Erwei Song’s research while affiliated with Sun Yat-sen University and other places

Background CAN1012 is a long-acting, highly selective TLR7 agonist. It can turn the ‘cold’ tumor into the ‘hot’ tumor through several mechanisms: (1) strong induction of proinflammatory and anti-tumor immune cytokines/chemokines (IFN-α, IP-10); (2) low induction of CRS-associated cytokines (IL-6 and TNF-α); (3) increased CD4+ and CD8+ T cell infiltration but decreased the number of myeloid-derived suppressor cells (MDSCs) and M2 macrophages in the tumor microenvironment (TME). CAN1012 is uniquely designed for intratumoral (IT) administration, where it is retained in tumor tissues with minimal systemic exposure. CAN1012 produced strong antitumor effects in various syngeneic mouse tumor models in vivo. Synergistic effects were observed in syngeneic animal models combined with CAN1012 with anti-CTLA-4, anti-PD-1, anti-PD-L1, anti-PD-L1-TGFβR, anti-VEGF, or anti-OX40 antibodies. Methods A first-in-human, multi-center, 3+3 trial design, phase I dose-escalation trial of CAN1012 administered intralesionally in advanced cancer patients (pts) Q4W was initiated both in China (CTR20222322) and in the US (NCT04987112). Results Seven cohorts of patients were enrolled in the current phase I trial, including 21 patients, 6 males, and 15 females, with a median age of 55 years (range 22–72) at doses ranging from 1 to 34 micrograms Q4W. Tumor types enrolled include breast, ovarian, colon, sarcoma, adenocarcinoma, neurofibroma, nasopharyngeal, and melanoma. CAN1012 was well-tolerated with no DLT and no or little systemic exposure. The main adverse events were laboratory, with absolute neutrophil count (ANC) and lymphocytes decreased. Immunological adverse events (fever and urticaria Grade 2) were observed at the higher dose of 34 mcg. One confirmed metabolic PR (mPR), 2 stable diseases (SD) ³ 14 mos, and 3 shorter SD were observed. Pharmacodynamcally, IP-10 and IFN-a were increased across cohorts, while IL-6 was increased only at the higher dose. pDC and monocytes were increased in the peripheral blood of mPR and SD patients, and increased CD8 T cells were also detected in tumor biopsy of these patients. Preliminary patient selection biomarkers were identified. Two cohorts (15 and 22.5 mcg Q4W) are being expanded to define the RP2D better. Conclusions CAN1012 is tolerable and active in an advanced cancer population; further clinical and pharmacodynamic data will be presented. The Phase 1/2 studies of CAN1012 in combination with Toripalimab have been started, which would provide more clinical and pharmacodynamic data.

PURPOSE SHR-A1811 is an antibody-drug conjugate composed of an anti–human epidermal growth factor receptor 2 (HER2) antibody trastuzumab, a cleavable linker, and a topoisomerase I inhibitor payload. We assessed the safety, tolerability, antitumor activity, and pharmacokinetics of SHR-A1811 in heavily pretreated HER2-expressing or mutated advanced solid tumors. METHODS This global, multi-center, first-in-human, phase I trial was conducted at 33 centers. Patients who had HER2-expressing or mutated unresectable, advanced, or metastatic solid tumors and were refractory or intolerant to standard therapies were enrolled. SHR-A1811 was administered intravenously at doses ranging from 1.0 to 8.0 mg/kg once every 3 weeks. The primary end points were dose-limiting toxicity, safety, and the recommended phase II dose. RESULTS From September 7, 2020, to February 27, 2023, 307 patients who had undergone a median of three (IQR, 2-5) previous treatment regimens in the metastatic setting received SHR-A1811 treatment. As of data cutoff (February 28, 2023), one patient from the 6.4 mg/kg group experienced dose-limiting toxicities (pancytopenia and colitis). The most common grade 3 or higher adverse events (AEs) included decreased neutrophil count (119 [38.8%]) and decreased WBC count (70 [22.8%]). Interstitial lung disease occurred in only eight (2.6%) patients. Serious AEs and deaths occurred in 70 (22.8%) and 13 (4.2%) patients, respectively. SHR-A1811 led to objective responses in 59.9% (184/307) of all patients, 76.3% (90/118) of HER2-positive breast cancer, 60.4% (55/91) of HER2 low-expressing breast cancer, and 45.9% (39/85 with evaluable tumor responses) of the 98 nonbreast tumors. CONCLUSION SHR-A1811 exhibited acceptable tolerability, promising antitumor activity, and a favorable pharmacokinetic profile in heavily pretreated advanced solid tumors. The recommended phase II dose of 4.8 or 6.4 mg/kg was selected for various tumor types.

RNA molecules have emerged as promising clinical therapeutics due to their ability to target “undruggable” proteins or molecules with high precision and minimal side effects. Nevertheless, the primary challenge in RNA therapeutics lies in rapid degradation and clearance from systemic circulation, the inability to traverse cell membranes, and the efficient intracellular delivery of bioactive RNA molecules. In this review, we explore the implications of RNAs in diseases and provide a chronological overview of the development of RNA therapeutics. Additionally, we summarize the technological advances in RNA-screening design, encompassing various RNA databases and design platforms. The paper then presents an update on FDA-approved RNA therapeutics and those currently undergoing clinical trials for various diseases, with a specific emphasis on RNA medicine and RNA vaccines.

Basal‐like breast cancer (BLBC) is the most aggressive molecular subtype of breast cancer with worse prognosis and fewer treatment options. The underlying mechanisms upon BLBC transcriptional dysregulation and its upstream transcription factors (TFs) remain unclear. Here, among the hyperactive candidate TFs of BLBC identified by bioinformatic analysis, POU4F1 is uniquely upregulated in BLBC and is associated with poor prognosis. POU4F1 is necessary for the tumor growth and malignant phenotypes of BLBC through regulating G1/S transition by direct binding at the promoter of CDK2 and CCND1. More importantly, POU4F1 maintains BLBC identity by repressing ERα expression through CDK2‐mediated EZH2 phosphorylation and subsequent H3K27me3 modification in ESR1 promoter. Knocking out POU4F1 in BLBC cells reactivates functional ERα expression, rendering BLBC sensitive to tamoxifen treatment. In‐depth epigenetic analysis reveals that the subtype‐specific re‐configuration and activation of the bivalent chromatin in the POU4F1 promoter contributes to its unique expression in BLBC, which is maintained by DNA demethylase TET1. Together, these results reveal a subtype‐specific epigenetically activated TF with critical role in promoting and maintaining BLBC, suggesting that POU4F1 is a potential therapeutic target for BLBC.

Background CAN1012 is a selective Toll-like receptor 7 (TLR7) agonist whose receptor locates in intracellular endosomes of plasmacytoid dendritic cells (pDC). Upon binding to TLR7 agonist, pDC secret high levels of type I interferons and other anti-viral cytokines/chemokines. Methods CAN1012 has been demonstrated to stimulate IFN-alpha releases in human PBMC in vitro and to produce antitumor effects, when given intratumorally (IT) in various syngeneic mouse tumor models in vivo. Furthermore, it can be used in combination with immune checkpoint inhibitors, anti-angiogenesis inhibitors or chemotherapy agents to enhance the anti-tumor effect. The exposure of CAN1012 in tumor tissues via IT route was over 1,000-fold higher than in blood, resulting in much less systemic toxicity. Pharmacodynamic studies revealed that it increased CD4+ and CD8+ T cell infiltration in the tumor microenvironment (TME), but decreased myeloid-derived suppressor cell (MDSCs) counts. It also has a favorable ADME/PK profile when administered subcutaneously in mice, rats and monkeys, and its pharmaceutical properties have also been optimized for IT administration. Results Based on the superior safety and efficacy of CAN1012 in preclinical studies, a first in-human Phase I dose-escalation trial for advanced cancer patients was initiated in multi clinical centers both in US (NCT04987112) and China (CTR20222322), using intratumoral administration and a standard 3+3 trial design. Up to now, four dose cohorts were successfully administered in patients. Preliminary results indicated that CAN1012 is well-tolerated with no severe adverse effect documented. In addition, a favorable efficacy is observed in some of treated patients. Conclusions The trial is still undergoing according to the initial design and is expected to be completed by the end of this year.

Mutations in a cell is natural, especially in aging cells. However, among all mutated cells, only a certain subset could clonally expand, leading to cancer. These cells then influence their surrounding cells to acquire cancerous phenotype - a phenomenon known as field cancerization. Field cancerization is both enabled by and causes changes to the tissue microenvironment. In this chapter, we introduce the concept of field cancerization in various human cancers. We also discuss how genetic and epigenetic changes in the local onco-sphere could affect field cancerization.

During cancer metastasis, cancer cells spread by dissemination into nearby normal tissue mostly via two major routes (i) lymph nodes and (ii) blood vessels. Cancer cells can travel through lymphatic system or extravasate into blood vessels to other parts of the body and forming new tumors at metastatic sites. In this chapter, we will focus on how vascular remodeling in the local onco-sphere could affect lymph node metastasis. We will also discuss the importance of the crosstalk between tumoral endothelial cells (lymphatic vessels, perivascular cells, endothelial progenitor cells) and tumor cells in lymph node metastasis in the regional onco-sphere.

The biochemical local onco-sphere changes as cancer grows, especially in the metabolic pathways of cancer cells. In cancer, formation and elimination of metabolically-active substances that favors the development of a pro-tumoral microenvironment could also induce a local onco-sphere that is fundamentally different from a normal cell (i.e. increased acidosis, amino acid and lipid metabolism). Metabolic alterations also cause redox imbalance, a major contributor to cancer growth. In this chapter, we discuss the major biochemical changes in the local onco-sphere and the important crosstalks between tumor cells and its surrounding metabolic substances in the creation of a pro-tumoral local onco-sphere.