Antitumor Immune Response Research Articles

A covalent peptide-based lysosome-targeting protein degradation platform for cancer immunotherapy

The lysosome-targeting chimera (LYTAC) strategy provided a very powerful tool for the degradation of membrane proteins. However, the synthesis of LYTACs, antibody-small molecule conjugates, is challenging. The ability of antibody-based LYTACs to penetrate solid tumor is limited as well, especially to cross the blood-brain barrier (BBB). Here, we propose a covalent chimeric peptide-based targeted degradation platform (Pep-TACs) by introducing a long flexible aryl sulfonyl fluoride group, which allows proximity-enabled cross-linking upon binding with the protein of interest. The Pep-TACs platform facilitates the degradation of target proteins through the mechanism of recycling transferrin receptor (TFRC)-mediated lysosomal targeted endocytosis. Biological experiments demonstrate that covalent Pep-TACs can significantly degrade the expression of PD-L1 on tumor cells, dendritic cells and macrophages, especially under acidic conditions, and markedly enhance the function of T cells and tumor phagocytosis by macrophages. Furthermore, both in anti-PD-1-responsive and -resistant tumor models, the Pep-TACs exert significant anti-tumor immune response. It is noteworthy that Pep-TACs can cross the BBB and prolong the survival of mice with in situ brain tumor. As a proof-of-concept, this study introduces a modular TFRC-based covalent peptide degradation platform for the degradation of membrane protein, and especially for the immunotherapy of brain tumors.

A Phase 2 Study of Sotigalimab, a CD40 Agonist Antibody, Plus Concurrent Chemoradiation as Neoadjuvant Therapy for Esophageal and Gastroesophageal Junction Cancers.

Neoadjuvant chemoradiation (NCRT) followed by surgical resection represents a standard approach for patients with locally advanced esophageal/GEJ cancers. Sotigalimab is a high affinity CD40 agonist antibody capable of inducing and expanding anti-tumor immune responses by activating dendritic cells, T and B lymphocytes, NK cells, and M1 macrophages. This study examined the safety and efficacy of combining sotigalimab with NCRT in patients with esophageal or GEJ cancers. Patients with resectable (T1-3, Nx) adenocarcinoma(AC) or squamous cell carcinoma(SCC) of the esophagus or GEJ were eligible. T1N0 and cervical tumors were excluded. Study treatment: weekly carboplatin/paclitaxel with concurrent radiation 5040 cGy plus 3-4 doses of sotigalimab prior to Ivor-Lewis esophagectomy. Primary efficacy endpoint was pathologic complete response (path CR) rate. 33 patients were enrolled (AC 76%, SCC 24%; clinical stage III 67%). Ninety percent of patients received all planned doses of sotigalimab. The most common adverse events attributed to sotigalimab were nausea, fever/chills, fatigue, and cytokine release syndrome (CRS); most of these were Grade 1-2. Grade >3 CRS was observed in 3 pts (9%). Twenty-five of the 29 efficacy-evaluable patients underwent an R0 resection (87.9%), with an overall path CR rate of 37.9% (11/29). Post-tumor samples demonstrated increased infiltration and activation of dendritic cells, monocytes, and cytotoxic T cells compared to baseline. Sotigalimab combined with NCRT for esophageal or GEJ cancers was generally well tolerated and achieved path CR rates that compare favorably to historical data and are promising for this treatment strategy. NCT03165994.

Unlocking the Power of Photothermal Agents: A Universal Platform for Smart Immune NIR-Agonists for Precise Cancer Therapy.

Selective ablation of tumor cells allows safe eradication, thereby minimizing off-target damage, while specifically inducing immunogenic cell death (ICD) rather than commonly non-immunogenic apoptosis of tumor cells enables activation of anti-tumor immune response against residual cancer cells, including metastatic lesions. Herein, we present a general strategy leveraging a novel photothermal agent (PTA) that concomitantly enables precise tumor killing and activation of anti-tumor immunity. The unique PTA scaffold exhibits unexpected inherent endoplasmic reticulum (ER)-targeting capability and potent near-infrared (NIR) photothermal activity, inducing NIR-controlled immunogenic pyroptosis in various tumor cell lines via targeting ER stress in an oxygen-independent manner. Moreover, both ER-targeting and NIR-activity of our scaffold can be modulated on demand by chemical caging/uncaging, allowing quick activation with diverse biological and bioorthogonal molecular triggers. The potency of this universal platform is demonstrated via its application to develop a membrane protein-activatable NIR-agonist that selectively activates ICD in tumor sites while priming anti-tumor immunity, minimizing off-target effects and enhancing efficacy against mouse breast tumors. This versatile approach could lead to customization of various personalized and effective immune NIR-agonists for specific photoimmunotherapy applicable to diverse solid tumors.

From heterogeneity to prognosis: understanding the complexity of tertiary lymphoid structures in tumors.

Tertiary lymphoid structures (TLSs) are aberrant lymphoid tissues found in persistent inflammatory settings, including malignancies, autoimmune disorders, and transplanted organs. The organization and architecture of TLS closely resemble that of secondary lymphoid organs (SLOs). The formation of TLS is an ongoing process, with varying structural features observed at different stages of maturation. The tumor microenvironment (TME) is a multifaceted milieu comprising cells, molecules, and extracellular matrix components in close proximity to the neoplasm. TLS within the TME have the capacity to actively elicit anti-tumor immune responses. TLSs exhibit tumor-specific and individual-specific characteristics, leading to varying immune responses towards tumor immunity based on their distinct cellular components, maturity levels, and spatial distribution. Cell interaction is the foundational elements of tumor immunity. Despite differences in the cellular composition of TLS, B cells and T cells are the main components of tumor-associated TLS。Recent research has highlighted the significance of diverse subtypes of B cells and T cells within TLSs in influencing the therapeutic outcomes and prognostic indicators of individual tumors. This review elucidates the diversity of TLS in terms of cellular composition, developmental stage, anatomical location, and the influence of cytokines on their initiation and progression. Furthermore, the article examines the involvement of B and T cells within TLS and the significance of TLS in relation to tumor prognosis.

Phase I study of intratumoral administration of CV8102 in patients with advanced melanoma, squamous cell carcinoma of the skin, squamous cell carcinoma of the head and neck, or adenoid cystic carcinoma

BackgroundCV8102, a toll-like receptor 7/8 and RIG I agonist, has demonstrated antitumor immune responses in preclinical studies. We investigated intratumoral (IT) administration of CV8102 in patients with anti-programmed cell death...

Leveraging the Immunological Impacts of Irreversible Electroporation as a New Frontier for Cancer Therapy.

Irreversible electroporation (IRE) is a nonthermally mediated tissue ablation modality that makes use of short pulsed electric fields to destroy cancerous lesions in situ. In the past two decades, IRE has established itself not only as an effective means to ablate small, unresectable tumor masses but also as a tool particularly qualified to modulate the tumor microenvironment in a way that dismantles pathways of cancer immunosuppression and permits the development of a systemic antitumor immune response. However, despite its immune-stimulating tendencies, for most cancers conventional IRE alone is insufficient to establish an immune response robust enough to fully eliminate disseminated disease and prevent recurrence. Here, we describe the current understanding of the histological and immunological effects of IRE, as well as recent efforts to optimize IRE parameters and develop rational combination therapies to increase the efficacy of the resulting immune response.

Tumor-Intrinsic SIRPA Drives Pyroptosis Evasion in Head and Neck Cancer.

Pyroptosis, a gasdermin-mediated immunogenic cell death, has been shown to elicit adaptive antitumor immune responses, thereby augmenting the response to cancer immunotherapy when pyroptosis is therapeutically activated. However, despite increased gasdermin E (GSDME) expression, significant pyroptosis remains elusive in certain tumor types, and the underlying regulatory mechanisms are poorly understood. In this study, we observed high signal regulatory protein α1 (SIRPA) expression in head and neck squamous cell carcinoma (HNSCC) cells, a target in cancer immunotherapy. Intriguingly, SIRPA inhibition markedly augmented pyroptosis activity in tumor tissues and modulated tumor growth in a HNSCC mouse model. Subsequent investigations revealed that SIRPA knockout upregulated GSDME expression and potentiated cisplatin-induced pyroptosis in cancer cells. Integrative transcriptomics and metabolomics analysis suggested that the SIRPA knockout profoundly altered protein ubiquitination and augmented argininosuccinic acid levels in cancer cells. Specifically, we demonstrated that ubiquitin-specific peptidase 18 (USP18), a deubiquitinating enzyme, targets GSDME for deubiquitination and that USP18 knockdown suppressed cisplatin-induced pyroptosis. Notably, we found that succinylation of GSDME, which is mediated by succinyl-CoA, promotes GSDME cleavage without affecting caspase-3 activation. Further experiments indicated that SIRPA expression in tumor cells can decrease the antitumor efficacy of chemotherapy and immunotherapy in HNSCC mouse models. In summary, our findings reveal a novel mechanism of pyroptosis evasion in HNSCC, whereby tumor-intrinsic SIRPA enhances GSDME ubiquitylation and inhibits its succinylation. These insights suggest that inhibiting SIRPA expression may improve the efficacy of immunotherapy for HNSCC by inducing pyroptosis.

Mitochondria-targeting of oxidative phosphorylation inhibitors to alleviate hypoxia and enhance anticancer treatment efficacy.

Hypoxia is a common feature of solid tumors and is associated with a poor response to anticancer therapies. Hypoxia also induces metabolic changes, such as a switch to glycolysis. This glycolytic switch causes acidification of the tumor microenvironment (TME), thereby attenuating the anticancer immune response. A promising therapeutic strategy to reduce hypoxia and thereby sensitize tumors to irradiation and/or antitumor immune responses is pharmacological inhibition of oxidative phosphorylation (OXPHOS). Several OXPHOS inhibitors (OXPHOSi) have been tested in clinical trials. However, moderate responses and/or substantial toxicity has hampered clinical implementation. OXPHOSi tested in clinical trials inhibit the oxidative metabolism in tumor cells as well as healthy cells. Therefore, new strategies are needed to improve the efficacy of OXPHOSi while minimizing side effects. To enhance the therapeutic window, available OXPHOSi have, for instance, been conjugated to triphenylphosphonium (TPP+) to preferentially target the mitochondria of cancer cells, resulting in increased tumor uptake compared to healthy cells, as cancer cells have a higher mitochondrial membrane potential. However, OXPHOS inhibition also induces reactive oxygen species (ROS), and subsequent antioxidant responses, which may influence the efficacy of therapies, such as platinum-based chemotherapy and radiotherapy. Here, we review the limitations of the clinically tested OXPHOSi metformin, atovaquone, tamoxifen, BAY 87-2243 and IACS-010759 and the potential of mito-targeted OXPHOSi and their influence on ROS production. Furthermore, the effect of the mitochondria-targeting moiety TPP+ on mitochondria is discussed as this affects mitochondrial bioenergetics.

Integrative analysis of immunogenic PANoptosis and experimental validation of cinobufagin-induced activation to enhance glioma immunotherapy.

Glioma, particularly glioblastoma (GBM), is a highly aggressive tumor with limited responsiveness to immunotherapy. PANoptosis, a form of programmed cell death merging pyroptosis, apoptosis, and necroptosis, plays an important role in reshaping the tumor microenvironment (TME) and enhancing immunotherapy effectiveness. This study investigates PANoptosis dynamics in glioma and explores the therapeutic potential of its activation, particularly through natural compounds such as cinobufagin. We comprehensively analyzed PANoptosis-related genes (PANoRGs) in multiple glioma cohorts, identifying different PANoptosis patterns and constructing the PANoptosis enrichment score (PANoScore) to evaluate its relationship with patient prognosis and immune activity. Cinobufagin, identified as a PANoptosis activator, was evaluated for its ability to induce PANoptosis and enhance anti-tumor immune responses both in vitro and in vivo GBM models. Our findings indicate that high PANoScore gliomas showed increased immune cell infiltration, particularly effector T cells, and enhanced sensitivity to immunotherapies. Cinobufagin effectively induced PANoptosis, leading to increased immunogenic cell death, facilitated tumor-associated microglia/macrophages (TAMs) polarization towards an M1-like phenotype while augmenting CD4+/CD8 + T cell infiltration and activation. Importantly, cinobufagin combined with anti-PD-1 therapy exhibited significant synergistic effects and prolonged survival in GBM models. These findings highlight the therapeutic potential of PANoptosis-targeting agents, such as cinobufagin, in combination with immunotherapy, offering a promising approach to convert "cold" tumors into "hot" ones and improving glioma treatment outcomes.

Oncolytic Viruses in Ovarian Cancer: Where Do We Stand? A Narrative Review

Ovarian cancer (OC) remains the most lethal gynecologic malignancy with limited effective treatment options. Oncolytic viruses (OVs) have emerged as a promising therapeutic approach for cancer treatment, capable of selectively infecting and lysing cancer cells while stimulating anti-tumor immune responses. Preclinical studies have demonstrated significant tumor regression and prolonged survival in OC models using various OVs, such as herpes simplex. Early-phase clinical trials have shown a favorable safety profile, though the impact on patient survival has been modest. Current research focuses on combining OVs with other treatments like immune checkpoint inhibitors to enhance their efficacy. We provide a comprehensive overview of the current understanding and future directions for utilizing OVs in the management of OC.

A Novel Multicompartment Barrier-Free Microfluidic Device Reveals the Impact of Extracellular Matrix Stiffening and Temozolomide on Immune-Tumor Interactions in Glioblastoma.

The immune system plays a crucial role in shaping the glioblastoma tumor microenvironment, characterized by its complexity and dynamic interactions. Understanding the tumor-immune crosstalk is essential for advancing cancer research and therapeutic development. Here, a novel multicompartment, barrier-free microfluidic device is presented that overcomes the limitations of existing models by enabling direct tumor-immune interactions without physical barriers, preserving natural immune cell infiltration. This platform supports the independent and simultaneous culture of tumor and immune cells, replicating the healthy-tumoral stroma interface, and allows investigating the effect of matrix stiffness and chemotherapy on both populations. The findings reveal that increased collagen concentration promotes tumor invasiveness while impairing immune cell infiltration. Additionally, temozolomide treatment reduces immune cell motility but enhances anti-tumor immune responses. These insights highlight the critical roles of extracellular matrix mechanics and chemotherapy in tumor progression and immune modulation, establishing this device as a powerful tool for studying glioblastoma-immune dynamics and evaluating therapeutic strategies.

Integrin‐Targeted, Activatable Nanophototherapeutics for Immune Modulation: Enhancing Photoimmunotherapy Efficacy in Prostate Cancer Through Macrophage Reprogramming

ABSTRACTProstate cancer is an epithelial malignancy with a high incidence among elderly men. Photochemistry‐based dye photodrugs (known as photosensitizers) offer a promising clinical approach for treating tumors. These agents work by inducing immunogenic cell death (ICD), which activates antitumor immune response. This approach is favored owing to its minimal invasiveness, low toxicity, and high efficiency. However, the immunosuppressive microenvironment of characteristics of “cold” tumors significantly restricts the clinical efficacy of photodrugs. Developing an advanced nanocarrier system to deliver photodrugs and immune agonists for efficient drug delivery to tumor lesion sites and to reshape the immunosuppressive microenvironment is crucial in clinical practice. Therefore, in this study, we designed an integrin‐targeted, activatable nano photodrug co‐assembly with an immune agonist (RPST@IMQ) for enhancing photoimmunotherapy in prostate cancer via the reprogramming of tumor‐associated macrophages. The active‐targeted nanosystem enhanced the dosage of photodrug at the lesion site through systemic administration. High doses of glutathione at the tumor site cleaved the disulfide bonds of RPST@IMQ, releasing the photodrug and the immune agonist imiquimod (IMQ). Under photoirradiation, the photodrug generated significant doses of singlet oxygen to eliminate tumor cells, thereby inducing ICD to activate antitumor immune responses. Simultaneously, the released IMQ reprograms immunosuppressive M2‐type tumor‐associated macrophages (TAMs) in the tumor microenvironment into M1‐type TAMs with tumor‐killing capabilities, thereby converting “cold” tumors into “hot” tumors. This conversion enhances the therapeutic efficacy against primary and distant tumors in vivo. This study offers new insights into the development of innovative, smart, activatable nano photodrugs to enhance anticancer therapeutic outcomes.

Functionalized aluminum hydroxide-based self-adjuvanted nanovaccine orchestrates antitumor immune responses via Dectin-1 signaling.

Self-adjuvanted vaccine delivery platforms possess potential for targeted delivery of antigens and initiation of potent immune responses. Although aluminum-containing adjuvants have been approved and widely used in human vaccines, their effectiveness in inducing Th1-type immune responses is far from satisfactory. To facilitate antigen delivery and activate potent antitumor immune responses, a self-adjuvanted nanovaccine (CPBG-Al@OVA) is constructed by functionalizing aluminum hydroxide with β-1,3-glucan, which recognizes pattern recognition receptors via Dectin-1. Carboxymethyl-phosphorylated β-1,3-glucan (CPBG) has been synthesized and optimized to achieve superior adjuvanticity while maintaining water solubility. CPBG then self-assembles with aluminum hydroxide and the targeted antigen, leading to the formation of a nanovaccine CPBG-Al@OVA. Owing to the favorable nanoscale size distribution, CPBG-Al@OVA effectively drains to the lymph nodes and is internalized by antigen-presenting cells (APCs) through Dectin-1-mediated endocytosis, activating the Syk and Raf1 signaling pathways and leading to upregulated TNFSF15 and OX40L expression to activate APCs. Following immunization, CPBG-Al@OVA activates potent CD8+ T cell and humoral responses to inhibit tumor growth. Notably, mice vaccinated with CPBG-Al@OVA showed extended survival, with more than 70% of the mice surviving for over 50days post-tumor challenge. Moreover, the CPBG-Al nanoparticle also possesses personalized immune-activating capacity by encapsulating tumor lysate as an antigen, specifically suppressing tumor growth. This strategy synergizes the adjuvant effects of aluminum and β-1,3-glucan, offering a platform for self-adjuvanted nanovaccine design with significant clinical translational potential.

DNA-PK inhibition sustains the antitumor innate immune response in Small Cell Lung Cancer

DNA-PK inhibition sustains the antitumor innate immune response in Small Cell Lung Cancer

Discovery of 22(S)-23-phenyl-24-norchol-5-en-3β,22-diol (PFM046) as the first-in-class, steroidal, non-sulfated Liver X Receptor antagonist with anticancer activity.

A plethora of studies have demonstrated the crucial role played by Liver X Receptors (LXRs) in cancer. However, whether LXRs activation results in pro-versus anti-tumor effects is still matter of debate. Recently, we have reported the ability of 22(S)-hydroxycholesterol-3-sulfate (PFM037) to antagonize LXRα activity, and, at the same time, its capability to improve in-vivo anti-tumor immune responses. Herein we report the first study aimed at the definition of structure-activity relationships of PFM037. Successfully, we identified 22(S)-23-phenyl-24-norchol-5-en-3β,22-diol (PFM046) as a more potent LXRs antagonist than PFM037. PFM046 showed a peculiar LXR target gene expression profile, being able, as expected for an antagonist, to suppress SCD1 and FASN expression, while surprisingly maintaining the ability to upregulate ABCA1 gene, as typical for an agonist. PFM046 showed a remarkable antitumor activity in two both in vitro-and in-vivo mouse models, highlighting the high potential of LXRs antagonists in oncological applications.

A mechanistic, functional, and clinical perspective on targeting CD70 in cancer.

The oncoimmunology research has witnessed notable advancements in recent years. Reshaping the tumor microenvironment (TME) approach is an effective method to improve antitumor immune response. The T cell-mediated antitumor response is crucial for favorable therapeutic outcomes in several cancers. The United States Food and Drug Administration (FDA) has approved immune checkpoint inhibitors (ICIs) for targeting the immune checkpoint proteins (ICPs) expressed in various hematological and solid malignancies. The ICPs are T cell co-inhibitory molecules that block T cell activation and, thus, antitumor response. Currently, most of the FDA-approved ICIs are antagonistic antibodies of programmed death-ligand 1 (PD-L1), programmed cell death protein 1 (PD-1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). In contrast to ICPs, the T cell costimulatory molecules are required for T cell activation, expansion, and effector function. However, the abrupt expression of these costimulatory molecules in tumors presents a concern for T cell-mediated antitumor response. One of the T cell costimulatory molecules, the cluster of differentiation 70 (CD70), has emerged as a druggable target in various hematological and solid malignancies due to its role in T cell effector function and immune evasion. The present review describes the expression of CD70, factors affecting the CD70 expression, the physiological and clinical relevance of CD70, and the current approaches to target CD70 in hematological and solid malignancies.

Berberine shaping the tumor immune landscape via pyroptosis.

Pyroptosis is a programmed cell death (PCD) mainly mediated by the Gasdermin family of proteins, among which Gasdermin E (GSDME) is considered a tumor suppressor gene. GSDME can recruit immune cells to the tumor microenvironment (TME) and promote their effects. Activating and enhancing adaptive immunity through GSDME is a potential solution for anti-tumor therapy. Here we reported that berberine (BBR), a small molecule from traditional Chinese medicine, as a GSDME activator, induced caspase-3 (C-3)/GSDME pathway-mediated pyroptosis through the mitochondrial pathway, improved the immunosuppressive state of the tumor microenvironment, and thus promoted anti-tumor immunity. We determined the induction of pyroptosis of 4T1 cells by BBR through various experiments, and investigated the immune activation effect of BBR by co-culture in vitro, which induced DCs maturation and macrophage polarization. Zebrafish embryo toxicity experiments were used to evaluate the in vivo safety of berberine. Furthermore, the in vivo antitumor and immune activation effects of BBR were investigated using 4T1 orthotopic model mice, and the results showed that BBR could eliminate orthotopic tumor cells by activating local and systemic immunity. Moreover, we observed that BBR significantly inhibited breast cancer lung metastasis. In summary, our results showd the role of BBR as a GSDME activator stimulated both local and systemic antitumor immune responses by inducing pyroptosis, effectively preventing tumor development and metastasis.

Investigation of synergistic effects in trials of combination therapies with immune-checkpoint inhibitors in advanced gastric or gastroesophageal junction cancer.

405 Background: Combinations of immune checkpoint inhibitors (ICI) and chemotherapy (CT) have been approved for gastric cancer. However, there is a hypothesis that this combination may blunt antitumor immune responses because most chemotherapeutic agents also target lymphocytes. The primary objective was to investigate that the ICI and CT does not interfere each other’s therapeutic effects in advanced gastric cancer (GC) or gastroesophageal junction cancer (GEJC) patients. Methods: The reconstructed individual patient data was electronically extracted from the Kaplan-Meier curve of phase III randomized controlled trials (RCTs). The observed PFS curve of each constituent monotherapies was used to estimate simulated PFS curves expected under a model of independent drug action. If the observed curve demonstrated significantly better PFS than simulated curve, the combination of ICI and CT may have a synergistic effect, implying a superior outcome compared to simply adding the component monotherapy. Results: The study included 2,538 unresectable advanced, recurrent, or metastatic GC or GEJC patients from three RCTs comparing pembrolizumab (KEYNOTE-061, KEYNOTE-062 and KEYNOTE-859). In patients with programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or greater, the 1-year and median PFS of the observed and simulated curves were 28.0% vs. 27.9%, and 6.89 months vs. 6.88 months, respectively. One sample log-rank test showed no significant differences between the observed and simulated curves (p = 0.107). In the subgroups with PD-L1 CPS ≥10 or <1, the 1-year PFS of the observed and simulated curves was 34.7% vs 32.8%, and 28.5% vs 26.8%. Conclusions: The observed PFS of ICT involving pembrolizumab was comparable to the simulated PFS estimated from the data for each monotherapy regardless of the magnitude of PD-L1 CPS. Although it was not clear whether potential synergies existed for ICT, these findings at least suggest that the benefits of ICI and CT are not interfering each other, thereby providing theoretical support for the efficacy of ICT in patients with advanced GC or GEJC.

STAT3-related lncRNAs in colorectal cancer progression; Special focus on immune cell's evasion.

Colorectal cancer (CRC) is globally ranked as the third leading cause of cancer-related deaths in both men and women. There is an urgent need for novel biomarkers to facilitate early diagnosis and enhance patient care, thereby improving treatment response and reducing mortality rates. Signal transducer and activator of transcription 3 (STAT3) is essential for controlling the anti-tumor immune response since it is a hub for several oncogenic signaling pathways. In the tumor environment, STAT3 is widely overactivated in both malignant and non-cancerous cells. It is involved in suppressing the expression of critical immune activation regulators and encouraging the synthesis of immunosuppressive substances. Long noncoding RNAs (lncRNAs), a kind of non-coding RNA, are critical for CRC development, apoptosis, and metastasis because they influence important signaling pathways such as STAT3 signaling and contribute to gene regulation at the epigenetic, transcriptional, and post-transcriptional levels. Moreover, lncRNAs have a significant role in modifying the TME and control the expression of important immunological checkpoints, such as PD-L1. Therefore, a comprehensive understanding of the regulatory roles of lncRNAs is crucial for identifying diagnostic, prognostic, and predictive biomarkers for CRC. Thus, the objective of the present review study is to provide a comprehensive overview of the interaction between the STAT3 signaling pathway and various lncRNAs, as well as their implications for apoptosis, metastasis, and immune evasion in CRC.

A phase 2, multicenter, open-label study of AlloStim combined with anti-PD-L1immunotherapy as 4L therapy in patients with MSS/pMMR metastatic colorectal cancer.

TPS318 Background: Microsatellite stable (MSS)/mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) are immunologically 'cold' tumors that do not respond to immunotherapy. Cold tumors represent a formidable hurdle for checkpoint blockade immunotherapy approaches. Therefore, there is a need for novel strategies that could reprogram mCRC cold tumors to become inflamed hot tumors in a manner that might potentially convert low tumor mutational burden (TMB) tumors into checkpoint blockade responsive tumors. AlloStim is an experimental allogeneic, non-genetically manipulated, Th1-like activated living cell immunotherapy derived from healthy unrelated blood donors. The mechanism of action is designed to convert immunologically cold tumors into inflamed hot tumors. A case study of a single 3L MSS/pMMR mCRC patient primed with AlloStim followed by combination anti-PD-1/anti-CTLA4 checkpoint blockade resulted in a rare objective tumor response (Hirschfeld, et al, Translational Medicine Communications (2024) 9:15). The AlloStim priming results in an abundance of infiltrating interferon-gamma producing Th1 cells. Interferon-gamma has been shown to increase expression of PD-L1 in the TME. Therefore, it is hypothesized that the combination of AlloStim with an anti-PD-L1 checkpoint inhibitor might optimally evoke anti-tumor immune responses in this immunotherapy-refractory MSS/pMMR mCRC population. Methods: The study is a phase 2, multicenter, single-arm clinical trial of MSS/pMMR mCRC subjects in 4L that have been previously treated with an oxaliplatin-containing and irinotecan-containing chemotherapy regimen, anti-EGFR (RAS wt and left-sided), anti-VEGF and have progressed on 3L TAS-102 +/- bevacizumab or regorafenib or fruquinitinib. The study is evaluating weekly AlloStim priming from day 0 to day 49 followed by combination of AlloStim IV infusion (q2w) followed a week later by anti-PD-L1 (avelumab 800mg/q2w) from days 63 to day 98. Objective tumor response and disease control rate are the primary end-points. Overall survival is the secondary end-point. Clinically stable patients at day 112 can continue in an expansion phase with another round of combination AlloStim and avelumab from day 119 to day 154. CT scans are conducted at baseline, day 56 after AlloStim priming, day 112 after combination of alternating q2w infusions of AlloStim and avelumab and day 168 in all patients. CT scans will be analyzed by independent central readers using RECIST 1.1. Up to 50 patients will be enrolled with an interim analysis performed to assess efficacy after 20 patients become evaluable. The study is open and has not yet enrolled any patients at time of submission. Clinical trial information: NCT06557278 .