Immunotherapy For Pancreatic Cancer Research Articles

SPOP expression is associated with tumor-infiltrating lymphocytes in pancreatic cancer.

Speckle Type POZ Protein (SPOP), despite its tumor type-dependent role in tumorigenesis, primarily as a tumor suppressor gene is associated with a variety of different cancers. However, its function in pancreatic cancer remains uncertain. SPOP expression and the association between its expression and patient prognosis and immune function were evaluated using The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), The Tumor Immune Estimation Resource 2.0 (TIMER2.0) database, cBioportal, and various bioinformatic databases. Enrichment analysis of SPOP and the association between SPOP expression with clinical stage and grade were analyzed using the R software package. Then immunohistochemistry (IHC) was used to estimate the correlation between SPOP and tumor-infiltrating lymphocytes (TILs) in patients with pancreatic cancer. As part of our study, we assessed that SPOP was anomalously expressed in kinds of cancers, associated with clinical stage and outcomes. Meanwhile, SPOP also played a crucial role in the tumor microenvironment (TME). The expression level of SPOP was significantly correlated to tumor-infiltrating immune cells (TICs) in pancreatic cancer. Our study uncovered the potential corrections in SPOP with TICs, suggesting that SPOP may act as a biomarker for immunotherapy in pancreatic cancer.

Nano-enabled regulation of DNA damage in tumor cells to enhance neoantigen-based pancreatic cancer immunotherapy

Low-expression antigens, especially neoantigens, pose a significant challenge in immunotherapy for low immunogenicity pancreatic cancer. Increasing the tumor mutation burden is crucial to enhance the expression of tumor antigens and improve tumor immunogenicity. However, the incomplete intervention in DNA stability hampers effective elevation of the tumor mutation burden, thus reducing the probability of neoantigen. To address this issue, we have developed a novel nano-regulator that intervenes in the DNA stability of tumor cells, thereby enhancing tumor mutations. This nano-regulator comprises metal-organic frameworks (MOFs) encapsulating DNA damage agent doxorubicin and DNA damage repair inhibitor siRNA-ATR, enabling simultaneous induction of DNA mutations and inhibition of their repair. Importantly, this regulator, named as MOFDOX&siATR, can modulate the tumor gene expression profile, induce the production of neoantigens of Atp8b1, and enhance the immunogenicity of pancreatic cancer. The characteristics of DNA stability intervention by MOFDOX&siATR hold promise for augmenting the immune response in low immunogenic tumors, making it a potential nanomedicine for the treatment of pancreatic cancer.

Coordination engineering of FeCo dual single-atom nanozymes with photothermal-enhanced cascaded catalysis for efficient pancreatic cancer immunotherapy

Cancer immunotherapy holds great promise in improving therapeutic outcomes. However, its effectiveness is significantly hindered by the inadequate immunogenicity and potent immuno-suppressive nature of the tumor microenvironment (TME). Herein, we elaborately design an advanced iron-cobalt dual-single-atom nanozyme (FeCo-DA) with adjacent Fe-N/O-C and Co-N/O-C pair sites. This design aims to induce potent immunogenic cell death (ICD), ultimately enhancing cancer immunotherapy by activating the immune microenvironment. Compared to Fe and Co single-atom nanozyme, FeCo-DA demonstrated superior photothermal effects and cascaded catalytic performance by simultaneously mimicking peroxidase (POD), catalase (CAT), and glutathione oxidase (GSH-OXD). The cascaded catalysis not only augmented oxidative stress but also exacerbated the redox imbalance through sustainable generation of hydroxyl radicals (∙OH) and depletion of glutathione (GSH). The comprehensive in vitro and vivo experiments demonstrated that FeCo-DA effectively induced immunogenic cell death (ICD) by releasing damage-associated molecular patterns (DAMPs). The photothermal-enhanced cascaded catalytic therapy exhibited remarkable therapeutic effects on a mouse model of pancreatic cancer. This work highlights the potential of structure engineering in enhancing the efficacy of dual single-atom nanozyme for ICD-based cancer immunotherapy.

The Current Landscape of Clinical Trials for Immunotherapy in Pancreatic Cancer: A State-of-the-Art Review.

Pancreatic cancer remains a lethal malignancy with a 5-year survival rate below 6% and about 500,000 deaths annually worldwide. Pancreatic adenocarcinoma, the most prevalent form, is commonly associated with diabetes, chronic pancreatitis, obesity, and smoking, mainly affecting individuals aged 60 to 80 years. This systematic review aims to evaluate the efficacy of immunotherapeutic approaches in the treatment of pancreatic cancer. A systematic search was conducted to identify clinical trials (Phases I-III) assessing immunotherapy in pancreatic cancer in PubMed/Medline, CINAHL, Scopus, and Web of Science, adhering to PRISMA Statement 2020 guidelines. The final search was completed on May 25, 2024. Ongoing trials were sourced from ClinicalTrials.gov and the World Health Organization's International Clinical Trials Registry Platform (ICTRP). Keywords such as "pancreatic," "immunotherapy," "cancer," and "clinical trial" were used across databases. Gray literature was excluded. Phase I trials, involving 337 patients, reported a median overall survival (OS) of 13.6 months (IQR: 5-62.5 months) and a median progression-free survival (PFS) of 5.1 months (IQR: 1.9-11.7 months). Phase II/III trials pooled in a total of 1463 participants had a median OS of 12.2 months (IQR: 2.5-35.55 months) and a median PFS of 8.8 months (IQR: 1.4-33.51 months). Immunotherapy shows potential for extending survival among pancreatic cancer patients, though results vary. The immunosuppressive nature of the tumor microenvironment and diverse patient responses underline the need for further research to optimize these therapeutic strategies.

Emerging Nanotechnology in Preclinical Pancreatic Cancer Immunotherapy: Driving Towards Clinical Applications.

The high malignant degree and poor prognosis of pancreatic cancer (PC) pose severe challenges to the basic research and clinical translation of next-generation therapies. The rise of immunotherapy has improved the treatment of a variety of solid tumors, while the application in PC is highly restricted by the challenge of immunosuppressive tumor microenvironment. The latest progress of nanotechnology as drug delivery platform and immune adjuvant has improved drug delivery in a variety of disease backgrounds and enhanced tumor therapy based on immunotherapy. Based on the immune loop of PC and the status quo of clinical immunotherapy of tumors, this article discussed and critically analyzed the key transformation difficulties of immunotherapy adaptation to the treatment of PC, and then proposed the rational design strategies of new nanocarriers for drug delivery and immune regulation, especially the design of combined immunotherapy. This review also put forward prospective views on future research directions, so as to provide information for the new means of clinical treatment of PC combined with the next generation of nanotechnology and immunotherapy.

Type I conventional dendritic cells facilitate immunotherapy in pancreatic cancer.

Inflammation and tissue damage associated with pancreatitis can precede or occur concurrently with pancreatic ductal adenocarcinoma (PDAC). We demonstrate that in PDAC coupled with pancreatitis (ptPDAC), antigen-presenting type I conventional dendritic cells (cDC1s) are specifically activated. Immune checkpoint blockade therapy (iCBT) leads to cytotoxic CD8+ T cell activation and elimination of ptPDAC with restoration of life span even upon PDAC rechallenge. Using PDAC antigen-loaded cDC1s as a vaccine, immunotherapy-resistant PDAC was rendered sensitive to iCBT with elimination of tumors. cDC1 vaccination coupled with iCBT identified specific CDR3 sequences in the tumor-infiltrating CD8+ T cells with potential therapeutic importance. This study identifies a fundamental difference in the immune microenvironment in PDAC concurrent with, or without, pancreatitis and provides a rationale for combining cDC1 vaccination with iCBT as a potential treatment option.

A microphysiological system reveals neutrophil contact-dependent attenuation of pancreatic tumor progression by CXCR2 inhibition-based immunotherapy

Cancer cells recruit neutrophils from the bloodstream into the tumor tissue, where these immune cells promote the progression of numerous solid tumors. Studies in mice suggest that blocking neutrophil recruitment to tumors by inhibition of neutrophil chemokine receptor CXCR2 could be a potential immunotherapy for pancreatic cancer. Yet, the mechanisms by which neutrophils promote tumor progression in humans, as well as how CXCR2 inhibition could potentially serve as a cancer therapy, remain elusive. In this study, we developed a human cell-based microphysiological system to quantify neutrophil-tumor spheroid interactions in both “separated” and “contact” scenarios. We found that neutrophils promote the invasion of tumor spheroids through the secretion of soluble factors and direct contact with cancer cells. However, they promote the proliferation of tumor spheroids solely through direct contact. Interestingly, treatment with AZD-5069, a CXCR2 inhibitor, attenuates invasion and proliferation of tumor spheroids by blocking direct contact with neutrophils. Our findings also show that CXCR2 inhibition reduces neutrophil migration toward tumor spheroids. These results shed new light on the tumor-promoting mechanisms of human neutrophils and the tumor-suppressive mechanisms of CXCR2 inhibition in pancreatic cancer and may aid in the design and optimization of novel immunotherapeutic strategies based on neutrophils.

The impact of KRAS mutations on the clinical outcome and immune response following immunotherapy for pancreatic cancer

The impact of KRAS mutations on the clinical outcome and immune response following immunotherapy for pancreatic cancer

Impact of concurrent antibiotics on survival with immunotherapy in metastatic colorectal and pancreatic cancer.

2609 Background: The interplay between antibiotics and the microbiome has been hypothesized to modify the immune response to cancer and may negatively affect immune checkpoint inhibitor (ICI) efficacy. Methods: We retrospectively reviewed concurrent antibiotics received in the randomized phase II Canadian Cancer Trials Group (CCTG) CO.26 and PA.7 clinical trials. CO.26 evaluated dual programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibition (with durvalumab and tremelimumab) versus best supportive care only (BSC) in metastatic refractory colorectal cancer (CRC). PA.7 evaluated gemcitabine and nab-paclitaxel +/- durvalumab and tremelimumab in metastatic pancreatic ductal adenocarcinoma. In CO.26, T cell receptor sequencing (TCR-seq) was available at baseline and week 8. Results: In CO.26 (n=180), median (range) age was 65 (36-87) years, 33% (n=59) were female, and 29% (n=50) were ECOG 0. Concurrent exposure to antibiotics was associated with improved overall survival (OS) (7.4 vs 6.2 months, adjusted hazard ratio (aHR) 0.66 (95% confidence interval (CI) 0.46-0.93), p=0.018) in patients with metastatic CRC who received ICIs, but not in patients who received BSC (3.5 vs 4.5 months, HR 1.49 (95% CI 0.81-2.73), p= 0.20); (p-interaction=0.094). In antibiotic class analysis, concurrent exposure of ICIs to fluoroquinolones (9.4 vs 6.2 months, aHR 0.50 (95% CI 0.30-0.82), p=0.0067), but not penicillins or cephalosporins, was associated with improved OS. There was no difference in RAS/RAF status or tumor mutation burden in patients who received antibiotics/fluoroquinolones or not. The results were consistent when also controlling for TMB (antibiotics aHR 0.63 (0.44, 0.91), p=0.013; fluoroquinolones aHR 0.51 (0.31, 0.84), p=0.009). Patients treated with antibiotics did not have a different TCR diversity or clonality between baseline and 8 weeks (p=0.37 and p=0.47) compared to those who did not receive antibiotics (p=0.26 and p=0.60). In PA.7 (n=180), median (range) age was 65 (29-84) years, 48% (n=87) were female, and 24% (n=44) were ECOG 0. Antibiotics were not associated with OS in patients who did/did not receive ICIs (9.7 vs 10.8 months, HR 0.97 (95% CI 0.64, 1.46), p=0.87; 7.4 vs 10.3 months HR 1.22 (95% CI 0.72, 2.09), p=0.46, respectively). Fluoroquinolones were also not associated with OS regardless of whether or not the patient received ICI therapy (10.9 vs 9.8 months, HR 0.74 (95% CI 0.47, 1.15), p=0.18; 7.2 vs 10.2 months, HR 1.18 (95% CI 0.62, 2.27), p=0.62). Conclusions: Concurrent exposure to antibiotics, and specifically fluoroquinolones during ICI therapy was associated with a statistically significant improvement in OS in patients with metastatic CRC, but not metastatic pancreatic cancer. This is discrepant from prior reports in other tumor types and suggests that the gut microbiome may impact ICI efficacy uniquely in patient with CRC. Clinical trial information: NCT02870920 , NCT02879318 .

The clinical application of circulating tumor cells (CTCs) for immunotherapy in advanced pancreatic cancer.

e14541 Background: Circulating tumor cell (CTCs) has the potential utility for screening, prognostic and predictive assessment, and offers the potential for personalized management. This trial aimed to evaluate the prognostic and predictive impact of programmed cell death ligand 1 (PD-L1) positive CTCs in patients with pancreatic ductal adenocarcinoma (PDAC). Methods: Twenty-three heavily treated advanced PDAC patients were randomized to receive camrelizumab combined with apatinib or capecitabine, or placebo plus capecitabine until disease progression or unacceptable toxicity, and peripheral blood CTCs samples were collected at baseline and after treatment. Forty-nine CTCs samples from 23 recruited advanced PDAC patients were detected by subtraction enrichment and immunostaining-FISH (SE-iFISH). PD-L1 expression level also was evaluated in tumor tissue samples by Immunohistochemistry (IHC). Investigator-assessed 6-month overall survival (OS) rate and 3-month progression-free survival (PFS) rate was evaluated. Results: The positive detection rate of CTCs in 23 PDAC patients was 95.7%. The cell sub-types of sizes of CTC analysis showed that 58.6% CTCs was the small CTCs (Diameter < 5μm). CTCs karyotypes analysis exhibited that triploid small CTCs were the main karyotype (41.2%) in small CTC, and pentaploid large CTCs was the major karyotype (74.7%) in large CTCs. PD-L1+ CTCs were detected in 43.5% of PDAC patients. Tissue PD-L1 positive detection rate was 50% (CPS > 1%) in available tissue samples(n=10). The presence of PD-L1+ CTCs cohort exhibited a significant increase in 6-month OS rate (80% versus 38.5%, P < 0.05) and 3-month PFS rate (70% versus 23.1%, P < 0.05) compared to PD-L1- CTCs cohort. Compared with the PD-L1- CTCs patients, the combination therapy camrelizumab markedly improved the 6-month OS rates (75% versus 50%) and 3-month PFS rate (62.5% versus 25%) in PD-L1+ CTC patients. Conclusions: PD-L1+ CTCs could be considered as a favorable prognostic marker in advanced PDAC. These results suggest that PD-L1+ CTCs might be used as a predictor of the efficacy of cancer immunotherapy in advanced PDAC, and provide a new monitoring method for the precise treatment of advanced PDAC. The expanding sample size test is now ongoing. Clinical trial information: ChiCTR1900024095 .

Retraction Note: ITGA3 acts as a purity-independent biomarker of both immunotherapy and chemotherapy resistance in pancreatic cancer: bioinformatics and experimental analysis

Retraction Note: ITGA3 acts as a purity-independent biomarker of both immunotherapy and chemotherapy resistance in pancreatic cancer: bioinformatics and experimental analysis

Frontiers and future of immunotherapy for pancreatic cancer: from molecular mechanisms to clinical application.

Pancreatic cancer is a highly aggressive malignant tumor, that is becoming increasingly common in recent years. Despite advances in intensive treatment modalities including surgery, radiotherapy, biological therapy, and targeted therapy, the overall survival rate has not significantly improved in patients with pancreatic cancer. This may be attributed to the insidious onset, unknown pathophysiology, and poor prognosis of the disease. It is therefore essential to identify and develop more effective and safer treatments for pancreatic cancer. Tumor immunotherapy is the new and fourth pillar of anti-tumor therapy after surgery, radiotherapy, and chemotherapy. Significant progress has made in the use of immunotherapy for a wide variety of malignant tumors in recent years; a breakthrough has also been made in the treatment of pancreatic cancer. This review describes the advances in immune checkpoint inhibitors, cancer vaccines, adoptive cell therapy, oncolytic virus, and matrix-depletion therapies for the treatment of pancreatic cancer. At the same time, some new potential biomarkers and potential immunotherapy combinations for pancreatic cancer are discussed. The molecular mechanisms of various immunotherapies have also been elucidated, and their clinical applications have been highlighted. The current challenges associated with immunotherapy and proposed strategies that hold promise in overcoming these limitations have also been discussed, with the aim of offering new insights into immunotherapy for pancreatic cancer.

Integrated analysis of single-cell and bulk RNA sequencing to construct a CD8 + T cell-related immune gene signature in pancreatic cancer

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor that responds poorly to immunotherapy. The pivotal influence of CD8 + T-cell infiltration on immunotherapy has been documented in various solid tumors. However, the specific contribution of CD8 + T cell-associated immune genes (TIGs) to the tumor immune microenvironment remains unclear. Methods: We obtained CD8 + T cell-related immune genes from the INNATE and IMMPORT databases. Univariate analysis and lasso regression analysis were utilized to screen hub TIGs and develop a prognostic signature, the TIGs score. This score was used to evaluate prognosis, immunocyte infiltration, cancer-associated signaling pathways, and the potential responsiveness of immunotherapy. The transcriptomic data and single-cell data from the GSE183795 and GE212966 datasets are employed to validate the reliability of the findings. Results: Our findings suggest that patients with low TIGs scores have stronger immune effector functions and immune checkpoint activation, resulting in a more favorable response to PD-L1 inhibitors. TIGs scores were significantly correlated with various molecular characteristics and clinical outcomes, such as tumor mutation burden, multiple tumor-associated pathways, and chemotherapeutic drug sensitivity. PSME2 was identified as a potential prognostic biomarker for predicting survival in patients with PDAC. Conclusions: This study elucidates the intricate regulatory mechanisms of TIGs within the tumor immune microenvironment of pancreatic cancer. Our findings strongly suggest that the TIGs score is a robust prognostic marker for prognosis and immunotherapy responsiveness. Additionally, targeting PSME2 may offer a novel avenue for enhancing the effectiveness of immunotherapy in pancreatic cancer.

BCL2A1 neoepitope-elicited cytotoxic T lymphocytes are a promising individualized immunotherapy of pancreatic cancer.

Conventional treatments have shown a limited efficacy for pancreatic cancer, and immunotherapy is an emerging option for treatment of this highly fatal malignancy. Neoantigen is critical to improving the efficacy of tumor-specific immunotherapy. The cancer and peripheral blood specimens from an HLA-A0201-positive pancreatic cancer patient were subjected to next-generation sequencing, and bioinformatics analyses were performed to screen high-affinity and highly stable neoepitopes. The activation of cytotoxic T lymphocytes (CTLs) by dendritic cells (DCs) loaded with mutBCL2A111-20 neoepitope targeting a BCL2A1 mutant epitope was investigated, and the cytotoxicity of mutBCL2A111-20 neoepitope-specific CTLs to pancreatic cancer cells was evaluated. The mutBCL2A111-20 neoepitope was found to present a high immunogenicity and induce CTLs activation and proliferation, and these CTLs were cytotoxic to mutBCL2A111-20 neoepitope-loaded T2 cells and pancreatic cancer PANC-1-Neo and A2-BxPC-3-Neo cells that overexpressed mutBCL2A111-20 neoepitopes, appearing to be a targeting neoepitope specificity. In addition, high BCL2A1 expression correlated with a low 5-yr progression-free interval among pancreatic cancer patients. Our findings provide experimental supports to individualized T cell therapy targeting mutBCL2A111-20 neoepitopes, and provide an option of immunotherapy for pancreatic cancer.

New avenues for the treatment of immunotherapy-resistant pancreatic cancer.

Pancreatic cancer (PC) is characterized by its extremely aggressive nature and ranks 14th in the number of new cancer cases worldwide. However, due to its complexity, it ranks 7th in the list of the most lethal cancers worldwide. The pathogenesis of PC involves several complex processes, including familial genetic factors associated with risk factors such as obesity, diabetes mellitus, chronic pancreatitis, and smoking. Mutations in genes such as KRAS, TP53, and SMAD4 are linked to the appearance of malignant cells that generate pancreatic lesions and, consequently, cancer. In this context, some therapies are used for PC, one of which is immunotherapy, which is extremely promising in various other types of cancer but has shown little response in the treatment of PC due to various resistance mechanisms that contribute to a drop in immunotherapy efficiency. It is therefore clear that the tumor microenvironment (TME) has a huge impact on the resistance process, since cellular and non-cellular elements create an immunosuppressive environment, characterized by a dense desmoplastic stroma with cancer-associated fibroblasts, pancreatic stellate cells, extracellular matrix, and immunosuppressive cells. Linked to this are genetic mutations in TP53 and immunosuppressive factors that act on T cells, resulting in a shortage of CD8+ T cells and limited expression of activation markers such as interferon-gamma. In this way, finding new strategies that make it possible to manipulate resistance mechanisms is necessary. Thus, techniques such as the use of TME modulators that block receptors and stromal molecules that generate resistance, the use of genetic manipulation in specific regions, such as microRNAs, the modulation of extrinsic and intrinsic factors associated with T cells, and, above all, therapeutic models that combine these modulation techniques constitute the promising future of PC therapy. Thus, this study aims to elucidate the main mechanisms of resistance to immunotherapy in PC and new ways of manipulating this process, resulting in a more efficient therapy for cancer patients and, consequently, a reduction in the lethality of this aggressive cancer.

The GFPT2-O-GlcNAcylation-YBX1 axis promotes IL-18 secretion to regulate the tumor immune microenvironment in pancreatic cancer

The immunosuppressive microenvironment caused by several intrinsic and extrinsic mechanism has brought great challenges to the immunotherapy of pancreatic cancer. We identified GFPT2, the key enzyme in hexosamine biosynthesis pathway (HBP), as an immune-related prognostic gene in pancreatic cancer using transcriptome sequencing and further confirmed that GFPT2 promoted macrophage M2 polarization and malignant phenotype of pancreatic cancer. HBP is a glucose metabolism pathway leading to the generation of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), which is further utilized for protein O-GlcNAcylation. We confirmed GFPT2-mediated O-GlcNAcylation played an important role in regulating immune microenvironment. Through cellular proteomics, we identified IL-18 as a key downstream of GFPT2 in regulating the immune microenvironment. Through CO-IP and protein mass spectrum, we confirmed that YBX1 was O-GlcNAcylated and nuclear translocated by GFPT2-mediated O-GlcNAcylation. Then, YBX1 functioned as a transcription factor to promote IL-18 transcription. Our study elucidated the relationship between the metabolic pathway of HBP in cancer cells and the immune microenvironment, which might provide some insights into the combination therapy of HBP vulnerability and immunotherapy in pancreatic cancer.

DR30318, a novel tri-specific T cell engager for Claudin 18.2 positive cancers immunotherapy

BackgroundClaudin 18.2 (CLDN18.2) is a highly anticipated target for solid tumor therapy, especially in advanced gastric carcinoma and pancreatic carcinoma. The T cell engager targeting CLDN18.2 represents a compelling strategy for enhancing anti-cancer efficacy.MethodsBased on the in-house screened anti-CLDN18.2 VHH, we have developed a novel tri-specific T cell engager targeting CLDN18.2 for gastric and pancreatic cancer immunotherapy. This tri-specific antibody was designed with binding to CLDN18.2, human serum albumin (HSA) and CD3 on T cells.ResultsThe DR30318 demonstrated binding affinity to CLDN18.2, HSA and CD3, and exhibited T cell-dependent cellular cytotoxicity (TDCC) activity in vitro. Pharmacokinetic analysis revealed a half-life of 22.2–28.6 h in rodents and 41.8 h in cynomolgus monkeys, respectively. The administration of DR30318 resulted in a slight increase in the levels of IL-6 and C-reactive protein (CRP) in cynomolgus monkeys. Furthermore, after incubation with human PBMCs and CLDN18.2 expressing cells, DR30318 induced TDCC activity and the production of interleukin-6 (IL-6) and interferon-gamma (IFN-γ). Notably, DR30318 demonstrated significant tumor suppression effects on gastric cancer xenograft models NUGC4/hCLDN18.2 and pancreatic cancer xenograft model BxPC3/hCLDN18.2 without affecting the body weight of mice.

Abstract 2129: Efficacy and underlying mechanisms of surufatinib combined with PD-1 monoclonal antibody and chemotherapy in pancreatic cancer

Abstract Background: A phase 1b/2 study (NCT05218889) of surufatinib combined with camrelizumab, nab-paclitaxel, and S-1 (NASCA) as first-line therapy for metastatic pancreatic adenocarcinoma has shown promising results, potentially overcoming the limitations of current pancreatic immunotherapies. Animal studies are underway to further explore the synergistic effects and mechanisms of this combined therapeutic approach. Methods: Genetically engineered KPC mouse cells were used to establish a subcutaneous transplantation tumor model in female mice, which were then divided into control group, AG group (nab-paclitaxel + gemcitabine), and NASCA group. Tumor metrics were recorded until euthanasia after 21 days. Blood and tumor samples were analyzed using Flow Cytometry. Results: Compared with the control group, the NASCA and AG groups demonstrated tumor volume reductions of 14.7% (p=0.172) and -0.4% (p=0.972) on day 7, respectively. At day 14, the reductions were 48.8% and 29.9% (p<0.001*, p=0.002*). At day 21, the reductions were 37.4% and 21.5% (p=0.001*, p=0.144). The tumor growth inhibitions (TGIs) for NASCA and AG group were 56.7% (p<0.001*) and 21.2% (p=0.36), respectively. Compare to AG group, the tumor volume reduction in NASCA group were 15.1% (p=0.050*), 26.9% (p=0.001*) and 20.3% (p=0.116), respectively. And the TGIs for NASCA group compare AG group was 45.0% (p=0.020*). Distinguishingly, the NASCA group, when compared to the AG group, had a heightened proportion of M1 macrophages (28.5% vs. 15.5%, p=0.019*), mCD68+ Macrophages (99.7% vs. 99.1%, p=0,014*) and mPD-1+/mCD8+ T cells (24.8% vs. 9.8%, p=0.03*). Furthermore, T-regulatory cells (T-regs) in peripheral blood demonstrated uniformity across the groups, were no statistically. RNA-seq analysis revealed that the NASCA significantly suppressed multiple anti-angiogenic pathways while enhancing the cytokine pathway (p=0.005*), indicating potential immune system activation. Conclusion: The NASCA group outperformed the AG group in controlling tumor growth and early tumor shrinkage, potentially due to macrophage polarization regulation. Further research is vital to understand the benefits of integrating targeted therapy, immunotherapy, and chemotherapy for pancreatic cancer. Citation Format: Nan Zhang, Ru Jia, Guanghai Dai. Efficacy and underlying mechanisms of surufatinib combined with PD-1 monoclonal antibody and chemotherapy in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2129.

Abstract 4008: DASH CAR-T: accelerating CD276-targeted immunotherapy for pancreatic cancer

Abstract B7 homolog 3 protein (B7-H3), recognized as CD276, is a pivotal immune checkpoint molecule extensively expressed in cancer cells, presenting a limited presence in normal tissues. Immunohistochemical analysis of 150 pancreatic cancer patients revealed positive CD276 staining in 66% of cases, with elevated expression correlating to diminished disease-free survival. Additional findings from an independent study on 59 patients highlighted significantly elevated CD276 levels, particularly in lymph node metastasis and advanced pathology. This study introduces an innovative Chimeric Antigen Receptor T (CAR-T) therapy targeting CD276, leveraging our DASH CAR-T manufacturing platform. Significantly, our approach reduces the ex vivo cell expansion time from 10 days to 1-2 days. T cells were enriched, activated, and transduced with a CD276 CAR-encoding retroviral vector, achieving the final product in 2-3 days. In preclinical models, our shorten-time CAR-T against CD276 exhibited superior expansion and heightened tumor-killing efficacy. Remarkably, DASH CAR-T demonstrated superior tumor control compared to conventional CAR-T, requiring only one-tenth of the dosage. This research advances our understanding of CD276 in pancreatic cancer and presents a transformative approach in CAR-T therapy manufacturing. The shortened production timeline and enhanced therapeutic outcomes underscore the potential clinical impact of our novel CAR-T strategy, offering a more efficient and potent treatment option for pancreatic cancer. Citation Format: Haiying Wang, Tian Deng, Hao Li, Yue Yao, Yuan Tian, Hongwei Wang, Pengfei Jiang. DASH CAR-T: accelerating CD276-targeted immunotherapy for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4008.

Genetically engineered membrane-based nanoengagers for immunotherapy of pancreatic cancer

Modulating macrophages presents a promising avenue in tumor immunotherapy. However, tumor cells have evolved mechanisms to evade macrophage activation and phagocytosis. Herein, we introduced a bispecific antibody-based nanoengager to facilitate the recognition and phagocytosis of tumor cells by macrophages. Specifically, we genetically engineered two single chain variable fragments (scFv) onto cell membrane: anti-CD40 scFv for engaging with macrophages and anti-Claudin18.2 (CLDN18.2) scFv for interacting with tumor cells. These nanoengagers were further constructed by coating scFv-anchored membrane into PLGA nanoparticle core. Our developed nanoengagers significantly boosted immune responses, including increased recognition and phagocytosis of tumor cells by macrophages, enhanced activation and antigen presentation, and elevated cytotoxic T lymphocyte activity. These combined benefits resulted in enhancing antitumor efficacy against highly aggressive “cold” pancreatic cancer. Overall, this study offers a versatile nanoengager design for immunotherapy, achieved through genetically engineering to incorporate antibody-anchored membrane.