Effective Cancer Immunotherapy Research Articles

Construction of nucleus-targeted photosensitizer and highly effective photodynamic immunotherapy for cancer

Nucleus is the largest and most important organelle within eukaryotic cells, containing most of the cell’s genetic material, DNA. It serves as the central hub for genetic regulation and metabolism, making it an ideal target for subcellular drug delivery. The development of nucleus-targeted photosensitizers allows for the rapid and effective destruction of critical components such as DNA within the nucleus. This achieves the goal of efficiently eliminating cancer cells. However, most organic molecules, including photosensitizers, cannot penetrate the nuclear membrane, making the design and synthesis of nucleus-targeted photosensitizers both significant and challenging. The authors have designed and synthesized a nucleus-targeted activatable photosensitive probe (CMT-I). In vitro spectral analyses demonstrate that CMT-I is specifically activated by ct-DNA, significantly enhancing fluorescence-a 49-fold increase is observed upon binding. Furthermore, under 590 nm light irradiation, CMT-I effectively generates 1O2. Molecular docking show that CMT-I selectively binds to DNA through hydrogen bonds and ᴨ-ᴨ conjugation. RNA sequencing experiments reveal that photodynamic therapy activates immunity within tumor cells, triggering an adaptive immune response. In vivo therapeutic experiments further verify the enhanced anti-tumor immunity of CMT-I, which is crucial for effectively eliminating immunologically cold tumors and highlights the potential of DNA-targeted photodynamic therapy in precise cancer treatment.

Enhancing preventive and therapeutic cancer vaccine efficacy through biotherapeutic ligand-associated extracellular vesicles

Extracellular vesicles (EVs), secreted by almost all living cells, have gained significant attention for their role in intercellular communication and their potential as versatile carriers for biotherapeutics. However, the clinical translation of EV-based therapies faces significant challenges, primarily due to the lack of efficient methods for loading biotherapeutic agents into EVs. This study introduces a simple, reproducible strategy for the simultaneous incorporation of various biotherapeutics within EVs. The process is gentle and preserves the essential physicochemical and biological characteristics of EVs, thereby protecting labile ligands from premature degradation and elimination. The binding and uptake efficiency of EVs by target cells reached approximately 97 % within 24 h of incubation. Administration of EVs loaded with oligodeoxynucleotides (ODN) resulted in a 4-fold increase in IFNγ+ CD4+ T cells and a 5-fold increase in IFNγ+ CD8+ T cells in the spleens and lymph nodes. Additionally, the co-administration of EVs with ODN and ovalbumin (OVA) induced elevated Th1-biased antibody responses and antigen-specific cytotoxic T-cell responses, providing long-lasting complete protection in 60 % of mice against T-cell thymoma challenge. Furthermore, EVs associated with three different ligands (OVA, CpG-ODN, and α-GalCer) effectively regressed established murine melanoma and significantly improved survival rates in mice. This study presents a powerful and promising approach to overcoming the limitations of EV-based cancer vaccines, advancing the development of effective cancer immunotherapies. SummaryImmunization with EVs that are co-associated with antigen and biotherapeutic cargo through a lyophilization-based technique elicits potent anti-cancer immunity.

An immunostimulatory liponanogel reveals immune activation-enhanced drug delivery and therapeutic efficacy in cancer

The clinical use of immunostimulatory polyinosinic:polycytidylic acid (pIC) for cancer therapy has been notably limited by its low tumor accumulation and poor cytosolic delivery to activate innate immune sensors. Here, we report a liponanogel (LNG)-based platform to address these challenges. The immunostimulatory LNG consists of an ionizable lipid shell coating a nanogel made of hyaluronic acid (HA), Mn2+ and pIC, which is denoted as LNG-Mn-pIC (LMP). The protonation of internal HA within acidic endosomes increases the endosomal membrane permeability and facilitates the cytosolic delivery of pIC. Moreover, Mn2+, previously reported to activate the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, synergizes with pIC to activate innate immune cells. Remarkably, intravenously injected LMP significantly induces tumor vasculature disruption and tumor cell apoptosis in an innate immune activation-dependent manner, facilitating the LMP delivery into tumors and leading to enhanced antitumor immunity that potently inhibits or even completely regresses the established tumors. In summary, this immunostimulatory LNG platform not only serves as a useful tool to uncover the immune activation-enhanced drug delivery profile but also represents a broadly applicable platform for effective cancer immunotherapy.

Biomimetic Nanovaccines Restore Immunosuppressive Tumor Antigen-Presenting Cells via the Saposin-Feeding Strategy.

Cancer cell membrane-derived biomimetic nanovaccines have shown tremendous potential in cancer immunotherapy. However, their efficacy is restricted by the insufficient cross-presentation of cell membrane-associated antigens. Saposins (SAs), which are vital for membrane vesicle disintegration and cell membrane-associated antigen presentation, are severely deficient in the antigen-presenting cells (APCs) within tumors. Herein, we propose a complementary strategy for increasing the efficacy of biomimetic nanovaccines via the use of SAs. Biomimetic nanovaccines were designed using cancer cell membrane shells to provide a comprehensive array of tumor-associated antigens and reactive oxygen species (ROS)-responsive nanoparticle cores that allowed the codelivery of cytosine-guanine dinucleotides (CpGs) and SAs. The biomimetic nanovaccines were ROS-responsive and highly internalized by APCs, which enabled the release of CpGs and SAs in the endo/lysosomes of APCs. Furthermore, biomimetic nanovaccines increased the activation of immunosuppressive APCs and enhanced T-cell priming by delivering SAs to the APCs. Consequently, biomimetic nanovaccines loaded with SAs not only suppressed tumor growth but also exhibited excellent therapeutic effects in combination with immune checkpoint blockade strategies. Overall, our study provides insights into the development of enhanced biomimetic nanovaccines via integrating SAs and offers a promising strategy for highly effective cancer immunotherapy.

IMMU-70. GLIOBLASTOMA DERIVED IL-8 INSTRUCTS IMMUNE CELL IDENTITY IN LATERAL VENTRICLE CONTACTING TUMORS

Abstract Adult IDH-wildtype glioblastoma (GBM) is an aggressive brain tumor with no established immunotherapy. Glioblastoma tumors that contact the ventricular-subventricular zone (V-SVZ) stem cell niche have especially poor clinical outcomes (PMC5771712, PMC5262526) and abnormal immune microenvironments filled with CD32+ HLA-DRhi macrophages that have displaced resident microglia (PMC10371245). Identifying the origin and role of these CD32+ macrophages is likely critical to developing successful GBM immunotherapies. Here, we present a mechanistic origin for these CD32+ cells as M_IL-8 macrophages. In ex vivo experiments with conditioned medium from primary human tumor cells, IL-8 was sufficient and necessary for tumor cells to instruct healthy macrophages, and inhibitory antibodies to IL-8 blocked the generation of CD32+ CD163+ M_IL-8 cells. Additionally, IL-8 protein was present in GBM tumor cells in vivo and especially common in tumors contacting the V-SVZ (p<0.0001, N=192 cores from 73 patients). Surface proteins CXCR1 and CXCR2, the primary receptors for IL-8, were detected on cells that were spatially separated from IL-8+ glioblastoma cells in tumors contacting the V-SVZ. These results suggest the hypothesis that glioblastoma-cell IL-8 instructs incoming CXCR1+ hematopoietic macrophages to adopt a suppressive M_IL-8 identity in V-SVZ-contacting GBM. Abundant HLA-DR (MHC II) observed on the CD32+ M_IL-8 cells closely matched the signature phenotype of cells in human tumors (PMC10371245) and contrasted with lower surface MHC II expression typically observed on human myeloid derived suppressor cells (PMC6608074). M_IL-8 cells might especially target CD4+ helper T cells required for effective cancer immunotherapy (PMC5312823). IL-8 and CD32+ macrophages should now be explored as targets in combination with GBM immunotherapies, especially for patients whose tumors present with radiographic contact with the V-SVZ stem cell niche. Some results here have been shared in a bioRxiv preprint by the these authors (PMC10996638).

Potent Amphiphilic Poly(Amino Acid) Nanoadjuvant Delivers Biomineralized Ovalbumin for Photothermal-Augmented Immunotherapy.

Cancer nanovaccines have emerged as an indispensable weapon for tumor treatment. However, insufficient immunogenicity and immunosuppression hamper the therapeutic effects of nanovaccines. Here, biodegradable nanovaccines (OMPP) composed of ovalbumin (OVA)-manganese oxide nanoparticles, amphiphilic poly(γ-glutamic acid) (γ-PGA), and ε-polylysine (PL) are constructed to realize enhanced cancer immunotherapy. Interestingly, amphiphilic γ-PGA and PL could serve as both carriers and immunoadjuvants to promote the cytosolic delivery of antigens and enhance the maturation of dendritic cells. Additionally, taking advantage of the photothermal property of OMPP, immunogenic cell death and in situ release of tumor-associated antigens can be triggered under near-infrared light irradiation for personalized tumor treatment. Moreover, OMPP nanovaccines can efficiently alleviate tumor hypoxia and downregulate programmed death-ligand 1 expression to reprogram the immunosuppressive tumor microenvironment. OMPP-mediated therapy has been shown to provoke robust immune responses to suppress B16-OVA melanoma and prevent postsurgical tumor recurrence. This work presents a facile strategy for the fabrication of nanovaccines by integrating carrier and adjuvant while exploring the inherent properties to promote antigen release and modulate immunosuppression, which demonstrates great potential for effective cancer immunotherapy.

The Dual Role of B Cells in the Tumor Microenvironment: Implications for Cancer Immunology and Therapy.

The tumor microenvironment (TME) is a complex and heterogeneous tissue composed of various cell types, including tumor cells, stromal cells, and immune cells, as well as non-cellular elements. Given their pivotal role in humoral immunity, B cells have emerged as promising targets for anti-tumor therapies. The dual nature of B cells, exhibiting both tumor-suppressive and tumor-promoting functions, has garnered significant attention. Understanding the distinct effects of various B cell subsets on different tumors could pave the way for novel targeted tumor therapies. This review provides a comprehensive overview of the heterogeneous B cell subsets and their multifaceted roles in tumorigenesis, as well as the therapeutic potential of targeting B cells in cancer treatment. To develop more effective cancer immunotherapies, it is essential to decipher the heterogeneity of B cells and their roles in shaping the TME.

The Emerging Role of gut Microbiota in Immunotherapy

The gastrointestinal tract contains a diverse and dynamic population of microorganisms called the gut microbiota, which is essential for immune system regulation. Recent studies have highlighted that gut microbiota has a major influence on the effectiveness of cancer immunotherapy, particularly immune checkpoint antagonists. This review explores the mechanisms of specific gut microbiota, such as Bifidobacterium and Lactobacillus, to enhance innate and adaptive immune responses, including activation of dendritic cells, polarization of macrophages, and stimulation of CD8+ T cells. In addition, this review discusses therapeutic strategies aimed at manipulating the gut microbiota to enhance the effects of immunotherapy, including fecal microbiota transplantation (FMT), probiotics, and engineered microbiota. Although these approaches have promising potential, the challenges still remain with the variability of patients and microbiota manipulation. This review emphasizes how crucial it is to combine immunotherapy and the gut microbial community to create more individualized, effective cancer treatments, which will eventually improve patient outcomes and advance the area of cancer treatment.

Biomimetic Nanomodulators With Synergism of Photothermal Therapy and Vessel Normalization for Boosting Potent Anticancer Immunity.

Combination therapy using photothermal therapy (PTT) and immunotherapy is one of the most promising approaches for eliciting host immune responses to ablate tumors. However, its therapeutic efficacy is limited due to inefficient immune cell infiltration and cellular immune responses. In this study, a biomimetic immunostimulatory nanomodulator, Tm@PDA-GA (4T1 membrane@polydopamine-gambogic acid), with homologous targeting is developed. The 4T1 membrane (Tm) coating reduced immunogenicity and facilitated uptake of Tm@PDA-GA by tumor cells. Polydopamine (PDA) as a drug carrier can induce PTT under near-infrared ray (NIR) irradiation and immunogenic cell death (ICD) to activate dendritic cells (DCs). Moreover, Tm@PDA-GA on-demand released gambogic acid (GA) in an acidic tumor microenvironment, inhibiting the expression of heat shock proteins (HSPs) for synergetic chemo-photothermal anti-tumor activity and increasing the ICD of 4T1 cells. More importantly, GA can normalize the vessels via HIF-1α and VEGF inhibition to enhance immune infiltration and alleviate hypoxia stress. Thus, Tm@PDA-GA induced ICD, activated DCs, stimulated cytotoxic T cells, and suppressed Tregs. Moreover, Tm@PDA-GA is combined with anti-PD-L1 to further augment the tumor immune response and effectively suppress tumor growth and lung metastasis. In conclusion, biomaterial-mediated PTT combined with vessel normalization is a promising strategy for effective immunotherapy of triple-negative breast cancer (TNBC).

Novel Endogenous Engineering Platform for Robust Loading and Delivery of Functional mRNA by Extracellular Vesicles.

Messenger RNA (mRNA) has emerged as an attractive therapeutic molecule for a plethora of clinical applications. For in vivo functionality, mRNA therapeutics require encapsulation into effective, stable, and safe delivery systems to protect the cargo from degradation and reduce immunogenicity. Here, a bioengineering platform for efficient mRNA loading and functional delivery using bionormal nanoparticles, extracellular vesicles (EVs), is established by expressing a highly specific RNA-binding domain fused to CD63 in EV producer cells stably expressing the target mRNA. The additional combination with a fusogenic endosomal escape moiety, Vesicular Stomatitis Virus Glycoprotein, enables functional mRNA delivery in vivo at doses substantially lower than currently used clinically with synthetic lipid-based nanoparticles. Importantly, the application of EVs loaded with effective cancer immunotherapy proves highly effective in an aggressive melanoma mouse model. This technology addresses substantial drawbacks currently associated with EV-based nucleic acid delivery systems and is a leap forward to clinical EV applications.

Light-Triggered PROTAC Nanoassemblies for Photodynamic IDO Proteolysis in Cancer Immunotherapy.

While proteolysis-targeting chimeras (PROTACs) hold great potential for persistently reprogramming the immunosuppressive tumor microenvironment via targeted protein degradation, precisely activating them in tumor tissues and preventing uncontrolled proteolysis at off-target sites remain challenging. Herein, a light-triggered PROTAC nanoassembly (LPN) for photodynamic indoleamine 2,3-dioxygenase (IDO) proteolysis is reported. The LPN is derived from the self-assembly of prodrug conjugates, which comprise a PROTAC, cathepsin B-specific cleavable peptide linker, and photosensitizer, without any additional carrier materials. In colon tumor models, intravenously injected LPNs initially silence the activity of PROTACs and accumulate significantly in targeted tumor tissues due to an enhanced permeability and retention effect. Subsequently, the cancer biomarker cathepsin B begins to trigger the release of active PROTACs from the LPNs through enzymatic cleavage of the linkers. Upon light irradiation, tumor cells undergo immunogenic cell death induced by photodynamic therapy to promote the activation of effector T cells, while the continuous IDO degradation of PROTAC simultaneously blocks tryptophan metabolite-regulated regulatory-T-cell-mediated immunosuppression. Such LPN-mediated combinatorial photodynamic IDO proteolysis effectively inhibits tumor growth, metastasis, and recurrence. Collectively, this study presents a promising nanomedicine, designed to synergize PROTACs with other immunotherapeutic modalities, for more effective and safer cancer immunotherapy.

Exploring potential roles of long non-coding RNAs in cancer immunotherapy: a comprehensive review.

Cancer treatment has long been fraught with challenges, including drug resistance, metastasis, and recurrence, making it one of the most difficult diseases to treat effectively. Traditional therapeutic approaches often fall short due to their inability to target cancer stem cells and the complex genetic and epigenetic landscape of tumors. In recent years, cancer immunotherapy has revolutionized the field, offering new hope and viable alternatives to conventional treatments. A particularly promising area of research focuses on non-coding RNAs (ncRNAs), especially long non-coding RNAs (lncRNAs), and their role in cancer resistance and the modulation of signaling pathways. To address these challenges, we performed a comprehensive review of recent studies on lncRNAs and their impact on cancer immunotherapy. Our review highlights the crucial roles that lncRNAs play in affecting both innate and adaptive immunity, thereby influencing the outcomes of cancer treatments. Key observations from our review indicate that lncRNAs can modify the tumor immune microenvironment, enhance immune cell infiltration, and regulate cytokine production, all of which contribute to tumor growth and resistance to therapies. These insights suggest that lncRNAs could serve as potential targets for precision medicine, opening up new avenues for developing more effective cancer immunotherapies. By compiling recent research on lncRNAs across various cancers, this review aims to shed light on their mechanisms within the tumor immune microenvironment.

A Comprehensive Guide to Hydrogel-Based Controlled Drug Delivery for Cancer Treatment

Common kinds of chemotherapy may cause harm to normal cells and tissues. Localised chemotherapy, unlike systemic chemotherapy, can lessen side effects by providing a consistent supply of chemotherapeutic chemicals directly to the tumour location. This emphasises the importance of controlled-release biodegradable hydrogels as chemotherapeutic drug delivery systems. This study looks at employing hydrogels as drug delivery methods for HCC, including thermosensitive, pH-sensitive, photosensitive, dual-sensitive, and glutathione-responsive hydrogels. Hydrogel-based drug delivery systems outperform traditional systemic chemotherapy in cancer treatment. Cancer immunotherapy has emerged as the new paradigm for cancer treatment. The development and discovery of new therapeutic molecules has increased the use of immunotherapy in clinical studies. This article discusses the current state of functional hydrogels for effective cancer immunotherapy. First, we will discuss the fundamental principles of cancer immunotherapy and the benefits of employing hydrogels to implement these mechanisms. Finally, we briefly explore the existing issues and potential applications of hydrogels for effective cancer immunotherapy. Keywords: Cancer, Hydrogel-based controlled drug delivery system, postoperative radiotherapy, chemotherapy, Immunotherapy.

Pickering emulsion-guided monomeric delivery of monophosphoryl lipid A for enhanced vaccination

Immunological adjuvants are vaccine components that enhance long-lasting adaptive immune responses to weakly immunogenic antigens. Monophosphoryl lipid A (MPLA) is a potent and safe vaccine adjuvant that initiates an early innate immune response by binding to the Toll-like receptor 4 (TLR4). Importantly, the binding and recognition process is highly dependent on the monomeric state of MPLA. However, current vaccine delivery systems often prioritize improving the loading efficiency of MPLA, while neglecting the need to maintain its monomeric form for optimal immune activation. Here, we introduce a Pickering emulsion-guided MPLA monomeric delivery system (PMMS), which embed MPLA into the oil-water interface to achieve the monomeric loading of MPLA. During interactions with antigen-presenting cells, PMMS functions as a chaperone for MPLA, facilitating efficient recognition by TLR4 regardless of the presence of lipopolysaccharide-binding proteins. At the injection site, PMMS efficiently elicited local immune responses, subsequently promoting the migration of antigen-internalized dendritic cells to the lymph nodes. Within the draining lymph nodes, PMMS enhanced antigen presentation and maturation of dendritic cells. In C57BL/6 mice models, PMMS vaccination provoked potent antigen-specific CD8+ T cell-based immune responses. Additionally, PMMS demonstrated strong anti-tumor effects against E.G7-OVA lymphoma. These data indicate that PMMS provides a straightforward and efficient strategy for delivering monomeric MPLA to achieve robust cellular immune responses and effective cancer immunotherapy.

"Target-and-release" nanoparticles for effective immunotherapy of metastatic ovarian cancer.

Immunotherapies such as checkpoint inhibitors (CPI) are effective in treating several advanced cancers, but these treatments have had limited success in metastatic ovarian cancer (OC). Here, we engineered liposomal nanoparticles (NPs) carrying a layer-by-layer (LbL) polymer coating that promotes their binding to the surface of OC cells. Covalent anchoring of the potent immunostimulatory cytokine interleukin-12 (IL-12) to phospholipid headgroups of the liposome core enabled the LbL particles to concentrate IL-12 in disseminated OC tumors following intraperitoneal administration. Shedding of the LbL coating and serum protein-mediated extraction of IL-12-conjugated lipids from the liposomal core over time enabled IL-12 to disseminate in the tumor bed following rapid NP localization in tumor nodules. Optimized IL-12 LbL-NPs promoted robust T cell accumulation in ascites and tumors in mouse models, extending survival compared to free IL-12 and remarkedly sensitizing tumors to CPI, leading to curative treatments and immune memory.

Antibody-Decorated Nanoplatform to Reprogram Macrophage and Block Immune Checkpoint LSECtin for Effective Cancer Immunotherapy.

Repolarizing tumor-associated macrophages (TAMs) into tumor-inhibiting M1 macrophages has been considered a promising strategy for enhanced cancer immunotherapy. However, several immunosuppressive ligands (e.g., LSECtin) can still be highly expressed on M1 macrophages, inducing unsatisfactory therapeutic outcomes. We herein developed an antibody-decorated nanoplatform composed of PEGylated iron oxide nanoparticles (IONPs) and LSECtin antibody conjugated onto the surface of IONPs via the hydrazone bond for enhanced cancer immunotherapy. After intravenous administration, the tumor microenvironment (TME) pH could trigger the hydrazone bond breakage and induce the disassociation of the nanoplatform into free LSECtin antibodies and IONPs. Consequently, the IONPs could repolarize TAMs into M1 macrophages to remodel immunosuppressive TME and provide an additional anticancer effect via secreting tumoricidal factors (e.g., interlukin-12). Meanwhile, the LSECtin antibody could further block the activity of LSECtin expressed on M1 macrophages and relieve its immunosuppressive effect on CD8+ T cells, ultimately leading to significant inhibition of tumor growth.

Physicochemical Cues Steering Spiky Mn/MoOx Nanocarriers to Mimic Oncolytic Virus for Potentiating Cancer Immunotherapy

AbstractThe approval of oncolytic viruses as antigen‐agnostic cancer vaccines provides a paradigm shift for immunotherapy. However, a delicate balance between safety and immunogenicity whether native or engineered oncolytic viruses remains elusive and further compounded by oncolysis‐induced immunosuppression. To address these dilemmas, the de novo design and synthesis of oncolytic viruses‐inspired nanoplatform are proposed by emulating desirable nanostructure and bioactivity for effective cancer immunotherapy. Initially, the influence of MoOx nanoparticles with varying physical morphologies on siRNA transfection are explored, wherein the virus‐inspired MoOx nanoparticles with spiky surfaces (Spi‐MoOx) are well positioned to serve as siRNA vectors to present the highest transfection efficacy. Given the preexisting immune suppression, defect engineering is incorporated into Spi‐MoOx through Mn dopants (Spi‐Mn/MoOx), in an effort to participate in tumor adaptation to hypoxia and maximize the oncolytic potency, while retaining favorable safety profiles. More importantly, the engineered oncolytic viruses hold considerable promise to function as a universal platform that enables any gene to be modulated precisely, allowing the selective activation of various pathways. Collectively, the study offers insights into the biomimetic synthesis and bioactivity of biological system through manipulating the physicochemical cues, while carrying significant implications to propel artificial oncolytic agents from the laboratory to clinical settings.

Exploring the Complexity and Promise of Tumor Immunotherapy in Drug Development.

Cancer represents a significant threat to human health, and traditional chemotherapy or cytotoxic therapy is no longer the sole or preferred approach for managing malignant tumors. With advanced research into the immunogenicity of tumor cells and the growing elderly population, tumor immunotherapy has emerged as a prominent therapeutic option. Its significance in treating elderly cancer patients is increasingly recognized. In this study, we review the conceptual classifications and benefits of immunotherapy, and discuss recent developments in new drugs and clinical progress in cancer treatment through various immunotherapeutic modalities with different mechanisms. Additionally, we explore the impact of immunosenescence on the effectiveness of cancer immunotherapy and propose innovative and effective strategies to rejuvenate senescent T cells.

Tumor-Associated Myeloid Cells Selective Delivery of a Therapeutic Tumor Nano-Vaccine for Overcoming Immune Barriers for Effective and Long-Term Cancer Immunotherapy.

Therapeutic cancer vaccines have the potential to induce regression of established tumors, eradicate microscopic residual lesions, and prevent metastasis and recurrence, but their efficacy is limited by the low antigenicity of soluble antigens and the immunosuppressive tumor-associated macrophages (TAMs) that promote tumor growth. In this study, a novel strategy is reported for overcoming these defenses: a dual-targeting nano-vaccine (NV) based on hepatitis B core antigen (HBcAg) derived virus-like particles (VLPs), N-M2T-gp100 HBc NV, equipped with both SIGNR+ dendritic cells (DCs)/TAMs-targeting ability and high-density display of tumor-associated antigen (TAA). N-M2T-gp100 HBc NVs-based immunotherapy has demonstrated an optimal interaction between tumor-associated antigens (TAAs) and the immune composition of the tumor microenvironment. In a melanoma model, N-M2T-gp100 HBc VLPs significantly reducing in situ and abscopal tumor growth, and provide long-term immune protection. This remarkable anti-tumor effect is achieved by efficiently boosting of T cells and repolarizing of M2-like TAMs. This work opens exciting avenues for the development of personalized tumor vaccines targeting not just melanoma but potentially a broad range of cancer types based on functionalized VLPs.

Effect of cancer immunotherapy with CD39/PD-L1 bispecific antibody OriA631-b.

e14508 Background: Despite significant advancements in cancer immunotherapy through the use of immune checkpoint inhibitors, there remains a need for more robust strategies to enhance anti-tumor immune responses. This study introduces and characterizes OriA631-B, an innovative CD39/PD-L1 bispecific antibody. By simultaneously targeting the metabolic checkpoint CD39 and the immune checkpoint PD-L1, this novel antibody has the potential to significantly augment anti-tumor efficacy, particularly in cold tumors characterized by a scarcity of infiltrating immune cells. The development of OriA631-B marks a breakthrough in concurrently addressing two crucial immunosuppressive pathways. Methods: The creation of OriA631-B involved cutting-edge antibody engineering methodologies to guarantee optimal binding affinity and specificity for its target antigens, CD39 and PD-L1. With meticulous design and refinement, OriA631-B was developed to exhibit robust binding capabilities to both CD39 and PD-L1, enabling simultaneous and precise recognition. Leveraging advanced antibody engineering techniques was instrumental in crafting OriA631-B as a potent tool with heightened binding properties, broadening its potential applications across diverse therapeutic contexts. Results: In vitro investigations revealed the efficacy of OriA631-B, derived from the foundation of a clinically validated in-house generated PD-L1 antibody (YN035). This innovative antibody effectively thwarted CD39-mediated adenosine production, resulting in heightened effector T cell function and proliferation. In vivo efficacy assessments conducted on syngeneic hot tumor models MC38 and Hepa1-6 underscored the remarkable effectiveness of OriA631, the CD39 monoclonal antibody (mAb), in controlling tumor growth. Notably, OriA631-B, the CD39/PD-L1 bispecific antibody, exhibited even more profound impacts, significantly restraining tumor growth beyond the effects observed with single-target treatments in the hot tumor model or combination therapies in both the hot tumor model MC38 and the cold tumor model CT26. These findings underscore the potent therapeutic potential of OriA631-B and its capacity to exert robust anti-tumor activity by concurrently targeting CD39 and PD-L1. Additionally, safety profiling revealed an acceptable toxicity profile for OriA631-B, with no significant adverse events observed during the study. Conclusions: In summary, OriA631-B demonstrates potential as an innovative immunotherapeutic strategy for cancer treatment by concurrently targeting CD39-mediated immune suppression and PD-L1-mediated T cell exhaustion. Further exploration, including clinical trials, is imperative to fully uncover the therapeutic capabilities of this groundbreaking bispecific antibody in cancer immunotherapy.