Breakthrough Clinical Results
Renovaro Biosciences announced the publication of a peer-reviewed study in *Vaccines* demonstrating the significant anti-tumor efficacy of its next-generation dendritic cell (DC) therapy. The study, conducted in humanized mouse models of pancreatic cancer, showed that the engineered DCs, expressing CD93, CD40L, and CXCL13, significantly reduced tumor burden (up to 81.7%) and activated robust immune responses. The allogeneic, off-the-shelf approach allows for scalable production, enhancing clinical utility. Renovaro plans to initiate further preclinical studies across multiple tumor types and explore combination therapies.
Key Highlights
- Significant reduction in pancreatic tumor burden (up to 81.7%) in humanized mouse models.
- Robust immune activation, including increased CD4⁺ T cells, CD8⁺ T cells, and NK cells.
- Antigen-specific response targeting pancreatic tumor cells.
- Scalable, off-the-shelf platform using CD34⁺ hematopoietic stem cells.
Incidence and Prevalence
Global Incidence and Prevalence of Pancreatic Cancer: Latest Estimates
Pancreatic cancer remains one of the most common malignant tumors worldwide with a poor prognosis. According to recent data, the global incidence of pancreatic cancer is relatively low at 13.1 per 100,000 people based on 2022 figures.
Despite this relatively low incidence, pancreatic cancer is characterized as a highly aggressive tumour that is very resistant to treatments and is rarely diagnosed early due to the absence of specific symptoms. This contributes to its status as the seventh leading cause of cancer-related deaths worldwide, with 432,242 related deaths reported in 2018.
In the United States, the overall incidence of pancreatic adenocarcinoma from 2001 to 2015 was 5.2 per 100,000 people per year. Notably, incidence rates were highest among males, blacks, those with distant disease, and in the Northeast region. The incidence in blacks continued to rise with an annual percent change (APC) of 2.28 between 2001 and 2015.
Regional variations exist, with the South showing an increasing incidence at an expeditious rate (APC 2.70). Between 2001 and 2006, the incidence of distant disease increased rapidly (APC 5.34), though this rate slowed after 2006 (APC 1.91).
Demographic patterns show that pancreatic cancer is more frequent in men than women. In Puerto Rico (2005-2010), the incidence was 6.5 per 100,000 in men compared to 5.2 per 100,000 in women. The disease is significantly more common in persons older than 65 years (32.0 per 100,000).
A Canadian study (1992-2008) including 34,577 patients found that 49.3% were male, with a mean age at diagnosis of 70.1 years. Approximately 60.0% of patients were older than 70 years at diagnosis.
Racial disparities exist in survival rates. The odds ratio of dying before reaching 5+ year survival is lowest for Asian or Pacific Islander groups (OR = 0.70), followed by Black patients (OR = 1.07), White patients (OR = 1.12), and American Indian/Alaskan Native groups (OR = 1.12). In Florida, Hispanic ethnicity is associated with improved survival compared to Non-Hispanics.
The survival outlook for pancreatic cancer remains grim. The five-year survival rate for pancreatic ductal adenocarcinoma (PDAC) is under 9% according to 2021 data. In Puerto Rico, the median survival was only 4 months, with just 13% of patients surviving three years after diagnosis.
Alarmingly, pancreatic cancer is predicted to become the second leading cause of cancer mortality by 2030, with an increase in incidence particularly expected among African Americans.
Unlike many other cancers that have seen improved survival rates over the past few decades, pancreatic cancer continues to have persistently poor outcomes with hardly any change in survival rates, giving it the grim supremacy in terms of unfavourable survival rates.
Emerging Mechanism of Action
Emerging Mechanisms of Action for Pancreatic Cancer Treatment
RNA-Binding Proteins and Post-transcriptional Regulation
Hu-antigen R (HuR) has emerged as a central player in posttranscriptional regulation of cancer-related gene expression. HuR contributes to tumorigenesis, tumor growth, metastasis, and drug resistance by binding to the 3'-UTR of Snail mRNA, promoting epithelial-to-mesenchymal transition (EMT) and formation of stem-like cancer cells. Novel compound KH-3 interrupts HuR-RNA binding, inhibiting pancreatic cancer cell viability and metastasis.
Circular RNAs as Regulatory Molecules
Several circRNAs play pivotal roles in pancreatic cancer progression. CircEYA3 increases energy production via ATP synthesis and functions as a miR-1294 sponge to elevate c-Myc expression. Circ_0087502 affects proliferation, migration, and gemcitabine sensitivity by sponging miR-1179. CircHIF-1α inhibits senescence through miR-375 sponging and interacts with HUR protein to increase HIF-1α expression.
Signaling Pathway Targets
The AKT/GSK-3β/β-catenin signaling pathway has been identified as a promising target, with Chlorogenic acid (CA) shown to inhibit this pathway. For KRASG12D-mutated pancreatic cancer, combination therapy of avutometinib (a dual RAF/MEK clamp) with KRASG12D inhibitor MRTX1133 demonstrated synergistic effects by upregulating BIM, downregulating survivin, and inducing apoptosis.
Tumor Microenvironment Modulation
The complement system pathways play an important role in cancer progression and chemoresistance by establishing the tumor microenvironment and upregulating inflammatory mediators that activate chemo-resistant pathways. Immune checkpoint molecule B7-H1 has been identified as a key regulator, with inhibition leading to reduced tumor volume and improved survival by abrogating immunosuppression provided by MDSCs, macrophages, DCs, and Tregs.
Glycosylation-Related Mechanisms
O-glycan biosynthesis has been linked to pancreatic cancer development, prognosis, and immune microenvironment. Two molecular subtypes (OGRGcluster C1 and C2) show different clinical outcomes and immune infiltration patterns. A prognostic model based on glycosylation-related genes (SEL1L, TUBA1C, and SDC1) effectively predicts survival.
Novel Therapeutic Approaches
Radioligand therapy using 90Y-FAPI-46-RLT targeting fibroblast activation protein (FAP) has shown promise in advanced pancreatic cancer. EUS-guided radiofrequency ablation (EUS-RFA) has emerged as a minimally invasive technique for unresectable pancreatic cancer. Traditional chemotherapy approaches like FOLFIRINOX continue to be evaluated in adjuvant and neoadjuvant settings, while Lapatinib in combination with platinum-containing chemotherapy has shown safety and feasibility.
Biomarkers for Precision Medicine
Novel tumor-associated autoantibodies (anti-HEXB, anti-TXLNA, anti-SLAMF6) have been identified for diagnosis, especially when combined with CA19-9. Inflammatory markers like the C-reactive protein/albumin ratio (CAR) and proliferative markers including Ki-67, PCNA, Cyclin D1, and PHH3 show promise in predicting chemotherapy response, potentially enabling more personalized treatment approaches.
Drug used in other indications
Genetically Engineered Dendritic Cell Therapy Expressing CD93, CD40L, and CXCL13: Indications Beyond Pancreatic Cancer
Based on a comprehensive review of available clinical trial data, there is currently no evidence of genetically engineered dendritic cell therapy expressing CD93, CD40L, and CXCL13 being trialed for any indications, including pancreatic cancer.
While dendritic cell therapies are being investigated for various cancers, and individual components like CXCL13 have been studied in contexts such as gastric cancer, the specific combination therapy mentioned in the query does not appear in current clinical trial registries.
Without active trials for this specific therapy, there are consequently no intervention models to report regarding trial designs such as randomized controlled, non-randomized, parallel assignment, crossover assignment, factorial assignment, or sequential assignment methodologies.
The field of dendritic cell immunotherapy continues to evolve, with various engineered approaches being developed, but this particular combination of CD93, CD40L, and CXCL13 expression in dendritic cells appears to represent either an emerging approach not yet in clinical trials or a theoretical therapeutic combination.
Researchers interested in this specific combination may need to monitor upcoming trial registrations or consult with specialists in immunotherapy development for the most current information on this potential therapeutic approach.