Therapy For Advanced Cancer Research Articles

Quantification of PD-L1 expression and tumor mutational burden in biologically distinct advanced pancreatic cancers responding to pembrolizumab: case reports

BackgroundThe advent of checkpoint therapy is one of the most important recent advancements in cancer therapy. Though checkpoint therapy is a mainstay in some cancers, it has been largely ineffective in treating cancers of the pancreas. Pancreatic ductal adenocarcinoma and pancreatic neuroendocrine tumors are seldom responsive to checkpoint inhibition.Case presentationsHere we present two cases of advanced pancreatic cancers that either failed to respond or recurred following conventional treatments. Tissue from each tumor was sequenced and analyzed for PD-L1 expression. Each patient was started on checkpoint blockade after assessing for a predictive biomarker, either the combined positive score or the tumor mutational burden. In each case, checkpoint blockade led to durable radiographic responses.ConclusionsWe therefore propose that it is reasonable to assess combined positive score and tumor mutational burden in refractory or recurrent pancreatic cancers when initiation of ICB is being considered.

Single-cell multiomics reveals simvastatin inhibits pan-cancer epithelial-mesenchymal transition via the MEK/ERK pathway in XBP1+ mast cells

Distant metastasis is the leading cause of cancer-related mortality, and achieving survival benefits through advancements in systemic therapy remains challenging. Mast cells play a dual role in shaping the tumor microenvironment (TME) and influencing distant metastasis, underscoring the significant research value of targeting mast cells for systemic therapy in advanced cancer. We investigated variations in mast cell infiltration levels in primary and metastatic malignancies using immunocyte infiltration analysis. Mast cell subsets were identified from pan-cancer distant metastasis single-cell sequencing data through dimensionality reduction clustering and cell type annotation, combined with cell trajectory and communication network analyses. A prognostic model was established using WGCNA and 12 machine learning algorithms to identify potential mast cell targets. Drug sensitivity and Mendelian randomization analyses were conducted to select potential drugs targeting mast cells, and their effects on epithelial-mesenchymal transition (EMT) were validated through in vitro experiments, including wound healing, transwell, and western blot assays. Results revealed that activated mast cells show increased infiltration in metastatic tumors, correlating with poor survival duration. XBP1+ mast cells were identified as key components of the inhibitory TME, potentially involved in EMT activation. Simvastatin was identified as a potential drug, reversing EMT induced by XBP1+ mast cells in pan-cancer. Aberrant activation of MEK/ERK signaling in XBP1+ mast cells can stimulate cancer cell EMT by modulating degranulation, while Simvastatin can inhibit EMT by suppressing degranulation.

Nanocarriers for Delivery of Anticancer Drugs: Current Developments, Challenges, and Perspectives

Cancer, the most common condition worldwide, ranks second in terms of the number of human deaths, surpassing cardiovascular diseases. Uncontrolled cell multiplication and resistance to cell death are the traditional features of cancer. The myriad of treatment options include surgery, chemotherapy, radiotherapy, and immunotherapy to treat this disease. Conventional chemotherapy drug delivery suffers from issues such as the risk of damage to benign cells, which can cause toxicity, and a few tumor cells withstand apoptosis, thereby increasing the likelihood of developing tolerance. The side effects of cancer chemotherapy are often more pronounced than its benefits. Regarding drugs used in cancer chemotherapy, their bioavailability and stability in the tumor microenvironment are the most important issues that need immediate addressing. Hence, an effective and reliable drug delivery system through which both rapid and precise targeting of treatment can be achieved is urgently needed. In this work, we discuss the development of various nanobased carriers in the advancement of cancer therapy—their properties, the potential of polymers for drug delivery, and recent advances in formulations. Additionally, we discuss the use of tumor metabolism-rewriting nanomedicines in strengthening antitumor immune responses and mRNA-based nanotherapeutics in inhibiting tumor progression. We also examine several issues, such as nanotoxicological studies, including their distribution, pharmacokinetics, and toxicology. Although significant attention is being given to nanotechnology, equal attention is needed in laboratories that produce nanomedicines so that they can record themselves in clinical trials. Furthermore, these medicines in clinical trials display overwhelming results with reduced side effects, as well as their ability to modify the dose of the drug.

Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) in combination with endocrine therapy improve the outcomes of patients with hormone-receptor (HR)-positive, HER2-negative advanced breast cancer and can be used early as first-line treatment or deferred to second-line treatment1-7. Randomized data comparing the use of CDK4/6i in the first- and second-line setting are lacking. The phase 3 SONIA trial (NCT03425838) randomized 1,050 patients who had not received previous therapy for advanced breast cancer to receive CDK4/6i in the first- or second-line setting8. All of the patients received the same endocrine therapy, consisting of an aromatase inhibitor for first-line treatment and fulvestrant for second-line treatment. The primary end point was defined as the time from randomization to disease progression after second-line treatment (progression-free survival 2 (PFS2)). We observed no statistically significant benefit for the use of CDK4/6i as a first-line compared with second-line treatment (median, 31.0 versus 26.8 months, respectively; hazard ratio = 0.87; 95% confidence interval = 0.74-1.03; P = 0.10). The health-related quality of life was similar in both groups. First-line CDK4/6i use was associated with a longer CDK4/6i treatment duration compared with second-line use (median CDK4/6i treatment duration of 24.6 versus 8.1 months, respectively) and more grade ≥3 adverse events (2,763 versus 1,591, respectively). These data challenge the need for first-line use of a CDK4/6i in all patients.

Atezolizumab plus bevacizumab and chemotherapy as first-line therapy for cervical cancer: a cost-effectiveness analysis in the US

ObjectiveMedication is the predominant therapy for advanced cancers. However, the use of novel anticancer medications is a major contributor to disease-related financial hardships. Recently, numerous countries have mandated the pharmacoeconomic assessments of novel oncological agents to mitigate patient financial risks and optimize resource allocation. The present study evaluated the cost-effectiveness of adding atezolizumab to standard therapy (atezolizumab plus bevacizumab [BC]) for metastatic, persistent, and recurrent cervical cancer from the perspective of US healthcare payers, with the aim of supporting policymaking and promoting the rational use of healthcare resources.MethodsUsing clinical efficacy and safety data from the BEATcc clinical trial, in addition to cost and utility values from publicly available databases and published literature, a partitioned survival model over a 20-year lifetime horizon was developed to assess the cost-effectiveness of atezolizumab plus bevacizumab and chemotherapy (ABC) versus BC. The primary output of the model was the incremental cost-effectiveness ratio (ICER) and sensitivity analyses were performed to assess its robustness.ResultsAt both 20 and 4.5 y of time horizon, ABC therapy showed poor cost-effectiveness, with ICER of $193926.48/QALY and $168482.26/QALY, respectively, which were higher than the $150,000/QALY willingness-to-pay threshold. One-way sensitivity analysis showed that the price of atezolizumab had the most significant impact on the model results. When the price of atezolizumab was reduced by 10%, ABC changed from being not cost-effective to cost-effective (ICER = $121531.24/QALY). Probabilistic sensitivity analysis showed a 32.6% probability that ABC would be cost-effective, which increased to 58.6% when the price of atezolizumab was reduced by 10%.ConclusionsFor patients with metastatic, persistent, and recurrent cervical cancer in the US, ABC was not as cost-effective as BC. Appropriate price reduction (10%) is recommended for atezolizumab to improve cost-effectiveness of ABC therapy.

Breathing down resistance: Tackling hypoxia to overcome immunotherapy barriers in lung cancer.

In this issue of JEM, Robles-Oteiza et al. (https://doi.org/10.1084/jem.20231106) present compelling evidence linking tumor hypoxia to acquired resistance mechanisms in non-small cell lung cancer (NSCLC) treatments involving immune checkpoint inhibitors (ICIs). Their research advocates targeting these hypoxic tumor regions with hypoxia-activated pro-drugs like TH-302, which may substantially delay the onset of resistance and herald a significant advancement in cancer therapy.

Talazoparib for the Treatment of Metastatic Castration-resistant Prostate Cancer

Breast and prostate cancer are among the most commonly diagnosed cancers worldwide. Recent advances in tumor sequencing and gene studies have led to a paradigm shift from treatment centered on the type of tumor to therapy more focused on specific immune phenotype markers and molecular alterations. In this review, we discuss the utility and function of talazoparib concerning prostate cancer treatment and summarize recent and planned clinical trials on talazoparib. We searched medical databases for articles relating to the use of talazoparib in prostate cancer from inception. Poly ADP ribose polymerase (PARP) is a family of 17 necessary DNA repair enzymes responsible for base excision repair, single-strand break repair, and double-strand break repair. PARP inhibitors are a class of oral targeted therapies that compete for the NAD+ binding site on PARP molecules. Talazoparib, a potent PARP inhibitor, has emerged as a significant therapeutic option in the treatment of metastatic castration-resistant prostate cancer (mCRPC), particularly for patients with specific genetic alterations. Its role as a PARP inhibitor makes it a targeted therapy, focusing on cancer cells with DNA repair deficiencies. Talazoparib’s role as a biomarker-directed therapy in advanced prostate cancer has been increasingly recognized. The TALAPRO-1 demonstrated durable antitumor activity in mCRPC patients. TALAPRO-2 is a notable clinical trial, specifically examining the effectiveness of Talazoparib when used in combination therapies. Current investigations demonstrate a significant improvement in survival outcomes for the patients of mCRPC, making Talazoparib a promising intervention.

Efficacy of neoadjuvant therapy and lymph node dissection in advanced gallbladder cancer without distant metastases: a SEER database analysis

PurposeTo investigate the effectiveness of neoadjuvant therapy and lymph node dissection(LND) on overall survival (OS) in patients with stage III/IV gallbladder cancer without distant metastases.MethodsData from 101 patients who received neoadjuvant therapy followed by surgery combined with adjuvant chemotherapy, and 1412 patients who received direct surgical treatment followed by adjuvant chemotherapy, were collected from the SEER database from 2004 to 2020. Patients were divided into group A (neoadjuvant therapy) and group B (direct surgery) based on the treatment modality. A total of 202 cases were obtained after propensity score matching, with 101 cases in each group (A and B). Cox unifactorial and multifactorial analyses were performed to identify independent risk factors for patients with advanced cholecystic carcinoma, and the Kaplan-Meier method was used to analyze overall survival (OS). The Cox proportional hazards model was used to investigate the effect of different subgroups on OS in both patient groups. Further survival analyses were conducted to determine whether lymph node dissection(LND) was beneficial for patients receiving neoadjuvant therapy for gallbladder cancer.ResultsCox univariate analysis showed that marital status, AJCC stage, number of LND, tumor size, and treatment modality were associated with OS (P<0.05). Cox multifactorial regression analysis indicated that AJCC stage, LND, tumor size, and treatment modality were independent risk factors for OS in patients with non-metastatic advanced gallbladder cancer (P<0.05). Survival curves demonstrated that the OS in group A was longer than in group B (median OS: 30 months vs. 14 months, P<0.001). Subgroup analysis indicated that neoadjuvant therapy had a consistent effect on the OS of patients with advanced gallbladder cancer, improving both survival time and outcomes. Survival curves indicated that lymph node dissection was not significant in group A patients (p>0.05) but was significant in group B (p<0.05).ConclusionNeoadjuvant therapy can improve the OS of patients with non-metastatic stage III/IV gallbladder cancer and is an independent risk factor affecting prognosis; however, the significance of lymph node dissection in these patients still needs further study.

Gold nanostars and nanourchins for enhanced photothermal therapy, bioimaging, and theranostics.

Photothermal therapy (PTT), a recently emerging method for eradicating tumors, utilizes hyperthermia induced by photo-absorbing materials to generate heat within cancer cells. Gold nanoparticles (AuNPs) have gained reliability for in vitro and in vivo applications in PTT due to their strong light absorbance, stability, and biocompatibility. Yet, their potential is limited by their spherical shape, impacting their size capabilities, electromagnetic enhancement effects, and localized surface plasmon resonance (LSPR). Anisotropic shapes have been tested and implemented in this treatment to overcome the limitations of spherical AuNPs. Nanostars (AuNSs) and nanourchins (AuNUs) offer unique properties, such as increased local electron density, improved catalytic activity, and an enhanced electromagnetic field, which have proven to be effective in PTT. Additionally, these shapes can easily reach the NIR-I and NIR-II window while exhibiting improved biological properties, including low cytotoxicity and high cellular uptake. This work covers the critical characteristics of AuNS and AuNUs, highlighting rough surface photothermal conversion enhancement, significantly impacting recent PTT and its synergy with other treatments. Additionally, the bioimaging and theranostic applications of these nanomaterials are discussed, highlighting their multifaceted utility in advanced cancer therapies.

CRISPR/Cas9 system: a novel approach to overcome chemotherapy and radiotherapy resistance in cancer.

Cancer presents a global health challenge with rising incidence and mortality. Despite treatment advances in cancer therapy, radiotherapy and chemotherapy remained the most common treatments for all types of cancers. However, resistance phenotype in cancer cells leads to unsatisfactory results in the efficiency of therapeutic strategies. Therefore, researchers strive to propose effective solutions to overcome treatment failure, which requires a deep knowledge of treatment-resistant mechanisms. The progression and occurrence of tumors can be attributed to gene mutation. Over the past decade, the emergence of clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 (CRISPR/Cas9) genome editing has revolutionized cancer research. This versatile technology enables cancer modeling, manipulation of specific DNA sequences, and genome-wide screening. CRISPR/Cas9 is an effective tool for identifying radio- and chemoresistance genes and offering potential adjunctive treatments to overcome tumor recurrence after chemo- and radiotherapy. This article aims to explain the potential of the CRISPR/Cas9 system in improving the effectiveness of chemo- and radiotherapy and ultimately overcoming treatment failure.

Enhancing lung cancer growth inhibition with calcium ions: Role of mid- and high-frequency electric field pulses

Calcium electroporation (CaEP) involves the combination of calcium ions with electroporation, which is induced by pulsed electric fields (PEFs). This study explores the application of high-frequency unipolar nanosecond pulsed electric fields (nsPEFs: 8–14 kV/cm, 200 ns, 10 kHz, 100 kHz, 1 MHz repetition frequency pulse bursts, n = 100) and their potential in inhibiting lung cancer cell growth. As a reference, standard microsecond range parametric protocols were used (100 µs x 8 pulses). Methods included cell permeability quantification through Yo-Pro-1 uptake, cell viability assays, immunofluorescence studies for apoptosis and EMT markers, analysis of cell death types depending on repetition frequency pulse bursts. We determined the susceptibility of human lung cancer to electric pulses, characterized the efficacy of CaEP, and investigated cell death types depending on repetition frequency pulse bursts. We have shown that adding calcium ions to the applied nsPEF protocol increases cytotoxicity. Additionally, the use of these electroporation parameters can modulate key cellular processes, such as the epithelial-mesenchymal transition and apoptosis, as indicated by changes in the expression of markers such as E-cadherin, N-cadherin, BCL-2, and p53. Changes in cell morphology over time were observed using holotomographic microscopy. The study provides insights into the modulation of key cellular processes, indicating that nsPEF technology could improve the outcomes of conventional cancer treatments through enhanced efficacy and potentially mitigating drug resistance mechanisms. The promising results advocate for further research to optimize nsPEF protocols for clinical application, highlighting the potential of electrical fields in advancing cancer therapy.

A PSMA-targeted Tri-specific Killer Engager enhances NK cell cytotoxicity against prostate cancer.

Natural killer (NK) cell tumor infiltration is associated with good prognosis in patients with metastatic castration-resistant prostate cancer (mCRPC). NK cells recognize and kill targets by a process called natural cytotoxicity. We hypothesized that promoting an antigen-specific synapse with co-activation may enhance NK cell function in mCRPC. We describe a Tri-specific Killer Engager (TriKE) construct that engages with the activating receptor CD16 on NK cells, prostate-specific membrane antigen (PSMA) on mCRPC cells, and has an interleukin (IL)-15 moiety that is essential for NK cell survival, proliferation, and priming. We show that the PSMA TriKE specifically binds to PSMA-expressing cells and significantly enhances expansion, degranulation and cytokine production of NK cells derived from healthy donors or prostate cancer patients. Bystander killing of PSMA-negative was also achieved with PSMA TriKE treatment when co-cultured with PSMA-positive cells, suggesting potential PSMA TriKE benefit in controlling tumor antigen escape. When tested under physiologic conditions recapitulating the mCRPC tumor microenvironment (TME), NK cells treated with PSMA TriKE and prolonged exposure to hypoxia or MDSCs maintained their potent function while IL-15 treated NK cells showed greatly impaired cytotoxicity. Finally, in vivo testing of PSMA TriKE showed improved tumor control and survival of mice as compared to IL-15 and untreated control groups. In conclusion, PSMA TriKE demonstrates potential as a new therapy for advanced prostate cancer by providing additional signals to NK cells to maximize their anti-tumor potential in prostate cancer, especially in the setting of a hostile TME.

LOXL1 promotes gastric cancer progression by β-catenin-cyclinD mediated proliferation

Although much progress has been made in chemotherapy or target therapy for advanced gastric cancer, the prognosis is still poor. It is necessary to screen biomarkers for early diagnosis and prognosis prediction. However, the prognostic value of LOX family in gastric cancer and the underlying molecular mechanisms for promoting the progression of gastric cancer remains unclear. Among five members of LOX family, LOXL1 was the unique independent prognostic risk factor. The nomogram established based on the expression of LOXL1 and other clinical parameters could predict the overall survival rate of gastric cancer. Knockdown (KD) of LOXL1 decreased cell proliferation and led to G1 phase arrest in gastric cells. According to GSEA analysis that LOXL1 was positively correlated with the WNT signaling pathway, in vitro experiment proved that LOXL1-KD reduced the phosphorylation level of β-catenin and the expression of the downstream G1 phase checkpoint CCND1. In conclusion, LOXL1 has been identified as a potential risk prognostic biomarker for gastric cancer by promoting gastric cancer proliferation via WNT/β-catenin/cyclinD1 pathway.

Vaccination Against Androgen Receptor Splice Variants to Immunologically Target Prostate Cancer.

Background/Objectives: Androgen receptor (AR) expression and signaling are critical for the progression of prostate cancer and have been the therapeutic focus of prostate cancer for over 50 years. While a variety of agents have been developed to target this axis, many of these fail due to the emergent expression of AR RNA splice variants, such as AR-V7, that can signal independently of ligand binding. Other therapies, such as vaccination against prostate-specific antigens, have achieved FDA approvals but have fallen short of being incorporated as standard-of-care therapies for advanced prostate cancer. This may be due to the elevated level of immunosuppression observed in prostate cancer, which remains largely refractory to immune checkpoint blockade. Methods: We developed a vaccine targeting AR-V7, a common isoform associated with treatment resistance, and demonstrated its ability to elicit AR-V7-specific immunity and enable anti-tumor responses against AR-V7+ cancers in subcutaneous tumor models. Results: Our studies also revealed that AR-V7 expression conferred an immune suppressive phenotype that was significant in a non-AR-dependent prostate cancer model. Notably, in this model, we found that vaccination in combination with enzalutamide, an AR antagonist, suppressed these aggressive immune suppressive cancers and resulted in enhanced survival in comparison to control vaccinated and enzalutamide-treated mice. While anti-PD-1 immune checkpoint inhibition (ICI) alone slowed tumor growth, the majority of vaccinated mice that received anti-PD-1 therapy showed complete tumor elimination. Conclusions: Collectively, these results validate the importance of AR signaling in prostate cancer immune suppression and suggest the potential of AR-V7-specific vaccines as therapeutic strategies against prostate cancer, offering significant protective and therapeutic anti-tumor responses, even in the presence of androgen signaling inhibitors.

Tertiary Lymphoid Structures and Immunotherapy: Challenges and Opportunities.

Tertiary lymphoid structures (TLS)are accumulations of lymphoid cells that arise in ectopic sites through the process of lymphoid neogenesis in chronic inflammation in autoimmunity, microbial infections, organ rejection, aging, and cancer. Their cellular composition and function and regulation via members of the lymphotoxin (LT)/tumor necrosis factor (TNF) family resemble that of secondary lymphoid organs (SLOs). Tumor-associated (TA)-TLS can be associated with favorable clinical outcomes. Immunotherapy in the form of immune checkpoint inhibitors (ICI) has contributed to tremendous advances in cancer therapy. However, ICI are effective in only some tumors, can give rise to resistance, and can precipitate immune-related adverse events (irAEs), many of which appear to have hallmarks of autoimmunity and can resemble TLS. TA-TLS correlate with a positive response to immunotherapy, but they can also be associated with susceptibility to irAEs, suggesting that TA-TLS in combination with ICI could lead to uncontrolled autoimmunity. The tumor environment can be manipulated to ensure that, not only the number of TLS, but also their cellular composition and appropriate function allow for judicious combinations of TLS and immunotherapy that can synergize and contribute to better outcomes with a minimum of destructive irAEs. Strategies include directed delivery of lymphoneogenic cytokines and chemokines or vascular growth factors directly, via transgenes or via adenovirus vectors.

INNV-06. ADULT GLIOBLASTOMA WITH MISMATCH REPAIR DEFICIENCY FORMS A DISTINCT HIGH-RISK MOLECULAR SUBGROUP FOR WHICH TREATMENT WITH IPILIMUMAB-NIVOLUMAB SHOWS SURVIVAL ADVANTAGE

Abstract Glioblastoma is the most frequent and malignant primary brain tumor. Although the survival is generally dismal for glioblastoma patients, risk stratification and the identification of high-risk subgroups is important for prompt and aggressive management. The G1-G7 molecular subgroup classification based on the MAPK pathway activation has offered for the first time a non-redundant, all-inclusive classification of adult glioblastoma. Five patients from the large, 220-patient prospective cohort showed germline mutations in mismatch repair (MMR) genes and significantly worse median survival (3.25 months post-surgery) than those from other subgroups or from the rest of the cohort adjusted for age. These tumors were assigned to a new subgroup, G3/MMR, a spin-off from the major G3/NF1 subgroup, as they generally show genomic alterations leading to RAS activation. An integrated clinical, histological, immunohistochemical and molecular analysis of the G3/MMR tumors showed distinct characteristics as compared to other glioblastomas, including those with iatrogenic high tumor mutation burden (TMB), warranting a separate subgroup. Among these, prior history of cancer, midline location or multifocality, presence of multinucleated giant cells, positive p53 and MMR immunohistochemistry, and specific molecular characteristics, including high TMB, alert to this high-risk G3/MMR subgroup. High TMB constitutes the criterium for treatment with immune checkpoint inhibitors in solid cancers. The FDA-approved first-line therapy for advanced non-small cell lung cancer and high-TMB colorectal cancer is with the dual ipilimumab-nivolumab regimen. One of the five G3/MMR subgroup patients received the dual ipilimumab-nivolumab regimen and survived much longer than the rest of the G3/MMR patients, setting a proof-of-principle example for the treatment of these very aggressive G3/MMR glioblastomas.

Short-term outcomes of a phase II trial of perioperative capecitabine plus oxaliplatin therapy for advanced gastric cancer with extensive lymph node metastases (OGSG1701).

The prognosis of advanced gastric cancer (GC) with extensive lymph node (LN) metastasis treated with surgery alone remains poor. We conducted a multicenter phase II study to evaluate the efficacy and safety of perioperative capecitabine plus oxaliplatin (CapeOx) therapy in patients with advanced GC with extensive LN metastases. Patients with histologically proven HER2-negative or unknown gastric adenocarcinoma with paraaortic LN (PALN) metastases and/or bulky LN metastases located at the celiac axis, common hepatic artery, and/or splenic artery were included in the study. Patients received three cycles of preoperative CapeOx every 3weeks, followed by five cycles of postoperative CapeOx after gastrectomy with D2 or D2 + including PALN dissection. The primary endpoint was the response rate (RR) according to the RECIST v1.0 criteria. Thirty patients from 14 institutions were enrolled from September 2017 to June 2022. Complete response, partial response, stable disease, and progressive disease occurred in zero, 20, eight, and one patient, respectively. One patient was not evaluated. The RR was 66.7% (90% confidence interval, 50.1-80.7%; one-sided P = 0.049). The preoperative chemotherapy completion rate and the curative resection rate were 96.7% and 93.3%, respectively. The minor (grade ≥ 1b) pathological RR was 66.7%. Grade 3 adverse events of preoperative chemotherapy included neutropenia in 3.3%, anemia in 6.7%, and anorexia in 10.0%. One treatment-related death occurred due to postoperative complications. Preoperative CapeOx chemotherapy showed a favorable RR, curative resection rate, and acceptable adverse events in patients with advanced GC with extensive LN metastasis. UMIN000028749 and jRCTs051180186.

Unveiling the influence of tumor and immune signatures on immune checkpoint therapy in advanced lung cancer.

This study investigates the variability among patients with non-small cell lung cancer (NSCLC) in their responses to immune checkpoint inhibitors (ICIs). Recognizing that patients with advanced-stage NSCLC rarely qualify for surgical interventions, it becomes crucial to identify biomarkers that influence responses to ICI therapy. We conducted an analysis of single-cell transcriptomes from 33 lung cancer biopsy samples, with a particular focus on 14 core samples taken before the initiation of palliative ICI treatment. Our objective was to link tumor and immune cell profiles with patient responses to ICI. We discovered that ICI non-responders exhibited a higher presence of CD4+ regulatory T cells, resident memory T cells, and TH17 cells. This contrasts with the diverse activated CD8+ T cells found in responders. Furthermore, tumor cells in non-responders frequently showed heightened transcriptional activity in the NF-kB and STAT3 pathways, suggesting a potential inherent resistance to ICI therapy. Through the integration of immune cell profiles and tumor molecular signatures, we achieved an discriminative power (area under the curve [AUC]) exceeding 95% in identifying patient responses to ICI treatment. These results underscore the crucial importance of the interplay between tumor and immune microenvironment, including within metastatic sites, in affecting the effectiveness of ICIs in NSCLC.

Unveiling the influence of tumor and immune signatures on immune checkpoint therapy in advanced lung cancer

This study investigates the variability among patients with non-small cell lung cancer (NSCLC) in their responses to immune checkpoint inhibitors (ICIs). Recognizing that patients with advanced-stage NSCLC rarely qualify for surgical interventions, it becomes crucial to identify biomarkers that influence responses to ICI therapy. We conducted an analysis of single-cell transcriptomes from 33 lung cancer biopsy samples, with a particular focus on 14 core samples taken before the initiation of palliative ICI treatment. Our objective was to link tumor and immune cell profiles with patient responses to ICI. We discovered that ICI non-responders exhibited a higher presence of CD4+ regulatory T cells, resident memory T cells, and TH17 cells. This contrasts with the diverse activated CD8+ T cells found in responders. Furthermore, tumor cells in non-responders frequently showed heightened transcriptional activity in the NF-kB and STAT3 pathways, suggesting a potential inherent resistance to ICI therapy. Through the integration of immune cell profiles and tumor molecular signatures, we achieved an discriminative power (area under the curve [AUC]) exceeding 95% in identifying patient responses to ICI treatment. These results underscore the crucial importance of the interplay between tumor and immune microenvironment, including within metastatic sites, in affecting the effectiveness of ICIs in NSCLC.

Plain language review: the safety of relugolix combination therapy for advanced prostate cancer.

Advanced prostate cancer is a cancer that began in the prostate (a part of the male body) and has spread to other parts of the body. This is a review of two clinical research studies of patients with advanced prostate cancer who were treated with relugolix combination therapy. Relugolix is a medicine taken by mouth that lowers a male sex hormone, called testosterone. Relugolix is sometimes combined with other medicines such as novel hormonal therapies (NHTs) or chemotherapy to treat advanced prostate cancer. In one study, patients were treated with relugolix combined with an NHT (abiraterone or apalutamide). In a second study, patients were treated with relugolix combined with an NHT (enzalutamide) or chemotherapy (docetaxel). Researchers wanted to understand what possible side effects may happen due to taking these medicines together as prescribed. They also wanted to see if relugolix combination therapy worked to lower testosterone in the same way as relugolix taken alone. Researchers found that most of the side effects of relugolix combined with an NHT or chemotherapy were mild or moderate. Side effects of relugolix combination therapy were similar to the side effects of the medicines when taken alone. However, patients who received relugolix with enzalutamide or docetaxel were more likely to have a serious side effect compared with patients who received relugolix taken alone. Testosterone stayed below 50 nanograms per deciliter (known as castration levels) for patients who received relugolix with NHT or chemotherapy. Patients who receive relugolix combination therapy generally experience mild or moderate side effects, rather than serious side effects. No new safety issues were found during these studies. Patients maintained low testosterone levels. Patients and their doctors should discuss the benefits and possible harms of relugolix combination therapy to treat advanced prostate cancer.