Tumor Cell Death Research Articles

Intratumoral Chemotherapy: The Effects of Drug Concentration and Dose Apportioning on Tumor Cell Injury.

The addition of intravenous (i.v.) chemotherapy to i.v. immunotherapy for patients with lung cancer results in improved overall survival but is limited by synergistic side effects and an unknown, highly variable final cytotoxic dose within the tumor. The synergy between i.v. chemo- and immunotherapies is hypothesized to occur as a result of cell injury caused by chemotherapy, a mechanism demonstrated to drive antigen presentation within the tumor microenvironment. Intratumoral delivery of chemotherapy may thus be optimized to maximize tumor cell injury. To assess the balance between the damage versus the death of tumor cells, we developed a computational model of intratumoral dynamics within a lung cancer tumor for three different chemotherapy agents following direct injection as a function of location and number of injection sites. We based the model on the morphology of a lung tumor obtained from a thoracic CT scan. We found no meaningful difference in the extent of tumor cell damage between a centrally injected versus peripherally injected agent, but there were significant differences between a single injection versus when the total dose was apportioned between multiple injection sites. Importantly, we also found that the standard chemotherapeutic concentrations used for intravenous administration were effective at causing cell death but were too high to generate significant cell injury. This suggests that to induce maximal tumor cell injury, the optimal concentration should be several orders of magnitude lower than those typically used for intravenous therapy.

PDL1/HER2-Targeted Lipid-Encapsulated Oxygen Nanobubbles Combined with Photodynamic Therapy for HER2+ Breast Cancer Immunotherapy.

Programmed death (PD) 1/PD ligand 1 (PDL1) inhibitors are immune checkpoint inhibitors (ICIs) that may facilitate HER2-positive breast cancer treatment; however, their clinical efficacy remains elusive. Oxygen-enhanced photodynamic therapy (PDT) increases immunogenic cell death (ICD), providing a promising strategy to render the tumor microenvironment more sensitive to the ICIs. Lipid-encapsulated oxygen nanobubbles (Lipo-NBs-O2) obtained using nanobubbles (NBs) water for oxygen delivery in vivo can facilitate enhanced PDT. Here, dual-receptor targeted Lipo-NBs-O2 (DRT@Lipo-NBs-O2) is prepared by modifying Lipo-NBs-O2 with anti-PDL1 scFv and the fusion protein anti-HER2 scFv-tandem-repeat cytochrome c (anti-HER2-nCytc). Copper phthalocyanine is the photosensitizer (PS). DRT@Lipo-PS-NBs-O2 plus near-infrared irradiation leads to robust ICD induction, increasing DC activation and CD8+ T-cell numbers. Modification with anti-PDL1 scFv improves tumor distribution of DRT@Lipo-PS-NBs-O2 and plays the ICI role, invigorating CD8+ T cells and boosting the effects of immunotherapy. Oxygen supplied through DRT@Lipo-PS-NBs-O2 reduces P-glycoprotein expression. Enhanced PDT and Cytc can cause tumor cell death, thereby reducing the immune burden. Under dual receptor targeting and laser local irradiation, tumor cells become subject to the combination effects of PDT, ICD, ICIs, and apoptosis; this effectively suppresses tumor growth and metastasis. Lipo-NBs-O2 affords a combination of oxygen delivery and multidrug therapy to alleviate HER2-positive breast cancer.

The current therapeutic cancer vaccines landscape in non-small cell lung cancer.

Currently, conventional immunotherapies for the treatment of non-small cell lung cancer (NSCLC) have low response rates and benefit only a minority of patients, particularly those with advanced disease, so novel therapeutic strategies are urgent deeded. Therapeutic cancer vaccines, a form of active immunotherapy, harness potential to activate the adaptive immune system against tumor cells via antigen cross-presentation. Cancer vaccines can establish enduring immune memory and guard against recurrences. Vaccine-induced tumor cell death prompts antigen epitope spreading, activating functional T cells and thereby sustaining a cancer-immunity cycle. The success of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rendered cancer vaccines a promising avenue, especially when combined with immunotherapy or chemoradiotherapy for NSCLC. This review delves into the intricate antitumor immune mechanisms underlying therapeutic cancer vaccines, enumerates the tumor antigen spectrum of NSCLC, discusses different cancer vaccines progress and summarizes relevant clinical trials. Additionally, we analyze the combination strategies, current limitations, and future prospects of cancer vaccines in NSCLC treatment, aiming to offer fresh insights for their clinical application in managing NSCLC. Overall, cancer vaccines offer promising potential for NSCLC treatment, particularly combining with chemoradiotherapy or immunotherapy could further improve survival in advanced patients. Exploring inhaled vaccines or prophylactic vaccines represents a crucial research avenue.

58 Tumor immune microenvironment determinants of response to Lenvatinib and aPD-1 blockade in clear cell renal cell carcinoma

Abstract Background Combinations of immune checkpoint blockade (ICB) and anti-angiogenesis tyrosine kinase inhibitors (TKI) are the mainstay of metastatic ccRCC front-line treatment, but heterogenous responses and lack of biomarkers strongly emphasizes the need to understand RCC-specific mechanisms of effective treatment-related anti-tumor immunity. Although prior work consistently highlights tumor associated macrophages (TAMs) in RCC prognosis and treatment response, TAM targeting has yet to experimentally assessed as a viable treatment sensitizer. Methods We therefore assessed the impact of TAM depletion using a clinical-grade colony stimulating factor receptor-1 inhibitor (CSF1Ri) on ICB or TKI sensitivity in a spontaneous mouse model of ccRCC with inducible kidney-specific Vhl, p53 and Rb1 deletions (KVpR). Mice were randomized to receive either no treatment, single agent Lenvatinib (TKI), aPD-1, or combinations with CSF1Ri. We longitudinally monitored a total of 307 tumors from 96 mice using magnetic resonance imaging (MRI) and collected responding and non-responding tumors for single cell RNA sequencing (scRNAseq) to elucidate the underlying mechanisms of response. Results Surprisingly we found that TAM depletion abolished aPD-1 response, with no effect on Lenvatinib response. ScRNAseq analyses suggest that CSF1R selectively depletes antigen presenting TAMs, leading to a striking loss of T cell infiltration. This suggests that TAMs, rather than dendritic cells as shown in other cancer types, may play a dominant role in eliciting T cells during aPD-1 therapy in RCC. On the other hand, Lenvatinib, which elicited a stronger T cell response than aPD-1, was associated with significant increases in cDC1 and plasma cells in responders, together suggesting that these two treatment modalities may operate through distinct antigen-presenting cells. Also unexpectedly, we found that both Lenvatinib and CSF1Ri induced severe intratumor hypoxia, which is typically associated with poor outcomes in most cancers. We identify a hypoxic niche-specific TAM subset that when abundant at baseline is predictive for poor response to ICB/TKI combos across multiple RCC trials, but post-treatment seems to capture hypoxia-mediated tumor cell death in responders in mouse and humans. We therefore wondered whether high levels of existing tumor hypoxia would exacerbate TKI-induced hypoxia leading to worst outcomes and found that in two novel RCC syngeneic models with high-baseline hypoxia, TKI indeed augments metastatic disease. Conclusions Our results offer mechanistic insight into the failure of CSF1R-based TAM depletion approaches in clinical trials and presents cautionary evidence against the use of hypoxia-inducing agents in tumors with high-baseline hypoxia. We show that TKI and ICB-induce distinct TME and hypoxia-related changes which require further study. More generally our study strongly emphasizes the importance of developing mechanism-guided clinical biomarkers. DOD CDMRP Funding: yes

29 Pilot study of an implantable microdevice forin vivo evaluation of drug response in renal cell carcinoma (NCT05700461)

Abstract Background There are multiple therapies for renal cell carcinoma (RCC), yet no personalized biomarkers exist that can guide optimal treatment for individual patients. We developed implantable microdevices (IMD) that can be placed within a target tumor using a standard small-gauge interventional needle under imaging guidance. The IMDs deliver spatially segregated microdoses of up to 20 different drugs and/or combinations over multiple days, and then are retrieved surgically with surrounding tissue. This allows for the assessment of tumor response to multiple drugs in vivo within the native tumor microenvironment, without exposing the patient to systemic drug toxicity. We are conducting a trial to evaluate the safety and feasibility of IMD implantation in RCC tumors and subsequent collection of drug response data on targeted, cytotoxic, and immune-modulatory agents. Methods Eligible patients have suspected or confirmed RCC and are planned for standard surgical resection of either their primary tumor or metastasis. Three days prior to surgery, one or more IMDs are implanted percutaneously into the tumor under CT guidance. Following nephrectomy or excision of a metastasis, the microdevices with surrounding tumor are removed en bloc; subsequently, the tissue is fixed, embedded and sectioned. The tumor/IMD cross-sections are analyzed for drug effect for each of the spatially separate treatment effects using a wide range of techniques, including immunohistochemistry for proliferation and pathway markers, spatial immune profiling using a panel of 25 tumor microenvironment markers, and spatial transcriptomics. Patients receive subsequent standard of care systemic treatment as per their oncologist’s discretion. Five patients have been enrolled and a total of 16 IMDs have been implanted to date. Enrollment is ongoing for a planned total of 20 patients. Success is defined as meeting both safety and feasibility endpoints. Safety is defined as two or fewer safety failures out of 20 enrolled patients. Feasibility is defined as 16 or more patients with successful microdevice implantation and retrieval of interpretable data. IMDs will be analyzed to explore spatially segregated drug effects on the tumor microenvironment including tumor cell death and immune cell activation, as well as evidence of differential tumor drug sensitivity across treatments and patients. Conclusions Implantation of microdevices in RCC tumors may be a useful approach to improve treatment selection and accelerate drug development. Trial enrollment is ongoing.

Transcriptomic Meta-analysis Identifies Long Non-Coding RNAs Mediating Zika's Oncolytic Impact in Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is an aggressive and lethal form of brain cancer with few effective treatments. In this context, Zika virus has emerged as a promising therapeutic agent due to its ability to selectively infect and kill GBM cells. To elucidate these mechanisms and expand the landscape of oncolytic virotherapy, we pursued a transcriptomic meta-analysis comparing the molecular signatures of Zika infection in GBM and neuroblastoma (NBM). Over-representation analysis of dysregulated coding genes showed significant enrichment of tumor necrosis factor (TNF), NF-κB, and p53 signaling pathways. A refined list of long non-coding RNAs consistently dysregulated in Zika-infected GBMs was also developed. Functional review of these candidates revealed their potential regulatory role in Zika-mediated oncolysis. We performed validation of the less-researched targets in adult and pediatric GBM cell lines and found significant differential regulation, as predicted. Altogether, our results provide novel insights into the molecular mechanisms underlying the effect of Zika on GBM. We highlight potential therapeutic targets that could be further interrogated to improve the efficacy of tumor cell death and the utility of Zika as an adjuvant virotherapy for GBM and other related cancers.

Micro/nano system-mediated local treatment in conjunction with immune checkpoint inhibitor against advanced-Stage malignant melanoma

Tumor relapse and metastasis become a big challenge in treating malignant melanoma because conventional therapeutic options often fail to eradicate the tumor residue after surgical resection, posing huge threat to human health. Herein, a feasible strategy is developed for fighting crafty melanoma pre- and postsurgery. Specifically, nitric oxide (NO)-carried micelles (NOM) are designed by conjugating S-nitrosoglutathione (GSNO) with poly(2-ethyl-2-oxazoline)-b-poly(D, L-lactide) (PEOz-b-PLA) to form amphipathic polymer, which can self-assemble into pH-sensitive micelle to encapsulate chemotherapeutic drug paclitaxel (PTX). By further loading PTX@NOM into the needle tips of dissolvable microneedle (MN) patch, a local synergistic strategy is achieved for combating melanoma via easy insertion. Meanwhile, due to the immunomodulatory ability of NO by inducing the immunogenic cell death (ICD) of tumor cells and polarizing M2-like tumor-associated macrophages (TAMs) into antitumoral M1-like type, the “cold” immune microenvironment of melanoma is effectively remodeled. When combining with aPD-L1-based immune checkpoint blockade therapy, the treatment outcome of aPD-L1 is dramatically boosted, which not only suppresses primary tumor growth, but also inhibits the notorious post-operative melanoma recurrence and metastasis. Overall, this local strategy mediated by nanoparticle-loaded MN patch expands the therapeutic regimen for melanoma treatment in clinic.

SMAC Mimetics for the Treatment of Lung Carcinoma: Present Development and Future Prospects.

Uncontrolled cell growth and proliferation, which originate from lung tissue often lead to lung carcinoma and are more likely due to smoking as well as inhaled environmental toxins. It is widely recognized that tumour cells evade the ability of natural programmed death (apoptosis) and facilitates tumour progression and metastasis. Therefore investigating and targeting the apoptosis pathway is being utilized as one of the best approaches for decades. This review describes the emergence of SMAC mimetic drugs as a treatment approach, its possibilities to synergize the response along with current limitations as well as future perspective therapy for lung cancer. Articles were analysed using search engines and databases namely Pubmed and Scopus. Under cancerous circumstances, the level of Inhibitor of Apoptosis Proteins (IAPs) gets elevated, which suppresses the pathway of programmed cell death, plus supports the proliferation of lung cancer. As it is a major apoptosis regulator, natural drugs that imitate the IAP antagonistic response like SMAC mimetic agents/Diablo have been identified to trigger cell death. SMAC i.e. second mitochondria activators of caspases is a molecule produced by mitochondria, stimulates apoptosis by neutralizing/inhibiting IAP and prevents its potential responsible for the activation of caspases. Various preclinical data have proven that these agents elicit the death of lung tumour cells. Apart from inducing apoptosis, these also sensitize the cancer cells toward other effective anticancer approaches like chemo, radio, or immunotherapies. There are many SMAC mimetic agents such as birinapant, BV-6, LCL161, and JP 1201, which have been identified for diagnosis as well as treatment purposes in lung cancer and are also under clinical investigation. SMAC mimetics acts in a restorative way in the prevention of lung cancer.

Synergistic Photothermal Tumor Immunotherapy by 1-MT Based on Zeolitic Imidazolate Framework-8 with pH-High Sensitivity.

A successful immune response against tumors depends on various cellular processes. Hence, there is an urgent need to construct a proficient nanoplatform for immunotherapy that can concurrently regulate the activities of various cells participating in the immune process. We have developed zeolitic imidazolate framework-8 (ZIF-8) formula, with good pH sensitivity, which is conducive to the release of drugs in the tumor site (acidic environment) and significantly improves immunotherapy. This is achieved through the coordinated action of different therapeutic agents, such as the photothermal agent polydopamine (PDA), the chemodrug camptothecin (CPT), and the immunomodulator 1-methyl-D-tryptophan (1-MT). In this study, we evaluated the antitumor effect of PDA/(CPT + 1-MT) @ZIF-8 (PCMZ) nanoparticles (NPs) in vitro and in vivo and investigated the molecular mechanism of PCMZ NPs in tumor suppression via photothermal-chemo-immunotherapy. MTT and Annexin V-FITC/PI double staining apoptosis test showed that PCMZ NPs could induce apoptosis of 4T1 cell, and PCMZ NPs could cause 4T1 cell necrosis under 808 nm laser irradiation. The objective is to establish a unilateral breast cancer model in mice and investigate the effect of PCMZ NPs on tumor growth and tumor suppression in tumor bearing mice. The results showed that PCMZ NPs showed good heating effect in vivo and effectively inhibited tumor growth under 808 nm laser irradiation. In addition, PCMZ NPs could induce the immunogenic death of tumor cells, promote the maturation of DCs, inhibit IDO pathway, and finally differentiate T cells into cytotoxic T cells and helper T cells, so as to effectively activate the anti-tumor immune response. The PCMZ NPs, possessing good photothermal conversion capabilities due to join of PDA, effectively overcome two main challenges in immunotherapy: insufficient stimulation of the immune response and evasion of the immune system. This provides a robust platform against invasive cancer and recurrent tumors.

Effect of Selinexor on Proliferation and Apoptosis of Acute Myeloid Leukemia Kasumi-1 Cells

To investigate the effects of selinexor, a inhibitor of nuclear export protein 1 (XPO1) on the proliferation inhibition and apoptosis of Kasumi-1 cells in acute myeloid leukemia (AML). MTS method was used to detect the inhibitory effect of different concentrations of selinexor on the proliferation of Kasumi-1 cells at different time points. The apoptosis rate and cell cycle changes after treatment with different concentration of selinexor were detected by flow cytometry. Selinexor inhibited the growth of Kasumi-1 cells at different time points in a concentration-dependent manner (r 24 h=0.7592, r 48 h=0.9456, and r 72 h=0.9425). Selinexor inhibited Kasumi-1 cells growth in a time-dependent manner (r =0.9057 in 2.5 μmol/L group, r =0.9897 in 5 μmol/L group and r =0.9994 in 10 μmol/L group). Selinexor could induce apoptosis of Kasumi-1 cells in a dose-dependent manner (r =0.9732), and the apoptosis of Kasumi-1 cells was more obvious with the increase of drug concentration. The proportion of G0/G1 phase was significantly increased and the proportion of S phase was significantly decreased after the treatment of Kasumi-1 cells by selinexor. With the increase of drug concentration, the proportion of Kasumi-1 cells cycle arrest in G0/G1 phase was increased and the cell synthesis was decreased. Selinexor can promote the death of tumor cells by inhibiting Kasumi-1 cells proliferation, inducing apoptosis and blocking cell cycle.

Blockade of glucose-6-phosphate dehydrogenase induces immunogenic cell death and accelerates immunotherapy

BackgroundEnhanced glucose metabolism has been reported in many cancers. Glucose-6-phosphate dehydrogenase (G6PD) is a rate-limiting enzyme involved in the pentose phosphate pathway, which maintains NADPH levels and protects cells from...

Cationic liposomes overcome neutralizing antibodies and enhance reovirus efficacy in ovarian cancer

Reovirus (Reo) has shown promising potential in specifically killing tumor cells, and offering new possibilities for ovarian cancer (OC) treatment. However, neutralizing antibodies in the ascites from OC patients greatly limit the further application of Reo. In this study, we employed cationic liposomes (Lipo) to deliver Reo, significantly enhancing its ability to enter OC cells and its effectiveness in killing these cells under ascitic conditions. Pre-treatment with the MβCD inhibitor notably decreased Reo-mediated tumor cell death, indicating that Lipo primarily enables Reo's cellular uptake through caveolin-mediated endocytosis. Our results demonstrate that Lipo effectively facilitates the entry of Reo into the cytoplasm and triggers cell apoptosis. The above findings provide a new strategy to overcome the obstacle of neutralizing antibodies in the clinical application of Reo.

Kuwanon C Inhibits Tumor Cell Proliferation and Induces Apoptosis by Targeting Mitochondria and Endoplasmic Reticulum.

Kuwanon C is a unique flavonoid found in the mulberry family, characterized by two isopentenyl groups. While previous research has focused on various properties of kuwanon C, such as antioxidant, hypoglycemic, antimicrobial, food preservation, skin whitening, and nematode lifespan extension, little attention has been given to its potential role in oncological diseases. In this study, we investigate the antitumor effect of kuwanon C in cervical cancer cells and elucidate its specific mechanism of action. We assessed the antitumor effects of kuwanon C using various experimental techniques, including cell proliferation assay, wound healing assays, EdU 488 proliferation assay, mitochondrial membrane potential assay, ROS level assay, cell cycle, apoptosis analysis, and studies on kuwanon C target sites and molecular docking. The results revealed that kuwanon C significantly impacted the cell cycle progression of HeLa cells, disrupted their mitochondrial membrane potential, and induced a substantial increase in intracellular ROS levels. Moreover, kuwanon C exhibited notable anti-proliferative and pro-apoptotic effects on HeLa cells, surpassing the performance of commonly used antitumor drugs such as paclitaxel and cisplatin. Notably, kuwanon C demonstrated superior efficacy while also being more easily accessible compared to paclitaxel. Our study demonstrates that kuwanon C exerts potent antitumor effects by its interaction with the mitochondrial and endoplasmic reticulum membranes, induces a significant production of ROS, disrupts their normal structure, inhibits cell cycle progression, and stimulates apoptotic signaling pathways, ultimately resulting in the death of HeLa tumor cells. As an isopentenyl compound derived from Morus alba, kuwanon C holds great promise as a potential candidate for the development of effective antitumor drugs.

Changes in Histone Code Regulation during the Initiation of Paraptosis-Like Death of HEp-2 Tumor Cells by Oxidized Disulfiram Derivatives

Disulfiram (DSF) and its oxidized derivatives (DSFoxy) are currently being investigated as possible anticancer agents. We previously found that DSFoxy initiate paraptosis-like death of tumor cells, which is of potential interest for the treatment of tumors resistant to the initiation of apoptosis. Based on bioinformatics analysis of mass spectrometric data on protein ubiquitination, we formulated a conception about the important role of disruption of the retrograde transport of damaged proteins from the endoplasmic reticulum to the cytosol in the mechanism of initiation of paraptosis-like cell death. In the present work, it was found that DSFoxy, in the process of initiating paraptosis-like death of human adenocarcinoma HEp-2 cells, also enhances the ubiquitination of histones and histone code enzymes. In particular, this applies to the ubiquitination of histone H2BC12, histone methyltransferases responsible for transcription and repair of damaged DNA, as well as acetylating and ubiquitin-conjugating proteins. Bioinformatics analysis of changes in ubiquitination of cell nuclear proteins using the STRING database revealed during this process an increase in the occurrence of ubiquitinated proteins (functional enrichment) of cell cycle regulation, cell response to DNA damage and DNA repair, the regulation of which also depends on the histone code. This directly indicates damage to the cell nucleus and is consistent with confocal microscopy data. These results indicate that when paraptosis-like death is initiated by DSFoxy, along with impairment of retrograde transport and ER stress, there is also a change in the regulation of the histone code, which points to a pleotropic mechanism of cell death induction.

Sphingolipid metabolism and regulated cell death in malignant melanoma.

Malignant melanoma (MM) is a highly invasive and therapeutically resistant skin malignancy, posing a significant clinical challenge in its treatment. Programmed cell death plays a crucial role in the occurrence and progression of MM. Sphingolipids (SP), as a class of bioactive lipids, may be associated with many kinds of diseases. SPs regulate various forms of programmed cell death in tumors, including apoptosis, necroptosis, ferroptosis, and more. This review will delve into the mechanisms by which different types of SPs modulate various forms of programmed cell death in MM, such as their regulation of cell membrane permeability and signaling pathways, and how they influence the survival and death fate of MM cells. An in-depth exploration of the role of SPs in programmed cell death in MM aids in unraveling the molecular mechanisms of melanoma development and holds significant importance in developing novel therapeutic strategies.

Aptamin C enhances anti-cancer activity NK cells through the activation of STAT3: a comparative study with vitamin C.

Vitamin C is a well-known antioxidant with antiviral, anticancer, and anti-inflammatory properties based on its antioxidative function. Aptamin C, a complex of vitamin C with its specific aptamer, has been reported to maintain or even enhance the efficacy of vitamin C while increasing its stability. To investigate in vivo distribution of Aptamin C, Gulo knockout mice, which, like humans, cannot biosynthesize vitamin C, were administered Aptamin C orally for 2 and 4 weeks. The results showed higher vitamin C accumulation in all tissues when administered Aptamin C, especially in the spleen. Next, the activity of natural killer (NK) cells were conducted. CD69, a marker known for activating for NK cells, which had decreased due to vitamin C deficiency, did not recover with vitamin C treatment but showed an increasing with Aptamin C. Furthermore, the expression of CD107a, a cell surface marker that increases during the killing process of target cells, also did not recover with vitamin C but increased with Aptamin C. Based on these results, when cultured with tumor cells to measure the extent of tumor cell death, an increase in tumor cell death was observed. To investigate the signaling mechanisms and related molecules involved in the proliferation and activation of NK cells by Aptamin C showed that Aptamin C treatment led to an increase in intracellular STAT3 activation. In conclusion, Aptamin C has a higher capability to activate NK cells and induce tumor cell death compared to vitamin C and it is mediated through the activation of STAT3.

Perovskite-structured ultrasensitive CaMnO3 nanoenzyme enables highly efficient ultrasound-amplified and catalysis-involved synergistic tumor therapy

Catalytic nanoenzyme-mediated therapy with reactive oxygen species generation feature and tumor microenvironment regulation characteristic has demonstrated high therapeutic efficacy in oncological field, whereas its low enzyme-mimicking reaction efficacy typically results in dissatisfied therapeutic effect and outcome. Herein, an ultrasensitive CaMnO3 (CMO) nanoenzyme has been rationally designed and engineered for enzyodynamic-calcium overload synergistic tumor therapy. CMO nanoenzyme with oxidase (OXD)-, peroxidase (POD)- and glutathione peroxidase (GPx)-mimic activities is responsible for the generation of reactive oxygen species, the consumption of intra-tumor glutathione and mitochondrial damage. For the evaluation of OXD and POD-mimicking activities, CMO with ultra low concentration (1 μg ml−1) can rapidly catalyze the color reaction of 3,3′,5,5′-tetramethylbenzidine (TMB) hydrochloride and reach the reaction termination in a very short time (1 s). Moreover, the release and overload of Ca2+ strengthen the tumor cell death. Exogenous ultrasound stimulation further amplifies the enzyodynamic-Ca2+ overload synergistic tumor-therapeutic efficacy. In vitro and in vivo results affirm the transcendent antineoplastic outcomes of CMO. Meanwhile, the existence of Mn2+ endows nanoenzyme with T1-weighted MR imaging capacity. This work provides new strategies for efficient enzyme-mimicking activity and tumor synergistic treatment based on new perspectives on the engineering of multifunctional therapeutic nanomedicine.

Disentangling Anti-Tumor Response of Immunotherapy Combinations: APhysiologically Based Framework for V937Oncolytic Virus and Pembrolizumab.

Immuno-oncology (IO) is a growing strategy in cancer treatment. Oncolytic viruses (OVs) can selectively infect cancer cells and lead to direct and/or immune-dependent tumor lysis. This approach represents an opportunity to potentiate the efficacy of immune checkpoint inhibitors (ICI), such as pembrolizumab. Currently, there is a lack of comprehensive quantitative models for the aforementioned scenarios. In this work, we developed a mechanistic framework describing viral kinetics, viral dynamics, and tumor response after intratumoral (i.t.) or intravenous (i.v.) administration of V937 alone or in combination with pembrolizumab. The model accounts for tumor shrinkage, in both injected and non-injected lesions, induced by: viral-infected tumor cell death and activated CD8 cells. OV-infected tumor cells enhanced the expansion of CD8 cells, whereas pembrolizumab inhibits their exhaustion by competing with PD-L1 in their binding to PD-1. Circulating viral levels and treatment effects on tumor volume were adequately characterized in all the different scenarios. This mechanistic-based model has been developed by combining top-down and bottom-up approaches and provides individual estimates of viral and ICI responses. The robustness of the model is reflected by the description of the tumor size time profiles in a variety of clinical scenarios. Additionally, this platform allows us to investigate not only the contribution of processes related to the viral kinetics and dynamics on tumor response, but also the influence of its interaction with an ICI. Additionally, the model can be used to explore different scenarios aiming to optimize treatment combinations and support clinical development.

STING activation disrupts tumor vasculature to overcome the EPR limitation and increase drug deposition.

The low success rate of cancer nanomedicines has raised debate on the role of the enhanced permeability and retention (EPR) effect on tumor deposition of nanotherapeutics. Here, we report a bifunctional nanoscale coordination polymer (NCP), oxaliplatin (OX)/2',3'-cyclic guanosine monophosphate-adenosine monophosphate (GA), to overcome the EPR limitation through stimulator of interferon genes (STING) activation and enhance chemotherapeutic and STING agonist delivery for tumor eradication. OX/GA encapsulates GA and OX in the NCP to protect GA from enzymatic degradation and improve GA and OX pharmacokinetics. STING activation by OX/GA disrupts tumor vasculatures and increases intratumoral deposition of OX by 4.9-fold over monotherapy OX-NCP. OX/GA demonstrates exceptional antitumor effects with >95% tumor growth inhibition and high cure rates in subcutaneous, orthotopic, spontaneous, and metastatic tumor models. OX/GA induces immunogenic cell death of tumor cells and STING activation of innate immune cells to enhance antigen presentation. NCPs provide an excellent nanoplatform to overcome the EPR limitation for effective cancer therapy.

Tarlatamab: First Approval.

Tarlatamab (tarlatamab-dlle: IMDELLTRA™) is a first-in-class, half-life extended bispecific delta-like ligand 3 (DLL3)-directed CD3 T-cell engager being developed by Amgen for the treatment of small cell lung cancer (SCLC) and neuroendocrine prostate cancer. Tarlatamab binds to DLL3 on the surface of tumour cells and CD3 on the surface of cytotoxic T lymphocytes (CTLs), resulting in T-cell activation, release of inflammatory cytokines and CTL-mediated cell death of DLL3-expressing tumour cells. In May 2024, tarlatamab received its first approval in the USA for the treatment of adults with extensive stage SCLC (ES-SCLC) with disease progression on or after platinum-based chemotherapy. Tarlatamab received accelerated approval for this indication based on overall response rate and duration of response in the pivotal phase 2 DeLLphi-301 study, and continued approval may be contingent on the demonstration of clinical benefit in a confirmatory trial(s). Tarlatamab is under regulatory review in Brazil, Canada, Israel and the UK, and clinical studies are underway in multiple countries. This article summarizes the milestones in the development of tarlatamab leading to this first approval for ES-SCLC with disease progression on or after platinum-based chemotherapy.