Recent Immunotherapy Research Articles

Post-intervention control in HIV immunotherapy trials.

While post-treatment control following interruption of standard-of-care antiretroviral therapy (ART) is well described, post-intervention control following immunotherapy in HIV cure-related clinical trials is less well understood. We provide an overview of recent studies that have identified post-intervention controllers and review the mechanisms that may drive this biologically important phenotype. Post-intervention controllers have been identified in recent immunotherapy trials testing broadly neutralizing antibodies, immune modulators, modified T cells, checkpoint inhibitors, and gene therapy administered individually or in combination. Currently, there is substantial variability in how each trial defines post-intervention control, as well as in how the mechanisms underlying such control are evaluated. Such mechanisms include ongoing activity of both exogenous and autologous antibodies, as well as changes in HIV-specific T cell function. While no therapeutic strategy to date has succeeded in definitively inducing HIV control, many studies have identified at least a small number of post-intervention controllers. The field would benefit from a standardized approach to defining and reporting this phenotype, as well as standardization in the approach to assessment of how it is achieved. Such efforts would allow for comparisons across clinical trials and could help accelerate efforts toward an HIV cure.

Immunotherapy-Based Strategies for Treatment of Type 1 Diabetes.

Type 1 diabetes (T1D) is more than an insulin-deficiency disease-it is an autoimmune disease, and the field is moving towards adopting disease-modifying immunotherapy as part of clinical care during T1D development. Recent successful immunotherapies as well as therapies that missed the mark are reviewed. T cell-directed therapies may allow for the greatest preservation of β cell function but also come with more side effects. Anti-cytokine therapies are very promising but likely need chronic administration. Antigen-specific therapies while safe have not produced meaningful results. Most successful trials have been conducted in adolescents and adults with stage 3 T1D (clinical T1D) with preserved C-peptide (up to 60% more compared to placebo) demonstrated 1-2 years post treatment. HbA1c and total insulin dose are less likely to be significantly different between treated and placebo groups because most participants in studies are meeting glycemic targets and because of the heterogeneous nature of these measures. In the prevention space (delaying progression from stage 2 to stage 3 T1D) the outcome is more discrete, and a T cell-directed therapy, teplizumab, has received FDA approval. Even negative studies with promising mechanistic and safety profiles have added value. What is clear, a single administration or short course of an immunotherapy is unlikely to provide sustained freedom from exogenous insulin.

Narrative review on efficacy and safety of anti-angiogenesis in combination with immunotherapy in the treatment of breast cancer.

Breast cancer was the second frequently diagnosed cancer in 2022 among all cancers. Besides classical chemotherapy and radiation, immunotherapy and targeted therapy are both identical treatment options for patients with advanced breast cancer. Immunotherapy is a therapeutic approach to control and eliminate tumors by restarting and maintaining the tumor-immunity cycle and restoring the body's normal anti-tumor immune response. Immunotherapy alone or in combination with other therapies has been shown to be clinically beneficial in a variety of solid tumors with a manageable safety profile. However, immunotherapy alone cannot fully satisfy the therapeutic needs for patients with breast cancer. Therefore, there is an urgent need for immunotherapy to be combined with other therapeutic approaches to increase treatment efficacy. We systematically searched PubMed database for relevant studies published over the past 5 years. Articles were screened for eligibility and key data extracted. We assess the current breast cancer treatment landscape, summarizing efficacy and safety of recent immunotherapy, chemotherapy combined with immunotherapy, immunotherapy combined with anti-angiogenic therapy. In the treatment of breast cancer, aiming to promote further research and applications of this novel treatment regimen in patients with breast cancer. Since anti-angiogenic therapy can reprogramme the tumor immune microenvironment, immunotherapy in combination with anti-angiogenic therapy might have a synergistic effect, igniting a new hope for immunotherapy for breast cancer patients. The review's conclusions offer insightful information on the state of breast cancer treatment today. In the end, improving clinical practice and pertinent research for immunotherapy combination therapy will contribute to bettering patient outcomes, raising quality of life, and creating more potent treatments. This review emphasizes the potential of immunotherapy combinations, especially with anti-angiogenic therapeutic regimens, as a viable strategy for the treatment of breast cancer through a thorough study of the literature. To improve treatment approaches, lessen side effects for patients, and find trustworthy biomarkers to forecast response to immunotherapy combo medicines, further research is necessary.

Personalized treatment approach for HER2-positive metastatic breast cancer.

Breast cancer (BC) is a leading global concern for women, with 30% being HER2-positive cases linked to poorer outcomes. Targeted therapies like trastuzumab deruxtecan (T-DXd), trastuzumab, pertuzumab, and T-DM1 have revolutionized HER2-positive metastatic breast cancer (MBC) treatment. Although these therapies have improved MBC management and patient outcomes, resistance can develop, reducing effectiveness. Personalized strategies based on tumor characteristics offer hope for better responses and longer outcomes. This review outlines insights into MBC patients responding well to anti-HER2 treatments, even across multiple treatment regimen. Recent immunotherapy, locoregional therapy, and liquid biopsy breakthroughs are covered, suggesting ways to increase long-term responders. Personalized approaches have boosted HER2-positive MBC outcomes, and ongoing research is crucial to uncover new treatments and biomarkers, potentially elevating long-term response rates and prognoses. This may aid in providing new direction to breast cancer clinics.

Emerging immunologic approaches as cancer anti-angiogenic therapies.

Targeting tumor angiogenesis, the formation of new blood vessels supporting cancer growth and spread, has been an intense focus for therapy development. However, benefits from anti-angiogenic drugs like bevacizumab have been limited by resistance stemming from activation of compensatory pathways. Recent immunotherapy advances have sparked interest in novel immunologic approaches that can induce more durable vascular pruning and overcome limitations of existing angiogenesis inhibitors. This review comprehensively examines these emerging strategies, including modulating tumor-associated macrophages, therapeutic cancer vaccines, engineered nanobodies and T cells, anti-angiogenic cytokines/chemokines, and immunomodulatory drugs like thalidomide analogs. For each approach, the molecular mechanisms, preclinical/clinical data, and potential advantages over conventional drugs are discussed. Innovative therapeutic platforms like nanoparticle delivery systems are explored. Moreover, the importance of combining agents with distinct mechanisms to prevent resistance is evaluated. As tumors hijack angiogenesis for growth, harnessing the immune system's specificity to disrupt this process represents a promising anti-cancer strategy covered by this review.

Natural killer cells in neuroblastoma: immunological insights and therapeutic perspectives.

Natural killer (NK) cells have multifaceted roles within the complex tumor milieu. They are pivotal components of innate immunity and shape the dynamic landscape of tumor-immune cell interactions, and thus can be leveraged for use in therapeutic interventions. NK-based immunotherapies have had remarkable success in hematological malignancies, but these therapies are met with many challenges in solid tumors, including neuroblastoma (NB), a childhood tumor arising from the sympathetic nervous system. With a focus on NB, this review outlines the mechanisms employed by NK cells to recognize and eliminate malignant cells, delving into the dynamic relationship between ligand-receptor interactions, cytokines, and other molecules that facilitate the cross talk between NK and NB cells. We discuss the immunomodulatory functions of NK cells and the mechanisms that contribute to loss of this immunosurveillance in NB, with a focus on how this dynamic has been utilized in recent immunotherapy advancements for NB.

Early defibrotide therapy and risk factors for post-transplant veno-occlusive disease/sinusoidal obstruction syndrome in childhood.

Veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is a life-threatening complications of hematopoietic cell transplantation (HCT). We studied the impact of early defibrotide (DF) therapy on the outcomes of pediatric patients with VOD/SOS after transplantation, focusing on recent immunotherapies. A total of 111 pediatric patients who underwent HCT for malignant disease between February 2017 and March 2023 at Kyushu University Hospital were included. Among 111 patients of less than 20years of age who underwent HCT for malignancy at a single institution between 2017 and 2023, VOD/SOS occurred in 25 (23%) patients. VOD/SOS developed more frequently in the post-DF era (2020-2023, n=58) than in the pre-DF era (31% vs. 13%, p=.04). The proportion of patients with relapsed/refractory acute lymphoblastic leukemia (ALL) was higher in the post-DF era than in the pre-DF era (44% vs. 8%, p=.04). Early DF therapy that was started at two European Society for Blood and Marrow Transplantation diagnostic criteria reduced the severity of VOD/SOS (p<.01) in comparison to non-early therapy started at less than two criteria. A multivariate analysis indicated that a history of cytokine release syndrome (odds ratio [OR]=10.4, p=.01) and juvenile myelomonocytic leukemia (OR=8.98, p=.04), but not an endothelial activation and stress index (EASIX) score of greater than 0.85, were independent risk factors for VOD/SOS. Early DF therapy improves the severity and survival outcomes of post-transplant VOD/SOS in children. However, its incidence is increasing in the era of immunotherapy for progressive diseases.

Efficacy and safety of palliative treatment in patients with autoimmune liver disease-associated hepatocellular carcinoma

Introduction and ObjectivesAutoimmune liver diseases (AILD) are rare causes hepatocellular carcinoma (HCC), and data on the efficacy and tolerability of anti-tumor therapies are scarce. This pan-European study aimed to assess outcomes in AILD-HCC patients treated with tyrosine kinase inhibitors (TKIs) or transarterial chemoembolization (TACE) compared with patients with more common HCC etiologies, including viral, alcoholic or non-alcoholic fatty liver disease. Materials and Methods107 patients with HCC-AILD (AIH:55; PBC:52) treated at 13 European centres between 1996 and 2020 were included. 65 received TACE and 28 received TKI therapy. 43 (66 %) were female (median age 73 years) with HCC tumor stage BCLC A (34 %), B (46 %), C (9 %) or D (11 %). For each treatment type, propensity score matching was used to match AILD to non-AILD-HCC on a 1:1 basis, yielding in a final cohort of 130 TACE and 56 TKI patients for comparative analyses of median overall survival (mOS) and treatment tolerability. ResultsHCC-AILD patients showed comparable mOS to controls for both TACE (19.5 vs. 22.1 months, p = 0.9) and TKI (15.4 vs. 15.1 months, p = 0.5). Adverse events were less frequent in AILD-HCC patients than controls (33 % % vs. 62 %, p = 0.003). For TKIs, there were no significant differences in adverse events (73% vs. 86%, p = 0.2) or interruption rates (44% vs. 36 %, p = 0.7). ConclusionsIn summary, this study demonstrates comparable mOS for AILD-HCC patients undergoing local and systemic treatments, with better tolerability than HCC of other causes. TKIs remain important therapeutic options for AILD-HCC patients, particularly given their exclusion from recent immunotherapy trials.

Lessons from Post-Immunotherapy Tumor Tissues in Clinical Trials: How Can We Fuel the Tumor Microenvironment in Gliomas?

Despite recent advancements in cancer immunotherapy, many patients with gliomas and glioblastomas have yet to experience substantial therapeutic benefits. Modulating the tumor microenvironment (TME) of gliomas, which is typically "cold", is crucial for improving treatment outcomes. Clinical tumor specimens obtained post-immunotherapy provide invaluable insights. However, access to such post-immunotherapy samples remains limited, even in clinical trials, as tumor tissues are often collected only at tumor relapse. Recent studies of neoadjuvant immunotherapy provided important insights by incorporating surgical resections of post-treatment tumors. Moreover, pre-surgical immunotherapies are increasingly integrated into clinical trial designs to evaluate treatment efficacy. These investigations reveal critical information, particularly regarding the delivery success of therapeutic agents, the expansion and persistence of immune products, and the cellular and molecular changes induced in the TME. In this review, we assess the findings on post-treatment tumor specimens obtained from recent immunotherapy clinical trials on gliomas, highlight the importance of these samples for understanding therapeutic impacts, and discuss proactive investigation approaches for future clinical trials.

Self-modifying NanoEnhancers facilitating lysosomal escape for cGAS-STING cascading activation in tumor immunotherapy

Targeting mitochondria has emerged as an effective approach in recent tumor immunotherapy. While nanosized carriers have been utilized for therapeutic drug delivery, their retention in lysosomes diminishes their efficacy in targeting mitochondria. Despite the use of polycationic materials and peptides to facilitate lysosomal escape through the proton sponge effect and destabilization of lysosomal membranes, concerns persist regarding their stability and biocompatibility. Our objective is to exploit Oroxylin A (OA), a polyphenolic compound, to synthesize metal-polyphenolic complexes, capitalizing on OA's inherent lysosomal self-modifying properties to achieve efficient lysosomal escape. Herein, we report the fabrication of polyphenol-based OA@Mn@3-TYP nanoenhancers, assembled with hyaluronic acid (HA) and denoted as OMT NEs, designed for effective lysosomal escape and targeted drug delivery to mitochondria. These nanoenhancers exhibit a positive targeting ability towards tumor cells and facilitate lysosomal escape through spontaneous glucuronidation and sialic acid transporter mechanisms. The incorporation of OA and 3-TYP in the nanoenhancers leads to a cascading effect resulting in mitochondrial dysfunction and subsequent release of mitochondrial DNA (mtDNA). Upon activation of the Mn2+-enhanced cGAS-STING pathway by the released mtDNA, a synergistic anti-PD-1 immunotherapy effect is augmented, ultimately enhancing anti-tumor treatment.

COVID vs. non-COVID oncology patient cohorts: Demographics and cancer variables.

e23046 Background: This study aimed to compare demographics and cancer-specific variables in oncology patients hospitalized with (n = 551) and without COVID-19 (n = 3674) during the first year of the pandemic. Methods: We analyzed prospectively collected data from March 2020 to February 2021 at a major US cancer center, comparing age, sex, cancer category, race, metastasis, treatments within one month prior to admission, and smoking history. Results: The study found no significant difference in mean age between COVID and non-COVID cohorts (60.7% vs. 60.9%; p = 0.830). Significant differences (p = 0.002) in cancer categories were noted between COVID and non-COVID cohorts. Hematological cancers had the highest hospitalization rates in both groups (38.8% vs 29.2%). Statistically significant racial differences were observed between COVID and non-COVID cohorts (p &lt; 0.001). Whites had the highest hospitalization rates in both groups, yet COVID-related admissions were lower for Whites (COVID cohort: 51.2% vs non-COVID cohort: 61.9%) and Asians (COVID cohort: 2.7% vs non-COVID cohort: 5.9%) compared to non-COVID admissions, while higher for Blacks (COVID cohort: 15.4% vs non-COVID cohort: 14%) and Hispanics (COVID cohort: 28.3% vs non-COVID cohort: 15.7). Significant differences (p &lt; 0.001) were noted in metastasis prevalence between COVID and non-COVID hospitalizations, with rates of 81.3% and 86.0%, respectively. Conversely, non-metastatic cancer was more prevalent in COVID hospitalizations (18.1%) than in the non-COVID cohort (8.7%). In the COVID cohort, 30.5% received chemotherapy within one month before admission, compared to 43.8% in the non-COVID cohort, showing a significant difference in admission rates (p &lt; 0.001). Similarly, recent immunotherapy (8.0% vs. 10.9%) and recent surgery (3.6% vs. 6.6%) were associated with higher hospitalization rates in the non-COVID cohort (p = 0.046 and p = 0.010, respectively). We observed significant differences (p &lt; 0.001) in the smoking history of the COVID and. non-COVID cohorts. While 2.5% of COVID patients were current smokers, 5.4% of non-COVID patients were, more than double the COVID rate. In the COVID cohort, 36.3% were former smokers, slightly lower than the 37.6% in the non-COVID cohort. Additionally, 59.3% of COVID patients were never smokers, compared to 56.3% in the non-COVID group. Conclusions: COVID-related admissions were lower for Whites and Asians compared to non-COVID admissions, while higher for Blacks and Hispanics. Lower rates of metastasis were noted in COVID cohort. Lower rates of hospitalizations among patients who received chemotherapy, immunotherapy, and surgery were observed in the COVID cohort. The smoking prevalence was higher in the non-COVID group, former smoking rates were similar across cohorts, and a higher proportion of COVID patients were never smokers.

Risk versus Benefit of Tyrosine Kinase Inhibitors for Hepatocellular Carcinoma: ASystematic Review and Meta-Analysis of Randomized Controlled Trials.

Although the treatment landscape has rapidly evolved over the last years, hepatocellular carcinoma (HCC) is one of the most lethal cancers. With recent advances, both immunotherapy and tyrosine kinase inhibitors (TKIs)-based chemotherapy constitute the standard treatment for advanced HCC. A systematic search of randomized clinical trials employing TKIs was performed in 17 databases, obtaining 25 studies evaluating the prognosis, tumor response, and presence of adverse events (AEs) related to TKIs in HCC. Overall effect sizes were estimated for the hazard ratios (HR) and odds ratios (OR) with 95% confidence interval (CI), either extracted or calculated with the Parmar method, employing STATA 16. Heterogeneity was assessed by Chi-square-based Q-test and inconsistency (I2) statistic; source of heterogeneity by meta-regression and subgroup analysis; and publication bias by funnel plot asymmetry and Egger's test. The research protocol was registered in PROSPERO (CRD42023397263). Meta-analysis revealed a correlation between survival and tumor response parameters and TKI treatment vs. placebo, despite detecting high heterogeneity. Combined TKI treatment showed a significantly better objective response rate (ORR) with no heterogeneity, whereas publication bias was only detected with time to progression (TTP). Few gastrointestinal and neurological disorders were associated with TKI treatment vs. placebo or with combined treatment. However, a higher number of serious AEs were related to TKI treatment vs. sorafenib alone. Results show positive clinical benefits from TKI treatment, supporting the approval and maintenance of TKI-based therapy for advanced HCC, while establishing appropriate strategies to maximize efficacy and minimize toxicity.

The fusion of light and immunity: Advancements in photoimmunotherapy for melanoma.

Metastatic melanoma is an aggressive skin cancer with high mortality and recurrence rates. Despite the clinical success of recent immunotherapy approaches, prevailing resistance rates necessitate the continued development of novel therapeutic options. Photoimmunotherapy (PIT) is emerging as a promising immunotherapy strategy that uses photodynamic therapy (PDT) to unleash systemic immune responses against tumor sites while maintaining the superior tumor-specificity and minimally invasive nature of traditional PDT. In this review, we discuss recent advances in PIT and strategies for the management of melanoma using PIT. PIT can strongly induce immunogenic cell death, inviting the concomitant application of immune checkpoint blockade or adoptive cell therapies. PIT can also be leveraged to selectively remove the suppressive immune populations associated with immunotherapy resistance. The modular nature of PIT therapy design combined with the potential for patient-specific antigen selection or drug co-delivery makes PIT an alluring option for future personalized melanoma care.

Protein Arginine Methyltransferases in Pancreatic Ductal Adenocarcinoma: New Molecular Targets for Therapy.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignant disease with a low 5-year overall survival rate. It is the third-leading cause of cancer-related deaths in the United States. The lack of robust therapeutics, absence of effective biomarkers for early detection, and aggressive nature of the tumor contribute to the high mortality rate of PDAC. Notably, the outcomes of recent immunotherapy and targeted therapy against PDAC remain unsatisfactory, indicating the need for novel therapeutic strategies. One of the newly described molecular features of PDAC is the altered expression of protein arginine methyltransferases (PRMTs). PRMTs are a group of enzymes known to methylate arginine residues in both histone and non-histone proteins, thereby mediating cellular homeostasis in biological systems. Some of the PRMT enzymes are known to be overexpressed in PDAC that promotes tumor progression and chemo-resistance via regulating gene transcription, cellular metabolic processes, RNA metabolism, and epithelial mesenchymal transition (EMT). Small-molecule inhibitors of PRMTs are currently under clinical trials and can potentially become a new generation of anti-cancer drugs. This review aims to provide an overview of the current understanding of PRMTs in PDAC, focusing on their pathological roles and their potential as new therapeutic targets.

Characterization of Immune Cell Heterogeneity, Key B Cell Subtypes, and Macrophages Functions Using Multiplex Immunofluorescence and Single-cell RNA Sequencing in Chordomas

INTRODUCTION: Chordomas are rare tumors that arise from remnants of the notochord. The standard of care for chordoma remains only surgery and radiotherapy. Though checkpoint inhibition therapy shows promise, recent immunotherapy trials failed to reach endpoints. This emphasizes the need to comprehensively understand the tumor and peripheral immune landscape of chordomas to establish a rationale for immunotherapeutic intervention. METHODS: We analyzed and quantified the immune cell composition (CD3+, CD4+, CD8+, CD20+, and CD163+ cells) of 33 chordomas (14 clival, 3 cervical, 2 lumbar, and 14 sacral tumors) through multiplex immunofluorescence. In addition, we investigated the phenotype of tumor-infiltrating and peripheral B cells and myeloid cells from five chordoma patients employing single-cell RNA sequencing. RESULTS: Hierarchical clustering analysis of 33 chordomas identified 3 distinct clusters based on the relative abundance of B cells, T cells, and macrophages. Cluster 1 was characterized by moderate immune cell infiltration, cluster 2 was immune-desertic, and cluster 3 was highly infiltrated by B and T cells. Findings from single-cell transcriptomics revealed that regulatory B cells and plasma cells were the most abundant B cell populations infiltrating tumors. In addition, we found the presence of tumor-infiltrating macrophages with angiogenic and complement-related functions. CONCLUSIONS: Our study provides crucial insights into the immune landscape of chordomas. The identification of distinct clusters based on immune cell infiltration emphasized the heterogeneity of chordomas. The findings from this study may serve as a foundation for future research and the development of targeted immunotherapies for chordomas.

The mechanism and eciency of mRNA-based dendritic cell immunotherapy

In the recent years, the mentions of immunotherapy has become more and more frequent. What emerged along with it are the various types of immunotherapies. This essay includes an introduction to cancer and tumor with the denition, epidemiology, etiology, statistics such as curability regarding types, gender, and race and typical treatments of cancer along with how the immune system functions when targeting tumor cells and how they could potentially disfunction when deceived by tumor cells for example through immune editing. Then, leading on to the main topic to this recent and innovative treatment immunotherapy. This essay emphasizes on two different types of immunotherapy which are dendritic cell therapy, and messenger RNA vaccine discussing their mechanism as separate treatments. Afterwards, Ill proceed to discuss the combination of the two which is known as dendritic cell based mRNA vaccine which is a form of mRNA vaccine and its own mechanism, advantages, eciency and current limitations in the conclusion.

Engineered Tumor-Immune Microenvironment On A Chip to Study T Cell-Macrophage Interaction in Breast Cancer Progression.

Evolving knowledge about the tumor-immune microenvironment (TIME) is driving innovation in designing novel therapies against hard-to-treat breast cancer. Targeting the immune components of TIME has emerged as a promising approach for cancer therapy. While recent immunotherapies aim at restoring antitumor immunity, counteracting tumor escape remains challenging. Hence there is a pressing need to better understand the complex tumor-immune crosstalk within TIME. Considering this imperative, this study aims at investigating the crosstalk between the two abundant immune cell populations within the breast TIME-macrophages and T cells, in driving tumor progression using an organotypic 3D in vitro tumor-on-a-chip (TOC) model. The TOC features distinct yet interconnected organotypic tumor and stromal entities. This triculture platform mimics the complex TIME, embedding the two immune populations in a suitable 3D matrix. Analysis of invasion, morphometric measurements, and flow cytometry results underscores the substantial contribution of macrophages to tumor progression, while the presence of T cells is associated with a deceleration in the migratory behavior of both cancer cells and macrophages. Furthermore, cytokine analyses reveal significant upregulation of leptin and RANTES (regulated on activation, normal T Cell expressed and secreted)in triculture. Overall, this study highlights the complexity of TIME and the critical role of immune cells in cancer progression.

Genome Engineering as a Therapeutic Approach in Cancer Therapy: A Comprehensive Review.

Cancer is one of the foremost causes of mortality. The human genome remains stable over time. However, human activities and environmental factors have the power to influence the prevalence of certain types of mutations. This goes to the excessive progress of xenobiotics and industrial development that is expanding the territory for cancers to develop. The mechanisms involved in immune responses against cancer are widely studied. Genome editing has changed the genome-based immunotherapy process in the human body and has opened a new era for cancer treatment. In this review, recent cancer immunotherapies and the use of genome engineering technology are largely focused on.

Immune checkpoint blockade combined with targeted therapies to provide disease control in mismatch repair-proficient colorectal cancer with peritoneal metastases.

133 Background: Metastatic colorectal adenocarcinoma (mCRC) with proficient mismatch repair (pMMR) is associated with poor response to cytotoxic chemotherapy in the refractory setting, with a median overall survival (OS) of 10.8 months. Recent immunotherapy (IO) regimens utilizing a combination of immune checkpoint blockade (ICB) and tyrosine kinase inhibitors (TKIs) that suppress tumor-associated macrophages (TAMs) have shown promise for extra-hepatic, but not hepatic metastases. However, few studies include patients with peritoneal metastases (PMs) and the response rate of PMs to these therapies is unknown. We sought to examine the disease control rates (DCR) and OS of patients treated with PM who were treated with ICB regimens. Methods: Patients with pMMR tumors treated with ICB and TKI after progression on 1st and 2nd-line therapy from 2015 to 2022 were identified. Date of start of therapy, end of therapy, last follow up and vital status were determined from the medical record. Radiographic disease response within each metastasis site at 6 months and at last follow-up on therapy was determined for each patient. Overall survival was estimated using the Kaplan-Meier method. Results: A total of 93 patients treated with an ICB and TKI after at least two lines of cytotoxic systemic therapy were identified. Five were excluded due to dMMR/MSI-H status and eight due to lack of follow-up. A total of 33 patients with PM, with or without other metastases, had a median follow-up on therapy of 6.1 months and median follow-up until death or censoring of 9.8 months. Median OS was 15.1 (9.7-29.5) months, and 18-month survival was 43% (95%CI: 24-62%). OS was not associated with either BRAF (HR 0.98, 0.38-2.6, p=0.98) or RAS (HR 1.50, 0.62- 3.63, p=0.37) mutation status. Partial response of PM was noted in 5 patients (15%), stable disease in 14 (42%) and progressive disease in 14 (42%), resulting in DCR of 57%. Disease control for all metastatic sites was noted in 9 (27%) of patients, and median OS was not reached at 2 years. Median OS for patients without peritoneal progression was 22.0 months [12.3-NR], and PM progression was associated with worse OS (HR 0.66, p=0.024). A total of 32 patients with any metastatic site were treated for at least 6 months. Median follow-up was 16.1 months for this cohort. DCR at 6 months for CRLM was 23% (3/13), PM was 58% (14/24, p=0.08 vs CRLM) and for LM was 62% (8/13, p=0.11 vs CRLM). Conclusions: Response to ICB and targeted therapy combinations can vary widely by metastatic site, with liver trending towards less response than peritoneum or lung. Disease control in the peritoneum can be achieved in the majority of patients, and median OS compares favorably to standard-of-care therapy in the refractory setting. Patients with peritoneal disease should be included in future trials of ICBs as treatment options are otherwise limited.

Lung Cancer Related Thrombosis (LCART): Focus on Immune Checkpoint Blockade.

Cancer-associated thrombosis (CAT) is a common complication in lung cancer patients. Lung cancer confers an increased risk of thrombosis compared to other solid malignancies across all stages of the disease. Newer treatment agents, including checkpoint immunotherapy and targeted agents, may further increase the risk of CAT. Different risk-assessment models, such as the Khorana Risk Score, and newer approaches that incorporate genetic risk factors have been used in lung cancer patients to evaluate the risk of thrombosis. The management of CAT is based on the results of large prospective trials, which show similar benefits to low-molecular-weight heparins (LMWHs) and direct oral anticoagulants (DOACs) in ambulatory patients. The anticoagulation agent and duration of therapy should be personalized according to lung cancer stage and histology, the presence of driver mutations and use of antineoplastic therapy, including recent curative lung surgery, chemotherapy or immunotherapy. Treatment options should be evaluated in the context of the COVID-19 pandemic, which has been shown to impact the thrombotic risk in cancer patients. This review focuses on the epidemiology, pathophysiology, risk factors, novel predictive scores and management of CAT in patients with active lung cancer, with a focus on immune checkpoint inhibitors.