Pancreatic Ductal Adenocarcinoma

Combinatorial nanobody-based CAR-M and CAR-NK therapy reprograms the TME and establishes a CXCL9-driven feed-forward loop between macrophages and NK cells, leading to synergistic innate immune activation and potent tumor control. This strategy provides a mechanistically grounded and translationally feasible framework for next-generation CAR-based immunotherapies targeting MSLN-expressing solid tumors.

Collectively, these findings establish estrogen as a key modulator of CAF heterogeneity and highlight a novel mechanism of tumor-stroma cross-talk with potential therapeutic implications for stroma-directed interventions in pancreatic cancer. See related article by Manoukian et al., p. 571.

It is the first pancreatic carcinoma type in which a basal molecular phenotype can be indicated clinically by both imaging and histopathology, with major potential management implications (as it is also enriched in actionable targets like ARID1A). Recognition of this category is critical for cancer research, as it offers an invaluable group to study plasticity, stroma versatility, necrosis mechanisms, and the basal type in pancreatic cancer.

Therapeutically, it caused dose-dependent tumor regression (TGI: 58% at 50 kBq; 92% at 150 kBq) and prolonged survival (>60 days vs. 0-1% in controls, p < 0.001). &lsqb;225Ac]Ac-Macropa-PEG6-Amatuximab is stable, selective, and therapeutically effective, demonstrating Macropa-based 225Ac chelation as a stable platform for targeted α-therapy of PDAC.

P1/2, N=37, Not yet recruiting, M.D. Anderson Cancer Center

Alterations in the homologous recombination (HR) DNA repair pathway are reported in 3.0-19.5% of PDAC patients. These types of alterations can sensitize tumors to platinum-based chemotherapy in PDAC as well as other cancers including ovarian, colorectal, and prostate cancers. Retrospective and prospective studies in locally advanced/metastatic PDAC demonstrate higher response rates and longer survival outcomes among HR-deficient (HRD) patients receiving platinum-based chemotherapy. A growing body of evidence in the neoadjuvant setting suggests a potential benefit for HRD-PDAC patients in terms of enhanced tumor downstaging, higher resectability, and improved survival outcomes compared with HR-proficient patients. However, prospective ad hoc studies are still warranted to confirm these findings Homologous recombination deficiency represents a promising biomarker to guide patient selection for neoadjuvant platinum-based chemotherapy in PDAC. Incorporation of HR deficiency-testing into neoadjuvant treatment schemes will enable a more personalized therapeutic approach, supporting the implementation of precision oncology for early-stage PDAC patients.

However, the randomized phase III POLO trial, upon which this standard is based, did not demonstrate an improved overall survival in patients who received olaparib compared to those who received placebo, highlighting the need for new therapeutic approaches...The model demonstrated high sensitivity to cisplatin plus gemcitabine, but limited efficacy of PARPi monotherapy...The addition of anti-PD1 treatment to PARPi maintenance enhanced tumor regression and prolonged overall survival. These findings provide preclinical support for ongoing clinical trials investigating immunotherapy with PARPi as a maintenance strategy in homologous recombination-deficient PDAC.

In post-hoc analyses, median progression-free survival was 26 months (95% CI: 14.7-34.3), and median overall survival was 38 months (95% CI: 27.9-not reached). Exploratory gene expression, immunohistochemistry and spatial transcriptomics showed increased intratumoral plasma cells and CD8 T cells in treated patients versus mFFX-only controls, and lymphoid aggregates with high plasma-cell-to-B cell ratios enriched for terminally exhausted CD8 T cells with fewer progenitor exhausted CD8 T cells and central memory CD4 T cells.

P1/2, N=20, Recruiting, West China Hospital,Sichuan University; West China Hospital,Sichuan University | N=10 --> 20

P=N/A, N=4000, Completed, ShangHai Changhai Hospital; ShangHai Changhai Hospital

P=N/A, N=0, Recruiting, Guangdong Provincial Hospital of Chinese Medicine (Guangdong Provincial Academic of Chinese Medicine Science; Second Clinical Medical College, Guangzh

P=N/A, N=0, Not yet recruiting, Southern Medical University Southern Hospital; Southern Medical University Southern Hospital