Syngeneic Mouse Tumor Models Research Articles

The molar dose of FAPI administered impacts on the FAP-targeted PET imaging and therapy in mouse syngeneic tumor models.

Since fibroblast activation protein (FAP), one predominant biomarker of cancer associated fibroblasts (CAFs), is highly expressed in the tumor stroma of various epidermal-derived cancers, targeting FAP for tumor diagnosis and treatment has shown substantial potentials in both preclinical and clinical studies. However, in preclinical settings, tumor-bearing mice exhibit relatively low absolute FAP expression levels, leading to challenges in acquiring high-quality PET images using radiolabeled FAP ligands (FAPIs) with low molar activity, because of which a saturation effect in imaging is prone to happen. Moreover, how exactly the molar dose of FAPI administered to a mouse influences the targeted PET imaging and radiotherapy remains unclear now. Therefore, this study aims to investigate the impacts of the molar dose of the administered FAPI on FAP-targeted PET imaging and radiotherapy in mouse syngeneic tumor models. [68Ga]Ga-FAPI-04 with various molar doses of FAPI-04 was administered to wild-type 4T1 tumor-bearing mice, followed by static PET imaging. Sigmoidal curves were generated to analyze the correlation between the standard uptake value (SUV) and the administered molar doses of FAPI-04. Similarly, [177Lu]Lu-DOTAGA.(SA.FAPi)2 with a consistent dose of radioactivity but containing different moles of DOTAGA.(SA.FAPi)2 were injected into 4T1 tumor-bearing mice to assess the therapeutic effect. [68Ga]Ga-FAPI-04 was also applied to different tumor models for PET/CT imaging. A gradient blocking effect was observed with increasing FAPI molar dose in [68Ga]Ga-FAPI-04 PET imaging and [177Lu]Lu-DOTAGA.(SA.FAPi)2 treatment, with various imaging and therapeutic outcomes. [68Ga]Ga-FAPI-04 PET exhibit potentials to characterize murine derived FAP expression with low molar dose of administered FAPI-04 using various tumor models. The molar dose of FAPI in [68Ga]Ga/[177Lu]Lu-FAPI had a substantial impact on FAP-targeted imaging and therapy in mouse syngeneic tumor models. To acquire enhanced reliability and reproducibility in preclinical situation, it is critical to carefully consider the molar dose of the radiotracer when applying radiolabeled FAP ligands to FAP-targeted imaging and radiotherapy.

Itaconate transporter SLC13A3 confers immunotherapy resistance via alkylation-mediated stabilization of PD-L1.

Itaconate is a metabolite catalyzed by cis-aconitate decarboxylase (ACOD1), which is mainly produced by activated macrophages and secreted into the extracellular environment to exert complex bioactivity. In the tumor microenvironment, itaconate is concentrated and induces an immunosuppressive response. However, whether itaconate can be taken up by tumor cells and its mechanism of action remain largely unclear. Here, we identified solute carrier family 13 member 3 (SLC13A3) as a key protein transporting extracellular itaconate into cells, where it elevates programmed cell death ligand 1 (PD-L1) protein levels and decreases the expression of immunostimulatory molecules, thereby promoting tumor immune evasion. Mechanistically, itaconate alkylates the cysteine 272 residue on PD-L1, antagonizing PD-L1 ubiquitination and degradation. Consequently, SLC13A3 inhibition enhances the efficacy of anti-CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) immunotherapy and improves the overall survival rate in syngeneic mouse tumor models. Collectively, our findings identified SLC13A3 as a key transporter of itaconate and revealed its immunomodulatory role, providing combinatorial strategies to overcome immunotherapy resistance in tumors.

Cancer vaccines compensate for the insufficient induction of protective tumor-specific immunity of CD3 bispecific antibody therapy

BackgroundCD3 bispecific antibody (CD3 bsAb) therapy has become an established treatment modality for some cancer types and exploits endogenous T cells irrespective of their specificity. However, durable clinical responses are...

Discovery of a non-nucleotide stimulator of interferon genes (STING) agonist with systemic antitumor effect.

Agonists of the stimulator of interferon genes (STING) pathway are increasingly being recognized as a promising new approach in the treatment of cancer. Although progress in clinical trials for STING agonists in antitumor applications has been slow, there is still an urgent need for developing new potent STING agonists with versatile potential applications. Herein, we developed and identified a non-nucleotide STING agonist called DW18343. DW18343 showed robust activation across different STING isoforms. Crystallography analysis revealed that DW18343 binds more deeply into the ligand binding domain (LBD) pocket of STING-H232 compared to other agonists such as MSA-2, SR-717, or cGAMP, which likely contributes to its high potency. DW18343 triggered downstream p-TBK1/p-IRF3 signaling, leading to the production of multiple cytokines. Additionally, DW18343 displayed broad and long-lasting antitumor effects in various syngeneic mouse tumor models, whether administered locally or systemically. Moreover, DW18343 induced immune memory to combat the growth of rechallenged tumors. Finally, DW18343 was shown to be an activator of both the innate and adaptive antitumor immunity in tumor tissue, potentially explaining its strong antitumor effects in vivo. In conclusion, DW18343 serves as a novel non-nucleotide STING agonist with systemic antitumor effect through the activation of antitumor immunity.

PK/PD Evaluation of Antibody-Drug Conjugates with Enhanced Immune Effector Functions.

Optimizing the interaction between antibody (mAb)-based therapeutics and immune effector functions (EFs) offers opportunities to improve the therapeutic window of these molecules. However, the role of EFs in antibody-drug conjugate (ADC) efficacy and toxicity remains unknown, with limited studies that have investigated how modulation of EF affects the pharmacology of ADCs. This study aimed to evaluate the effect of EF modulation on ADC efficacy using trastuzumab-vc-MMAE as a model ADC. A series of ADCs with enhanced or eradicated EF were synthesized through Fc engineering of the antibody. Cell-based assays confirmed that the alteration of EFs in ADCs did not change their in vitro potency, and the conjugation of vc-MMAE did not alter the trends in EFs modulation. Pharmacokinetic/pharmacodynamic (PK/PD) studies of Fc engineered ADCs were conducted in a syngeneic mouse system. The enhancement of EFs led to lower systemic exposure, faster clearance, and potentially enhanced tissue distribution and accumulation of ADCs. ADCs with enhanced EFs demonstrated improved efficacy in the syngeneic mouse tumor model, which was quantitatively confirmed by PK/PD modeling. The model indicated that EF enhancement was synergistic for ADC efficacy, whereas the complete removal of EF was less than additive. Our study suggests that developing ADCs with enhanced EF may improve the therapeutic effectiveness of ADCs, although the effect of this modification on ADC safety and extrapolation of our findings to other ADCs necessitates further investigation.

CDC20-Mediated Selective Autophagy Degradation of PBRM1 Affects Immunotherapy for Renal Cell Carcinoma.

Polybromo 1 (PBRM1) inactivating mutations are associated with clinical benefit from immune checkpoint inhibitor treatments in clear cell renal cell carcinoma (ccRCC). However, whether targeting PBRM1 has the potential to enhance immunotherapy efficacy in patients with wild-type PBRM1 and the upstream pathways that regulate PBRM1 protein stability remain unclear. Here, it is demonstrated that PBRM1 knockdown induced M1 macrophage polarization and infiltration, which enhanced the efficacy of anti-PD-1 immunotherapy in RCC. Meanwhile, CDC20 catalyzes K27 ubiquitination of PBRM1 and promotes its degradation via p62-mediated selective autophagy. A bicyclic peptide (PB1-p62) is designed and constructed to target PBRM1 and p62, thereby promoting the degradation of PBRM1. As a result, the efficacy of anti-PD-1 immunotherapy is enhanced, leading to improved overall survival rates in syngeneic mouse tumor models. Overall, this finding suggest the clinical application of PB1-p62 and provide a novel approach for enhancing the effectiveness of immunotherapy in RCC patients with wild-type PBRM1.

RNA N6-Methyladenosine-Binding Protein YTHDFs Redundantly Attenuate Cancer Immunity by Downregulating IFN-γ Signaling in Gastric Cancer.

Immunotherapy holds potential as a treatment for gastric cancer (GC), though immune checkpoint inhibitor (ICI) resistance remains an obstacle. One resistance mechanism involves defects in interferon-γ (IFN-γ) signaling, in which IFN-γ is linked to improved responsiveness to ICIs. Herein, the roles of RNA N6-methyladenosine (m6A) modifications in regulation of IFN-γ signaling and the responsiveness to ICIs are unveiled. The m6A-binding protein YTH N6-methyladenosine RNA-binding protein F1 (YTHDF1) is overexpressed in GC tissues, correlating with the suppression of cancer immunity and poorer survival rates. YTHDF1 overexpression impaired the responsiveness to IFN-γ in GC cells, and knockdown studies indicated the redundant effects of YTHDF2 and YTHDF3 with YTHDF1 in IFN-γ responsiveness. RNA immunoprecipitation sequencing revealed YTHDFs directly target interferon regulatory factor 1 (IRF1) mRNA, a master regulator of IFN-γ signaling, leading to reduced RNA stability and consequent downregulation of IFN-γ signaling. Furthermore, in mouse syngeneic tumor models, Ythdf1 depletion in cancer cells resulted in reduced tumor growth and increased tumor-infiltrating lymphocytes, which are attributed to the augmentation of IFN-γ signaling. Collectively, these findings highlight how YTHDFs modulate cancer immunity by influencing IFN-γ signaling through IRF1 regulation, suggesting their viability as therapeutic targets in cancer immunotherapy.

Oncolytic virus encoding 4-1BBL and IL15 enhances the efficacy of tumor-infiltrating lymphocyte adoptive therapy in HCC.

Previous studies have found that oncolytic virus (OVs) can improve the efficacy of TIL adoptive therapy in oral cancer, colon cancer, and pancreatic cancer. However, the curative effect in hepatocellular carcinoma (HCC) is still unclear. Therefore, this study aims to explore the therapeutic effect and mechanism of OVs encoding 4-1BBL and IL15 (OV-4-1BBL/IL15) combined with TIL adoptive therapy on HCC. In this study, the role and immunological mechanism of armed OVs combined with TILs were evaluated by flow cytometry and ELISA in patient-derived xenograft and syngeneic mouse tumor models. Co-culturing with TILs can up-regulate the expression of antigen-presenting cell (APC) markers on the surface of OV-infected primary HCC cells, and promote the specific activation ability and tumor-killing ability of TILs. OV-4-1BBL/IL15 combined with TIL adoptive therapy could induce tumor volume reduction and anti-tumor immune memory in patient-derived xenograft and syngeneic mouse tumor models. Furthermore, OV combined with TIL adoptive therapy can endow tumor cells with aAPC characteristics, activate T cells at the same time, and reprogram tumor macrophages into anti-tumor phenotype. OV-4-1BBL/IL15 can stimulate the anti-tumor potential of TIL therapy in HCC, and possess broad clinical application prospects.

Abstract B001: CircRNA-derived neoantigen identification in cancer vaccine development

Abstract Immunotherapy has been a popular topic in combating cancer for its great performance in specificity, versatility and durability recently. Cancer vaccines targeting neoantigens have shown clinical efficacy against cancer, eliciting long-lasting immune response and offering a more selective therapeutic approach with less side effects. However, rare mutation rates and low expression levels of neoantigen make it challenging to identify suitable neoantigens. Traditionally, researchers focus on the canonical mRNA transcriptome and proteome to find potential targets. Recent studies suggest that exploring the non-canonical transcriptome and proteome, particularly circular RNAs (circRNAs), can expand the search. CircRNAs, endogenously formed by the unique back-splicing events during pre-RNA processing, can serve as templates for protein synthesis. Some of these non-canonical peptides are specifically expressed in cancer cells, making circRNAs a valid source for neoantigen discovery. We have developed high-throughput circRNA reporter screening methods and mass spectrometry-based peptidomic workflow to pinpoint translating circRNAs and their derived peptides. Using these techniques, we have identified circRNA-derived neoantigens in breast cancer (BC) cell lines that can be used as possible targets for cancer vaccines. These circRNA-derived neoantigens are immunogenic and can trigger dendritic cell (DC) maturation and T cell activation in vitro. Next, we will test these findings by transferring to in vivo mouse system. We will assess cancer vaccine efficacy by targeting the neoantigens using syngeneic mouse tumor models. Our long- term goal is to apply the circRNA neoantigen identification technology to BC patient samples to facilitate cancer vaccine development and improve cancer immunotherapy. Our work will demonstrate the potential of circRNA-derived non canonical neoantigens in cancer vaccines, serving as a crucial first step to prove their effectiveness in therapy. By expanding our search beyond the traditional transcriptome and proteome, we will explore new targets and transform the neoantigen-based treatment. This innovative effort shifts the current understanding of neoantigen sources and opens up new possibilities for targeted cancer therapy strategies. Citation Format: Yi-Cian Zheng, Chun-Kan Chen. CircRNA-derived neoantigen identification in cancer vaccine development [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr B001.

Microdissected tumor cuboids: a microscale cancer model for large-scale testing that retains a complex tumor microenvironment.

To bridge the gap between bench and bedside, there is a need for more faithful models of human cancers that can recapitulate key features of the human tumor microenvironment (TME) and simultaneously facilitate large-scale drug tests. Our recently developed microdissection method optimizes the yield of large numbers of cuboidal microtissues (″cuboids″, ~(400 µm) 3 ) from a tumor biopsy. Here we demonstrate that cuboids from syngeneic mouse tumor models and human tumors retain a complex TME, making them amenable for drug and immunotherapy evaluation. We characterize relevant TME parameters, such as cellular architecture, cytokine secretion, proteomics profiles, and response to drug panels in multi-well arrays. Despite the cutting procedure and the time spent in culture (up to 7 days), the cuboids display strong cytokine expression and drug responses, including to immunotherapy. Overall, our results suggest that cuboids could provide essential therapeutic information for personalized oncology applications and could help the development of TME-dependent therapeutics and cancer disease models, including for clinical trials.

A splicing isoform of PD-1 promotes tumor progression as a potential immune checkpoint

The immune checkpoint receptor, programmed cell death 1 (PD-1, encoded by PDCD1), mediates the immune escape of cancer, but whether PD-1 splicing isoforms contribute to this process is still unclear. Here, we identify an alternative splicing isoform of human PD-1, which carries a 28-base pairs extension retained from 5′ region of intron 2 (PD-1^28), is expressed in peripheral T cells and tumor infiltrating lymphocytes. PD-1^28 expression is induced on T cells upon activation and is regulated by an RNA binding protein, TAF15. Functionally, PD-1^28 inhibits T cell proliferation, cytokine production, and tumor cell killing in vitro. In vivo, T cell-specific exogenous expression of PD-1^28 promotes tumor growth in both a syngeneic mouse tumor model and humanized NOG mice inoculated with human lung cancer cells. Our study thus demonstrates that PD-1^28 functions as an immune checkpoint, and may contribute to resistance to immune checkpoint blockade therapy.

Local delivery of cell surface-targeted immunocytokines programs systemic antitumor immunity

Systemically administered cytokines are potent immunotherapeutics but can cause severe dose-limiting toxicities. To overcome this challenge, cytokines have been engineered for intratumoral retention after local delivery. However, despite inducing regression of treated lesions, tumor-localized cytokines often elicit only modest responses at distal untreated tumors. In the present study, we report a localized cytokine therapy that safely elicits systemic antitumor immunity by targeting the ubiquitous leukocyte receptor CD45. CD45-targeted immunocytokines have lower internalization rates relative to wild-type counterparts, leading to sustained downstream cis and trans signaling between lymphocytes. A single intratumoral dose of αCD45-interleukin (IL)-12 followed by a single dose of αCD45-IL-15 eradicated treated tumors and untreated distal lesions in multiple syngeneic mouse tumor models without toxicity. Mechanistically, CD45-targeted cytokines reprogrammed tumor-specific CD8+ T cells in the tumor-draining lymph nodes to have an antiviral transcriptional signature. CD45 anchoring represents a broad platform for protein retention by host immune cells for use in immunotherapy.

ALK5/VEGFR2 dual inhibitor TU2218 alone or in combination with immune checkpoint inhibitors enhances immune-mediated antitumor effects

Transforming growth factor β (TGFβ) is present in blood of patients who do not respond to anti-programmed cell death (ligand) 1 [PD-(L)1] treatment, and through synergy with vascular endothelial growth factor (VEGF), it helps to create an environment that promotes tumor immune evasion and immune tolerance. Therefore, simultaneous inhibition of TGFβ/VEGF is more effective than targeting TGFβ alone. In this study, the dual inhibitory mechanism of TU2218 was identified through in vitro analysis mimicking the tumor microenvironment, and its antitumor effects were analyzed using mouse syngeneic tumor models. TU2218 directly restored the activity of damaged cytotoxic T lymphocytes (CTLs) and natural killer cells inhibited by TGFβ and suppressed the activity and viability of regulatory T cells. The inactivation of endothelial cells induced by VEGF stimulation was completely ameliorated by TU2218, an effect not observed with vactosertib, which inhibits only TGFβ signaling. The combination of TU2218 and anti-PD1 therapy had a significantly greater antitumor effect than either drug alone in the poorly immunogenic B16F10 syngeneic tumor model. The mechanism of tumor reduction was confirmed by flow cytometry, which showed upregulated VCAM-1 expression in vascular cells and increased influx of CD8 + CTLs into the tumor. As another strategy, combination of anti-CTLA4 therapy and TU2218 resulted in high complete regression (CR) rates in CT26 and WEHI-164 tumor models. In particular, immunological memory generated by the combination of anti-CTLA4 and TU2218 in the CT26 model prevented the development of tumors after additional tumor cell transplantation, suggesting that the TU2218-based combination has therapeutic potential in immunotherapy.

OMIP-105: A 30-color full-spectrum flow cytometry panel to characterize the immune cell landscape in spleen and tumor within a syngeneic MC-38 murine colon carcinoma model.

This panel was designed to characterize the immune cell landscape in the mouse tumor microenvironment as well as mouse lymphoid tissues (e.g., spleen). As an example, using the MC-38 mouse syngeneic tumor model, we demonstrated that we could measure the frequency and characterize the functional status of CD4 T cells, CD8 T cells, regulatory T cells, NK cells, B cells, macrophages, granulocytes, monocytes, and dendritic cells. This panel is especially useful for understanding the immune landscape in "cold" preclinical tumor models with very low immune cell infiltration and for investigating how therapeutic treatments may modulate the immune landscape.

Genome-wide CRISPR screening identifies tyrosylprotein sulfotransferase-2 as a target for augmenting anti-PD1 efficacy

BackgroundImmune checkpoint therapy (ICT) provides durable responses in select cancer patients, yet resistance remains a significant challenge, prompting the exploration of underlying molecular mechanisms. Tyrosylprotein sulfotransferase-2 (TPST2), known for its role in protein tyrosine O-sulfation, has been suggested to modulate the extracellular protein-protein interactions, but its specific role in cancer immunity remains largely unexplored.MethodsTo explore tumor cell-intrinsic factors influencing anti-PD1 responsiveness, we conducted a pooled loss-of-function genetic screen in humanized mice engrafted with human immune cells. The responsiveness of cancer cells to interferon-γ (IFNγ) was estimated by evaluating IFNγ-mediated induction of target genes, STAT1 phosphorylation, HLA expression, and cell growth suppression. The sulfotyrosine-modified target gene of TPST2 was identified by co-immunoprecipitation and mass spectrometry. The in vivo effects of TPST2 inhibition were evaluated using mouse syngeneic tumor models and corroborated by bulk and single-cell RNA sequencing analyses.ResultsThrough in vivo genome-wide CRISPR screening, TPST2 loss-of-function emerged as a potential enhancer of anti-PD1 treatment efficacy. TPST2 suppressed IFNγ signaling by sulfating IFNγ receptor 1 at Y397 residue, while its downregulation boosted IFNγ-mediated signaling and antigen presentation. Depletion of TPST2 in cancer cells augmented anti-PD1 antibody efficacy in syngeneic mouse tumor models by enhancing tumor-infiltrating lymphocytes. RNA sequencing data revealed TPST2’s inverse correlation with antigen presentation, and increased TPST2 expression is associated with poor prognosis and altered cancer immunity across cancer types.ConclusionsWe propose TPST2’s novel role as a suppressor of cancer immunity and advocate for its consideration as a therapeutic target in ICT-based treatments.

Targeting TNFRSF25 by agonistic antibodies and multimeric TL1A proteins co-stimulated CD8+ T cells and inhibited tumor growth

BackgroundTumor necrosis factor receptor superfamily 25 (TNFRSF25) is a T-cell co-stimulatory receptor. Expression of its ligand, TNF-like cytokine 1A (TL1A), on mouse tumor cells has been shown to promote tumor...

An exhaustive pre-clinical study of a circRNA drug candidate (cmRNA1210) encoding IL-12sc for anti-tumor therapeutics.

e14569 Background: Circular RNA as emerging technology hasn't been approved of acceptance of any IND application. What’s the pharmacokinetics, pharmacodynamics and toxicity study of circular RNA drug candidate would be like is still unpublished. Here we provide an exhaustive pre-clinical study of a novel circular RNA drug candidate encoding IL-12sc, the immune stimulatory effector. Methods: Here, we performed an exhaustive pre-clinical study of a circular RNA drug candidate(cmRNA1210) encoding IL-12sc, including pharmacokinetics, pharmacodynamics, pharmacology and toxicology study. Meanwhile, we explored the bioactivity and cross reactivity of cmRNA1210 in vitro and the pharmacokinetics in vivo. Results: cmRNA1210 and its replace molecule exhibits robust therapeutic effect and good safety in syngeneic mouse tumor model and humanized human tumor mouse model. In situ administration of cmRNA1210 achieves abscopal effect and inhibits lung metastasis progression. Treatment with cmRNA1210 leads to cytokines change in plasma and tumor, cytotoxic immune cells accumulation in tumor and tumor tissue necrosis. Dynamic transcriptome profiling of tumor tissue post cmRNA1210 treatment. Combination with checkpoint inhibitor exhibits synergy effect and significantly decreases tumor relapse rate. Kaplan-Meier survival curve in TCGA dataset shows strong correlation of high IL-12A/B expression and long survival. Conclusions: The bioactivity and cross reactivity in rodents and primates of cmRNA1210 were validated in vitro. The advantage of pharmacokinetics of circular RNA was confirmed in vivo. cmRNA1210 exhibits robust anti-tumor effect in various tumor models, indicating its wild application situation in clinical. In situ treatment achieves abscopal effect and significantly inhibits lung metastasis progression. Systemic anti-tumor effect has been successfully initiated. The pharmacodynamics study reveals there are cytokine changes, immune cells activation or accumulation at tumor site and tumor tissue necrosis after cmRNA1210 treatment. cmRNA1210 as immune stimulatory effector works synergistically with checkpoint inhibitor. Kaplan-Meier survival analysis of IL-12 expression based on TCGA dataset shows there is a strong correlation of high expression and long survival. Overall, this pre-clinical study provides elaborate results of cmRNA1210 as anti-tumor therapeutics and demonstrates the great potential to enter clinical trial in the future.

Cell based and In vivo systematic evaluation of some Egyptian plant extracts targeting breast cancer

The prevalence of breast cancer as a significant public health concern necessitates continued exploration of natural resources for novel anti-cancer agents is crucial. Material and methodsAnticancer activity of plant extracts on monolayer breast cancer cell line (MCF7) with lower levels of toxicity towards normal (RPE1) underwent further assessment using a three-dimensional model (3D). The extract's effects were investigated through multiple assays including apoptosis induction using quantifying cleaved cytokeratin-18 (CK18) and DNA fragmentation. Additionally, the expression of Bcl-2 and Bax was quantitative using real-time PCR. The median lethal dose (LD50) was determined by the acute oral toxicity, while biomarkers associated with tumorigenesis, metastasis, and cell death were quantified by ELISA. ResultsLimoniastrum monopetalum and Bauhinia variegata exhibited the most potent antitumor efficacy among the investigated extracts. They demonstrated potent cytotoxicity against MCF7 with no significant effect on hTERT RPE-1, with an IC50 of 100 μM. The extract demonstrated effectiveness in killing cancer cells within 3D tumor-like structures, induced apoptosis through caspase-3 activation and cleavage of cytokeratin-18, up-regulated the tumor suppressor p53, down-regulated the anti-apoptotic Bcl-2 gene, and caused DNA fragmentation. Acute oral toxicity studies in mice indicated low toxicity, and in a syngeneic mouse tumor model, the extract significantly inhibited tumor growth, suggesting its potential for further development. ConclusionLimoniastrum monopetalum and Bauhinia variegata exhibited the most potent antitumor efficacy among the investigated extracts.

A new MVA ancestor-derived oncolytic vaccinia virus induces immunogenic tumor cell death and robust antitumor immune responses

Vaccinia viruses (VACV) are versatile therapeutic agents and different features of various VACV strains allow for a broad range of therapeutic applications. Modified Vaccinia virus Ankara (MVA) is a particularly altered VACV strain that is highly immunogenic, incapable of replicating in mammalian hosts, and broadly used as a safe vector for vaccination. Alternatively, Western Reserve (WR) or Copenhagen (Cop) are VACV strains that efficiently replicate in cancer cells and therefore are used to develop oncolytic viruses. However, the immune evasion capacity of WR or Cop hinders their ability to elicit antitumor immune responses, which is crucial for efficacy in the clinic. Here, we describe a new VACV strain named Immune-Oncolytic Vaccinia virus Ankara (IOVA), which combines efficient replication in cancer cells with induction of immunogenic tumor cell death (ICD). IOVA was engineered from an MVA ancestor and shows superior cytotoxicity in tumor cells. In addition, the IOVA genome incorporates mutations that lead to massive fusogenesis of tumor cells, which contributes to improved antitumor effects. In syngeneic mouse tumor models, induction of ICD results in robust antitumor immunity directed against tumor neo-epitopes and eradication of large established tumors. These data present IOVA as an improved immunotherapeutic oncolytic vector.

The EGFR inhibitor exerts a suppressive influence on the response of CD8+ T cells in Non-Small Cell Lung Cancer

Abstract Lung cancer is the leading cause of death worldwide, predominantly characterized by non-small cell lung cancer (NSCLC). The foremost treatment for NSCLC patients with EGFR mutations involves EGFR-tyrosine kinase inhibitors (EGFR-TKIs), demonstrating notable enhancements in patient survival and the preservation of quality of life. Immune checkpoint blockade (ICB) that reinvigorates T cell response is a promising immunotherapeutic approach to treat NSCLC patients with an efficacy of approximately 20%. Thus, comprehending the intricate interplay between EGFR-TKIs and immune regulation is pivotal, laying the groundwork for strategic combination therapies. Despite its critical importance, the relationship between EGFR-TKIs and immune regulation remains elusive, necessitating further investigation into the immunomodulatory role of EGFR-TKIs. This study unveils that EGFR-TKIs contribute to the reduced proliferation and effector cytokine production of CD8+ T cells. Treatment with EGFR-TKIs suppresses the response of tumor-infiltrating T cells in two syngeneic tumor mouse models. Furthermore, employing EGFR-TKI-specific antibodies and mass spectrum analysis, we identified the target profile of EGFR-TKIs. Remarkably, NSCLC patients undergoing EGFR-TKI therapy exhibited a diminished frequency of IFNγ-producing CD8+ T cells. These findings significantly inform the future development of therapeutic strategies and the optimization of drug administration timing for NSCLC patients.