breast cancer. This widely distributed and diverse form of cancer represents a major threat to women worldwide. The incidence of breast cancer is related to several risk factors, notably genetic predisposition and family antecedents. Despite progress in treatment modalities varying from surgery and chemotherapy to radiotherapy and targeted therapies, persistently high rates of recurrence, metastasis, and treatment resistance underscore the urgent need for new therapeutic approaches. Immunotherapy has gained considerable ground in the treatment of breast cancer, as it takes advantage of the complex interactions within the tumor microenvironment. This dynamic interplay between immune and tumor cells has become a key point of focus in immunological research. This study investigates the role of various cancer markers, such as neoantigens and immune regulatory genes, in the diagnosis and treatment of breast tumors. Moreover, it explores the future potential of immune checkpoint inhibitors as therapeutically effective agents, as well as the challenges that prevent their efficacy, in particular tumor-induced immunosuppression and the difficulty of achieving tumor specificity.

Escalation of neoadjuvant therapy in triple-negative breast cancer—balancing effectiveness and toxicities

SummaryWith the incorporation of immune checkpoint inhibitors into the neoadjuvant treatment of patients with triple-negative breast cancer, we are confronted with a new toxicity profile, while adding significant improvement in pathologic complete response rates and event-free survival.

Emerging Strategies for Local Delivery of Immune Checkpoint Inhibitors to Potentiate Cancer Immunotherapy: Current Status and Future Prospects.

Cancer constitutes a significant threat to patients' lives worldwide. Immunotherapy, particularly immune checkpoint inhibitors (ICIs) that boost antitumor immunity by targeting immune checkpoint components, has emerged as a promising strategy for its treatment in recent years. However, the objective response rates of the ICIs are unsatisfactory. As the primary route, systemic administration of ICIs is often accompanied by immune-related adverse events. Local delivery of ICIs serves as a potential therapeutic strategy that can improve the efficacy while simultaneously reducing side effects through precise drug release at the tumor site. Initial validation of direct local application of ICIs for tumors in clinical trials has indicated reduced side effects and improved efficacy, while low bioavailability remains a challenge. Furthermore, research on various carriers, including nanoparticles, microneedles, hydrogels, combined platforms, and implantable devices for local release of ICIs has exhibited applying potential in treating murine tumors, among which combined platforms such as combined hydrogel system hold the highest promise due to their encompassment of the advantages of multiple carriers. These carriers, by incorporating ICIs and other therapeutics, could manage cancers more potently, which needs to be confirmed in clinical trials after the refinement of their biocompatibility. This review summarizes the latest research advancements regarding local administration of ICIs, with a particular focus on the carriers for local delivery as well as the combination therapies, thus providing novel insights and research guidance for scholars to enhance the efficacy of locally delivered ICIs on managing multiple cancers in the future.

Role of Immunotherapy in Gastroesophageal Cancer with Liver Metastasis.

The role of immune checkpoint inhibitors (ICIs) for patients with gastroesophageal (GE) cancer with liver metastasis remains unclear. Our objective was to investigate if ICIs are beneficial in patients with GE cancer with liver metastasis. We searched PubMed, Embase, ESMO, and ASCO Meeting Abstracts for phase III randomized clinical trials (RCTs) testing ICIs in metastatic/advanced GE cancer from 2017 to 2023. Seven studies were included. OS was similar among all patients (HR 0.72 [0.67,0.77], p < .001), in patients without (HR 0.73 [0.67,0.81], p < .001, I2 = 0.0%), and with liver metastasis (HR 0.74 [0.67,0.81], p < .001, I2 = 0.0%). PFS was also similar among all patients (HR 0.63 [0.57,0.70], p < .001), without (HR 0.62 [0.51,0.76], p < .001), and with liver metastasis (HR 0.66 [0.57,0.76], p < .001). ICIs showed no difference in benefit in patients with GE cancer regardless of liver metastasis. Future studies could focus on deciphering the tumor microenvironment of liver metastasis as an area of translational research.

Cost-effectiveness analysis of Tumor Treating Fields treatment in Chinese patients with metastatic non-small cell lung cancer

BackgroundThe LUNAR trial demonstrated the significant efficacy and safety of Tumor Treating Fields (TTFields) plus standard-of-care (SOC) [immune checkpoint inhibitor (ICI) and docetaxel (DTX)] for patients with previously treated metastatic non-small cell lung cancer (mNSCLC). However, it remains uncertain as to whether the high costs are justified by the corresponding survival benefits. Here, the cost-effectiveness of using TTFields plus SOC for treating mNSCLC was evaluated from the perspective of the Chinese healthcare system.MethodsA Markov model with a 15-year time horizon was established and used to comparedeveloped to enable the simulation of treatment-associated costs and patient outcomes when comparing TTFields plus SOC to SOC alone. Primary outcomes for these analyses included total costs, life-years (LYs), quality-adjusted LYs (QALYs), and incremental cost-effectiveness ratio (ICER) values. The impact of paramere uncertainty on model outcomes was evaluated through sensitivity analyses. Additional subgroup and scenario analyses were also performed to extend these results.ResultsWhile TTFields plus SOC exhibited a $74,688 increase in total costs relative to SOC ($96,092 vs. $21,404), it was associated with 0.38 additional QALYs (1.08 vs. 0.82 QALYs) for an ICER of $284,490/QALY. This value exceeded the $35,983/QALY willingness-to-pay (WTP) threshold selected for these analyses by a wide margin. Relative to ICI and DTX treatment, the incremental costs of TTFields plus ICI and TTFields plus DTX were $78,115 and $71,307, respectively, with corresponding gains of 0.42 and 0.13 QALYs, yielding ICERs of $187,434/QALY, and $546,386/QALY. The parameter that most strongly impacted the results of these analyses was the cost of TTFields.ConclusionThe results indicated that given current treatment costs, TTFields plus SOC was insufficiently cost-effective in treating patients with mNSCLC in China, although TTFields plus ICI yields substantial health benefits.

Body composition derangements in lung cancer patients treated with first-line pembrolizumab: A multicentre observational study.

While immune checkpoint inhibitors (ICIs) are increasingly reshaping the therapeutic landscape of non-small-cell lung cancer (NSCLC), only a limited proportion of patients achieve a relevant and long-lasting benefit with these treatments, calling for the identification of clinical and, ideally modifiable, predictors of efficacy. Body composition phenotypes may reflect aspects of patients' immunology and thereby their ability to respond to ICIs. This study aims to explore the possible association between pre-treatment body composition phenotypes, tumour response, and clinical outcomes in patients receiving first-line pembrolizumab monotherapy for advanced NSCLC. A retrospective review of consecutive patients with treatment-naïve NSCLC and PD-L1 expression ≥50% undergoing pembrolizumab at three academic institutions was performed. Pre-treatment body composition parameters were measured at the third lumbar vertebra level by computed tomography, defined using pre-established cut-offs. Primary endpoint was objective response rate (ORR), secondary endpoints progression-free survival and overall survival (PFS and OS), compared through the log-rank test and the Cox proportional hazards model. Data from 134 patients (93 males [69.4%] and 41 females [30.6%]) were collected. Median age was 69years (range 36-85), with a median follow-up of 12months (range 1-131). The median body mass index (BMI) was 24.5 (IQR 21.5; 26.1) kg/m2. Overall, 59.0% and 51.5% of patients met established radiographic criteria for evidence of sarcopenia and myosteatosis, respectively, which occur across the BMI spectrum. Multivariate regression analysis, adjusted for co-morbidities, revealed that sarcopenia (aOR 5.56, 95% CI. 2.46-12.6, P<0.0001) and low intermuscular adipose tissue (IMAT) area (aOR 1.83, 95% CI. 1.22-2.83, P=0.001) were associated with a lower rate of ORR (30.4% vs. 70.5%, P<0.0001 and 30.7% vs. 73.2%, P<0.0001, respectively). Moreover, both in univariate and multivariate analysis, adjusted for co-morbidities, low performance status according to the Eastern Cooperative Oncology Group scale (ECOG PS), sarcopenia and low IMAT were significantly related to short PFS (ECOG PS: aHR 2.73, 95% CI 1.60-4.66, P<0.0001; sarcopenia: aHR 2.24, 95% CI 1.37-3.67, P=0.001; IMAT depot: aHR 2.26, 95% 1.40-3.63, P=0.002) and OS (ECOG PS: aHR 3.44, 95% CI 1.96-6.01, P<0.0001; sarcopenia: aHR 4.68, 95% CI 2.44-8.99, P<0.0001; IMAT depot: aHR 3.18, 95% 1.72-5.88, P<0.0001). Skeletal muscle abnormalities, apparently frequent in NSCLC, potentially represent intriguing predictive markers of response to ICIs and survival outcomes. Large prospective trials are needed to validate ICIs responders' clinical biomarkers.

Guiding treatment decisions in renal cell carcinoma: the role of biomarkers and clinical factors.

Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for metastatic renal cell carcinoma (mRCC), significantly improving overall survival and achieving durable responses. This review is timely due to the increasing number of ICI-based regimens now considered standard care for RCC. There is an urgent need to identify reliable biomarkers that can predict therapeutic responses and resistance, a key challenge in current research. While tumor-specific factors such as pathological characteristics, genomic mutations, and transcriptional profiles have been extensively studied, no definitive predictive biomarker has yet emerged. Additionally, advanced technologies are being explored to address tumor heterogeneity. Recent research has focused on novel areas such as the microbiome, radiomics, and spatial transcriptomics, which show promise as potential biomarkers. The translation of these emerging biomarker findings into clinical practice is essential to improving personalized treatment strategies for RCC. Until reliable biomarkers are clinically available, clinical factors may play a pivotal role in guiding individualized treatment decisions to optimize patient outcomes.

Medicinal Mishap: Immune checkpoint inhibitors and immune-related adverse events

Medicinal Mishap: Immune checkpoint inhibitors and immune-related adverse events

Immunotherapy in the Fight Against Bone Metastases: A Review of Recent Developments and Challenges.

Bone metastasis, a frequent and detrimental complication of advanced cancers, often triggers bone deterioration events that severely compromise patient quality of life and prognosis. The past few years have witnessed the emergence and continuous advancements in immunotherapy, ushering in innovative therapeutic prospects for bone metastasis. These advancements include not only the use of immune checkpoint inhibitors (ICIs), both as standalone and combined treatments, but also the investigation of novel targets within immune cells residing in bone metastases. These breakthroughs have instilled fresh optimism for effectively managing patients with bone metastasis. This article endeavors to present an exhaustive review of the recent progress made across a spectrum of immunotherapeutic strategies and targeted therapies specifically designed for individuals battling bone metastasis from malignant tumors. By doing so, it seeks to offer insights that can inform clinical practices and guide further medical research in this domain.

Conversion surgery for esophageal and esophagogastric junction cancer.

As a result of the recent advances in first-line treatment including chemotherapy, radiation therapy, targeted therapy, and immune checkpoint inhibitor immunotherapy (ICI) for locally advanced/metastatic initially unresectable esophageal and esophagogastric junction cancer, surgery aiming at cure after initial treatment, so-called "conversion surgery" has become more common in this field. Several studies have indicated encouraging survival outcomes for patients after conversion surgery with R0 resection. However, various issues, such the utility and the safety of conversion surgery remain unclear. In this review, we will focus on the surgical treatment for initially unresectable esophageal and esophagogastric junction cancer after first- or later- line treatment and review recent evidence regarding the safety and the efficacy of conversion surgery. Multidisciplinary treatment including surgery may serve as a novel treatment strategy for esophageal and esophagogastric junction cancer, thus provide a curative treatment option and potentially contribute to better prognosis for initially untreatable diseases.

Esophageal cancer: new developments in prevention and therapy

Esophageal carcinomas comprise 2 entities, squamous cell carcinoma and adenocarcinoma, which differ in pathogenesis and treatment. Elimination of inflammatory influences and risk factors, such as obesity and gastroesophageal reflux that contribute to a rising incidence of adenocarcinoma, is crucial for tumor prevention. In Germany, general endoscopic screening for upper GI tumors is not recommended, whereas endoscopic surveillance is applied in the presence of Barrett's metaplasia. In the future, better prediction models will be needed to identify patients at risk who will benefit from endoscopic surveillance. Precancerous lesions and early tumor stages can be removed endoscopically using modern resection methods. In recent years, therapeutic strategies for advanced esophageal tumors have undergone significant changes. In the multimodal treatment of locally advanced stages, radiochemotherapy remains to play a key role for squamous cell carcinoma, whereas new evidence highlights the importance of perioperative chemotherapy for the optimal management of adenocarcinoma. Systemic treatment options for both tumor entities have been significantly expanded due to the successful use of immune checkpoint inhibitors in adjuvant and palliative treatment regimen. Determination of PD-L1 and MSI status has therefore become decisive for the choice of therapy. In metastatic stages of adenocarcinoma, chemotherapy can now be supplemented by multiple antibodies directed against Her2, PD1, or claudin 18.2, and the antibody-drug conjugate trastuzumab deruxtecan has become a Her2-targeted option in second line treatment.