Search Results (3,613)

Richter’s syndrome (RS) or transformation of chronic lymphocytic leukemia (CLL) into a more aggressive lymphoma (e.g., diffuse large B cell lymphoma, DLBCL) is a distinct disease that portends an overall poor prognosis and remains a challenge for clinicians to identify and treat effectively. This review of the current literature focuses on the pathology, diagnosis, and management of Richter’s syndrome. Clonally related RS has been found to have a worse prognosis than unrelated disease and the genomic profile of DLBCL-RS differs from that of de novo DLBCL. The standard of care therapy for RS has historically been chemoimmunotherapy; consolidative stem cell transplants have a role in improving durability of disease response. Given generally poor response rates to chemotherapy, there have been recent investigations into combination treatments with immune checkpoint inhibitors and small molecule targeted therapies, which have had mixed results. Additional studies are evaluating the use of bispecific antibodies, chimeric antigen receptor T cell therapy, and antibody drug conjugates. RS remains difficult to manage; however, advancements in the understanding of the underlying pathology of transformation and continued investigations into new therapies demonstrate promise for the future. Full article

Background/Objectives: Anal cancer is a rare malignancy with limited treatment options. Immune checkpoint inhibitors have shown benefits in some patients with metastatic disease, but predictive factors for immunotherapy response remain undefined. This study retrospectively evaluated clinical and pathological features associated with survival outcomes in metastatic anal cancer treated with immunotherapy. Methods: Data from 105 patients with metastatic anal cancer were analyzed. Kaplan–Meier analysis was used to estimate progression-free survival (PFS) and overall survival (OS), with subgroup comparisons utilizing the Mantel–Cox test. Associations between survival and clinicopathologic features were assessed with Fisher’s exact test. Results: Of the patients, 69 (65.7%) received immunotherapy during the first three treatment lines. With a median follow-up of 23.2 months, the median PFS for first-, second-, and third-line systemic therapies was 7.2, 3.7, and 4.7 months, respectively (χ² = 14.2; p < 0.001). In the treatment-refractory setting, median PFS was similar for immunotherapy and chemotherapy: 3.6 months (95% CI, 2.3–4.9) vs. 4.4 months (95% CI, 3.8–5.0), respectively (HR 0.89, 95% CI 0.60–1.3; p = 0.52). Among patients treated with immunotherapy, patients with lymph node-only metastases had significantly prolonged PFS compared to patients with visceral organ involvement (11.3 vs. 3.1 months; HR 0.49, 95% CI 0.21–0.74; p = 0.03). Conclusions: Patients with lymph node-only metastatic anal cancer experienced significantly prolonged PFS with immunotherapy relative to those with involvement of other distant organs, highlighting a distinct subgroup of patients who may benefit from immunotherapy. We also contextualize PFS outcomes across treatment lines for metastatic anal cancer, which can be applied towards the design of future immunotherapy clinical trials. Full article

Phosphoinositide 3-kinases (PI3Ks), members of the lipid kinase family, play a significant role in modulating immune cell functions, including activation, proliferation, and differentiation. Recent studies have identified the PI3K signaling pathway as a key regulator in tumor biology and the immune microenvironment. This pathway enhances the activity of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), contributing to an immunosuppressive tumor microenvironment that impairs the effectiveness of cancer vaccines and immunotherapies. The present study explores PI3K isoforms, particularly p110γ and p110δ, and their associated signaling pathways. The therapeutic potential of selective PI3K inhibitors and their capacity to act synergistically with immunization strategies are analyzed. Targeting the PI3K signaling pathway represents a promising approach to counteract tumor-induced immune suppression and improve the efficacy of immune checkpoint inhibitors and vaccines, ultimately leading to better clinical outcomes. Full article

Chronic viral infections like HIV, HBV, and HCV establish persistent interactions with the host immune system, resulting in immune evasion and long-term immune dysfunction. These viruses use a range of strategies to limit host defenses, such as downregulating MHC class I, disrupting interferon signaling, altering apoptosis pathways, and suppressing cytotoxic T-cell activity. Key viral proteins, including HIV Nef, HBV X protein, and HCV NS5A, interfere with antigen presentation and JAK/STAT signaling, thereby reducing antiviral immune responses. Chronic infections induce immune exhaustion due to persistent antigen exposure, which leads to the expression of inhibitory receptors like PD-1 and CTLA-4 on T cells. Viral epigenetic changes, such as N6-methyladenosine modifications and histone deacetylation, enhance immune evasion by modulating gene expression in infected cells. Viruses further manipulate host cytokine networks by promoting an immunosuppressive environment through IL-10 and TGF-β secretion, which suppress inflammatory responses and inhibit T-cell activation. This review examines the molecular/cellular mechanisms that enable chronic viruses to escape host immunity, focusing on antigenic variation, cytokine disruption, and control of apoptotic pathways. It also addresses how host genetic factors, such as HLA polymorphisms, influence disease progression. Lastly, we discuss host-targeted therapies, including immune checkpoint inhibitors, cytokine treatments, and CRISPR. Full article

Cancer-related cognitive decline refers to a deterioration in cognitive function affecting adults with cancer at any stage of their cancer journey. Older adults are at increased risk of cognitive decline. As the indications for immune checkpoint inhibitors expand in the treatment of cancer, understanding the potential complicating cognitive issues experienced by those receiving this therapy will be important. The aim of this scoping review is to identify the literature regarding immune checkpoint inhibitors and subjective/objective decline, to identify evidence in older adults, differences between older and younger adults, and outline areas for further research. Four large electronic databases were searched. Records were screened using standardised methodology. Ten studies were identified that met the inclusion criteria for review. Six studies objectively evaluated cognitive function in adults receiving ICI treatment; eight studies performed subjective cognitive assessments. There were differences identified in the cognitive assessment tools used and the methodology between studies. Few studies reported on age-dependent findings. The results of this scoping review highlight the need for further research in this area using standardised methodology and testing, with a particular focus on the cognitive outcomes of older adults who may be at increased risk of developing cognitive decline while on treatment. Full article

Osteosarcoma (OS) is the predominant mesenchymal primary malignant bone tumor in oncology and pathology, impacting a wide age range from adolescents to older adults. It frequently advances to lung metastasis, ultimately resulting in the mortality of OS patients. The precise pathological pathways responsible for OS progression and dissemination are not fully understood due to its heterogeneity. The integration of surgery with neoadjuvant and postoperative chemotherapy has significantly increased the 5-year survival rate to more than 70% for patients with localized OS tumors. However, about 30% of patients experience local recurrence and/or metastasis. Hence, there is a requirement for innovative therapeutic approaches to address the limitations of traditional treatments. Immunotherapy has garnered increasing attention as a promising avenue for tumors resistant to standard therapies, including OS, despite the underlying mechanisms of disease progression and dissemination remaining not well elucidated. Immunotherapy may not have been suitable for use in patients with OS because of the tumor’s immunosuppressive microenvironment and limited immunogenicity. Nevertheless, there are immune-based treatments now being developed for clinical use, such as bispecific antibodies, chimeric antigen receptor T cells, and immune checkpoint inhibitors. Also, additional immunotherapy techniques including cytokines, vaccines, and modified-Natural Killer (NK) cells/macrophages are in the early phases of research but will certainly be popular subjects in the nearest future. Our goal in writing this review was to spark new lines of inquiry into OS immunotherapy by summarizing the findings from both preclinical and current clinical studies examining different approaches. Full article

Treatment of resectable advanced-stage melanoma with neoadjuvant immunotherapy is rapidly becoming the new standard of care due to significant improvements in event-free survival (EFS) compared to surgery first followed by immunotherapy. The level of responsiveness seen in patients receiving immune checkpoint inhibitors (ICIs) must be mechanistically understood not only for the standardization of treatment but also to advance the novel concept of personalized cancer immunotherapy. This review aims to elucidate markers of the tumor microenvironment (TME) and blood that can predict treatment outcome. Interestingly, the canonical proteins involved in the molecular interactions that immunotherapies aim to disrupt have not been consistent indicators of treatment response, which amplifies the necessity for further research on the predictive model. Other major discussions surrounding neoadjuvant therapy involve the higher-level investigation of ICI efficacy due to the ability to examine a post-treatment tumor molecularly and pathologically, which this review will also cover. As neoadjuvant ICI becomes the standard of care in advanced melanoma treatment, further research aiming to identify more predictive biomarkers of treatment response to advance medical decision-making and patient care should continue to be sought after. Full article

Non-small-cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. Immunotherapy targeting the PD-1/PD-L1 axis has revolutionized treatment, providing durable responses in a subset of patients. However, with fewer than 50% of patients achieving significant benefits, there is a critical need to expand therapeutic strategies. This review explores emerging targets in immune checkpoint inhibition beyond PD-1/PD-L1, including CTLA-4, TIGIT, LAG-3, TIM-3, NKG2A, and CD39/CD73. We highlight the biological basis of CD8 T cell exhaustion in shaping the antitumor immune response. Novel therapeutic approaches targeting additional inhibitory receptors (IR) are discussed, with a focus on their distinct mechanisms of action and combinatory potential with existing therapies. Despite significant advancements, challenges remain in overcoming resistance mechanisms and optimizing patient selection. This review underscores the importance of dual checkpoint blockade and innovative bispecific antibody engineering to maximize therapeutic outcomes for NSCLC patients. Full article

Background: Platinum-based chemotherapy (PBC) followed by avelumab maintenance is a treatment option for patients with advanced urothelial carcinoma (aUC) patients. However, the optimal treatment sequencing in the era of antibody–drug conjugates (ADCs) is yet to be determined. Recent studies suggest that the timing of immune checkpoint inhibitor (ICI) administration may impact patient outcomes, with a potential benefit from morning infusions. Methods: This retrospective study included 105 patients with aUC treated with avelumab in Portugal and intended to assess the safety and clinical outcomes (progression-free survival (PFS), overall survival (OS), and overall response rate (ORR)) and evaluate the impact of treatment timing (morning vs. afternoon) on patient outcomes. Results: The median follow-up from the start of avelumab was 17.7 months, the median PFS (mPFS) was 9.8 months (95% CI 4.9–14.7), and the median OS (mOS) was 39.5 months (95% CI 13.2–65.7). Immune-related adverse events (irAEs) were reported in 65.8% of patients, with 6.7% experiencing G3 irAEs. Among those who received a subsequent-line ADC upon disease progression (43%), the mOS from the start of avelumab was 23.1 months (95% CI 9.2–37.0). Multivariate analysis showed significant improvement in mOS with morning avelumab infusions (HR 0.35, 95% CI: 0.12–0.97, p = 0.042) and a trend towards improved mPFS (HR 0.43, 95% CI: 0.179–1.02, p = 0.055). Conclusions: This study confirms the clinical efficacy and safety of avelumab, showing improved outcomes over JAVELIN Bladder 100 and suggesting that morning infusions may offer a survival benefit in this context. Further research is needed to optimize treatment sequencing and explore the impact of infusion timing in ICI strategies. Full article

This study characterizes real-world treatment patterns and economic and healthcare resource utilization (HCRU) burden associated with first-line (1L) treatment of metastatic non-small cell lung cancer (NSCLC) without actionable alterations in the United States. This retrospective observational study used Optum Clinformatics^® data. A total of 15,659 patients with metastatic NSCLC who started 1L treatment between January 2020 and March 2023 were included (52% male; mean age at the start of 1L treatment 71.7 years; 86% Medicare Advantage). The most frequent 1L regimens were immune checkpoint inhibitor (ICI) + platinum-based chemotherapy (PBCT) (47%), PBCT only (26%), and ICI only (20%). The median 1L treatment duration was 4.2 months (range 2.7–6.5) and was shorter with chemotherapy-only regimens. Outpatient visits accounted for the majority of HCRU (mean 6.6 visits per patient per month [PPPM]). Outpatient, inpatient, and emergency department visits were highest for chemotherapy-only regimens. Mean total (all-cause) healthcare costs were $32,215 PPPM and were highest for ICI + chemotherapy ($34,741–38,454 PPPM). Inpatient costs PPPM were highest for PBCT ($4725) and ICI + non-PBCT ($4648). First-line treatment of metastatic NSCLC without actionable alterations imposes a notable HCRU and cost burden, underscoring the need for better treatment options to improve outcomes and reduce economic impact. Full article

Background: Macrophages play an important role in eliminating diseased and damaged cells through programmed cell death. Signal regulatory protein alpha (SIRPα) is a crucial immune checkpoint primarily expressed on myeloid cells and macrophages. It initiates a ‘do not eat me’ signal when engaged with CD47, which is typically expressed at elevated levels on multiple solid tumors. The phospholipase A2 Group 7 (PLA2G7), which is mainly secreted by macrophages, interacts with oxidized low-density lipoprotein (oxLDL) and associates with several vascular diseases and cancers. Methods: To identify potent fully human monoclonal antibodies (mAbs) against human SIRPα and PLA2G7, we conducted bio-panning of phage antibody libraries. Results: We isolated one human Fab (1B3) and VH (1A3) for SIRPα, as well as one human Fab (1H8) and one VH (1A9) for PLA2G7; the 1B3 Fab and 1A3 VH are competitively bound to SIRPα, interfering with CD47 binding. The 1B3 IgG and 1A3 VH-Fc augmented macrophage-mediated phagocytic activity when combined with the anti-EGFR antibody, cetuximab. The anti-PLA2G7 antibodies exhibited high specificity for the PLA2G7 antigen and effectively blocked the PLA2G7 enzymatic activity with half-maximal inhibitory concentrations (IC₅₀) in the single-digit nanomolar range. Additionally, 1H8 IgG and its derivative bispecific antibody exhibited the ability to block PLA2G7-mediated tumor cell migration. Conclusions: Our anti-SIRPα mAbs are expected to serve as potent and fully human immune checkpoint inhibitors of SIRPα, enhancing the antitumor responses of SIRPα-positive immune cells. Moreover, our anti-PLA2G7 mAbs represent promising fully human PLA2G7 enzymatic blockade antibodies with the potential to enhance both anti-tumor and anti-aging responses. Anti-SIRPα and PLA2G7 mAbs can modulate macrophage phagocytic activity and inflammatory responses against tumors. Full article

Esophageal cancer is one of the most common and deadliest cancers worldwide. Rates of esophageal cancer worldwide have been steadily rising over the past decade due to higher incidence of gastroesophageal reflux disease (GERD). Current therapies include surgical resection, chemotherapy, and limited targeted therapies. One obstacle to care is tumor cells’ ability to evade immune surveillance, which can render certain therapeutics ineffective. Immunotherapy provides a new paradigm to cancer treatment, which has proven to be effective in evasive tumors. In recent years, PD-1/PD-L1 and CLTA-4 inhibitors have been used as frontline treatment and have shown to be extremely effective in the treatment of hard-to-treat tumors. Here, we aim to analyze the current literature regarding current therapeutics along with emerging techniques and future receptor targets for immunotherapy. Full article

Patients with advanced melanoma who progress on standard-dose ipilimumab (Ipi) + nivolumab continue to have poor prognosis. Studies support a dose–response activity of Ipi, and one promising combination is Ipi 10 mg/kg (Ipi10) + temozolomide (TMZ). We performed a retrospective cohort analysis of patients with advanced melanoma treated with Ipi10 + TMZ in the immunotherapy refractory/resistant setting (n = 6, all progressed after prior Ipi + nivolumab), using similar patients treated with Ipi3 + TMZ (n = 6) as comparison. Molecular profiling by whole-exome sequencing (WES) and RNA-sequencing (RNA-seq) of tumors harvested through one responder’s treatment was performed. With a median follow up of 119 days, patients treated with Ipi10 + TMZ had a statistically significant longer median progression-free survival of 144.5 days (range 27–219) vs. 44 (26–75) in Ipi 3 mg/kg (Ipi3) + TMZ, p = 0.04, and a trend of longer median overall survival of 154.5 days (27–537) vs. 89.5 (26–548). Two patients in the Ipi10 + TMZ cohort had a partial response, and both responders had BRAF V600E mutant melanoma. RNA-seq showed enrichment of inflammatory signatures, including interferon responses in metastases after Ipi10 + TMZ compared to the primary tumor, and downregulated negative immune regulators. Ipi10 + TMZ demonstrated efficacy, including dramatic responses in patients refractory to prior Ipi + anti-PD1. Molecular data suggest a potential threshold of Ipi dose for activation of sufficient anti-tumor immune response, and higher doses are required for some patients. Full article