Remodeling of tumour microenvironment of pancreatic cancer: can agonistic anti-CD40 antibodies give a new direction?

Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive intrabdominal malignancies. Although surgical technique and systemic treatment improved a lot in the past 3 decades, the prognosis remains poor (5-year survival rate, 3–13.7%) (1-3). The term “pancreatic cancer” usually denotes PDAC, comprising >90% of cases. Currently, “pancreatic cancer or PDAC” is the 3^rd most common cause of global malignancy-related mortality, and at the time of year 2030, it is predicted to be the 2^nd most common cause of global malignancy-related mortality (2,3). Due to the lack of specific symptoms at an early stage, approximately 80% of patients with PDAC were diagnosed at the stage of inoperable disease. At the time of diagnosis, almost half were found to be at the stage of metastatic disease (1-4).

Systemic chemotherapy remains the only effective treatment strategy aiming at palliation and improvement of survival for advanced disease. The introduction of combined chemotherapy regimens including “FOLFIRINOX” (oxaliplatin, irinotecan, folinic acid, and fluorouracil) and “gemcitabine + nab-paclitaxel” has a positive impact for survival outcomes of advanced PDAC. Currently, for metastatic disease, the recommended regimens of 1^st line systemic chemotherapy for patients with good functional status is either “FOLFIRINOX” or “gemcitabine + nab-paclitaxel”, and the recommended regimen of 1^st line systemic chemotherapy for patients with suboptimal functional status is monotherapy “gemcitabine” (2). Randomized study (Von Hoff et al.) evaluated PDAC patients with metastasis receiving either “gemcitabine + nab-paclitaxel” or “monotherapy gemcitabine” (n, 431 vs. 430) (5). The gemcitabine/nab-paclitaxel group had a significant better objective response rate (ORR) (23% vs. 7%), progression-free survival (PFS) (median, 5.5 vs. 3.7 months), overall survival (OS) (median, 8.5 vs. 6.7 months), and 2-year survival rate (9% vs. 4%). However, adverse (grade ≥3) events were higher in the gemcitabine/nab-paclitaxel group, including peripheral neuropathy, fatigue, and neutropenia. Randomized study (Conroy et al.) evaluated patients with PDAC patients with metastasis receiving either “FOLFIRINOX” or “monotherapy gemcitabine” (n, 171 vs. 171) (6). ORR was significantly better in the FOLFIRINOX group (31.6% vs. 9.4%). The FOLFIRINOX group also had a significantly better PFS (median, 6.4 vs. 3.3 months) and OS (median, 11.1 vs. 6.8 months). The FOLFIRINOX group had a significant higher rate of adverse (grade ≥3) events, including neutropenia, neutropenic fever, thrombocytopenia, sensory neuropathy, and diarrhoea. For the subgroup of PDAC patients with metastasis accompanied with BRCA1 or BRCA2 gene mutations and at least stable disease after 16 weeks of platinum-based treatment regimen, olaparib as maintenance therapy is an option (7). Olaparib was demonstrated to improve median PFS, but not OS, compared to placebo. Olaparib has benefit for patients who not well tolerate systemic chemotherapy, and olaparib allows for maintaining the achieved chemotherapy’s therapeutic effect without adverse impact on quality of life. However, immunotherapy usage in PDAC has not been shown to be promising.

Even with the initial responses to chemotherapy, most patients still have tumour progression in some time. Apart from cancer cell-intrinsic factors, the lack of therapeutic effectiveness of system treatments is also due to the presence of a complex and highly immunosuppressive tumour microenvironment (TME) of PDAC (immunologically ‘cold’ condition), which characterizes by: (I) a profound desmoplastic reaction, featuring dense fibrosis, and; (II) a significant heterogeneous environment of immune cell composition, spatial distribution and activation status (8,9). Firstly, the surrounding cellular microenvironment [such as macrophages, cancer-associated fibroblasts (CAFs)] contributes to immune evasion via promoting a barrier with a profound desmoplastic reaction, featuring dense fibrosis that limiting perfusion, drug delivery, and tumour-infiltrating lymphocytes (TIL) infiltration. Secondly, PDAC is basically an immune-cold complex with limited effector T-cell infiltration. TIL play a crucial role in immune regulation, and TIL’s prognostic value is increasingly noted. A higher TIL density correlates with a better survival. On the other hand, regulatory T-cell infiltration and immunosuppressive stromal interactions are associated with poor prognosis (8-10). The key to improving the effectiveness of systemic therapy lies in way of reprogramming this hostile milieu from an immune-cold TME to an immune-hot or chemo-sensitive TME. This immunomodulation theory may lead to a new direction in designing future combined immunotherapy and chemotherapy regimens.

Human CD40 [a member of tumour necrosis factor (TNF) receptor superfamily] of receptors expressed on a variety type of cells. Agonistic human anti-CD40 antibodies are emerging as an option for cancer treatment, and early-phase clinical trials explored its role of immunomodulation. The CD40-its ligand (CD40L) interaction led to a series of immune events [include the licensing of dendritic cells (DCs) to activate CD8⁺ effector T-cells, and the facilitation of B-cell activation, proliferation, and differentiation] (10). In malignant cells, the expression of CD40 varies among cancer types (mediating cellular proliferation, apoptosis, survival, and the secretion of chemokines and cytokines). A few early trials provided important insights for the development of agonistic human anti-CD40 antibodies. Beatty et al. evaluated the combination of an agonist CD40 antibody with gemcitabine in a small cohort of patients with inoperable PDAC and found partial response (PR) in 4 out of 21 patients (11). This treatment effect in a genetically engineered mouse model of PDAC, and found that tumour regression required macrophages but not T cells or gemcitabine. CD40-activated macrophages rapidly infiltrated tumours, became tumoricidal, and facilitated the depletion of tumour stroma. In clinical trial of Byrne et al., neoadjuvant agonist CD40 antibody was administered ± chemotherapy to 16 patients with resectable PDAC before surgery followed by adjuvant chemotherapy and agonist CD40 antibody (12). For agonist CD40 antibody-treated tumours, T-cell was significantly enriched compared to untreated tumours and chemotherapy/chemoradiation-treated tumours (82% vs. 37% vs. 23%). T cells were more active in both the TME and circulation, and more proliferative after agonist CD40 antibody. Tumour fibrosis was decreased, M2-like tumour-associated macrophages were fewer, and intratumoral DC were more mature. A randomized phase 2 (PRINCE) trial evaluating the efficacy of nivolumab (anti-PD-1) and/or sotigalimab (agonist CD40 antibody) with gemcitabine/nab-paclitaxel in patients with first-line metastatic PDAC (13). In the analysis of efficacy in 105 patients, the primary endpoint of 1-year OS was met for anti-PD-1/chemotherapy (57.7% compared to historical 1-year OS of 35%, n=34) but was not met for agonist CD40 antibody/chemotherapy (48.1%, n=36) or agonist CD40 antibody/anti-PD-1/chemotherapy (41.3%, n=35). Survival after anti-PD-1/chemotherapy correlated with a less suppressive TME and higher numbers of activated, antigen-experienced circulating T cells at baseline. Survival after agonist CD40 antibody/chemotherapy correlated with greater intratumoral CD4 T cell infiltration and circulating differentiated CD4 T cells and antigen-presenting cells (APCs). A patient subgroup benefitting from agonist CD40 antibody/anti-PD-1/chemotherapy was not identified. These early examinations of agonist CD40 antibody therapeutic mechanisms in patients provide insights for design of subsequent clinical trials targeting CD40 in cancer.

Mitazalimab is a human CD40 agonistic IgG1 antibody currently under clinical evaluation, which can bind to CD40 receptors on DC and other APC, activating them to trigger a potent anti-tumor immune response, including T-cell activation, repolarize intratumoral macrophages to remodel the extracellular matrix, and alleviate the immunosuppressive TME. Preclinical studies showed that mitazalimab has the effect of induces durable antitumor responses and also immunologic memory attributed by CD40 stimulation. Furthermore, preclinical studies showed that mitazalimab has the potential to be used across various types of malignancy, and as combination treatments with other systemic treatment (14,15). In a phase-1, multicentre study (Irenaeus et al.), 23 patients (advanced solid malignancies patients who had received established treatments) were treated via intratumoral or intravenous route (16). Adverse events were mostly grades 1/2 and transient. Another phase-1 (dose-escalation, safety) study (Moreno et al.) evaluated pharmacokinetic, pharmacodynamic profile, and dose-limiting toxicity (DLT) of mitazalimab (intravenously once/2-week) in patients with advanced solid malignancies [7 cohorts (75–2,000 µg/kg) with corticosteroids, n=50; 5 cohorts (75–1,200 µg/kg) without corticosteroids, n=45] (17). Two patients experienced grade 3 DLT (transient headache and drug-induced liver injury). The most frequently reported (≥25%) adverse events were fatigue (44.2%), pyrexia (38.9%), pruritus (38.9%), chills (27.4%), and headache (26.3%). 51.6% of patients had infusion-related reactions with pruritus as the most frequent reaction. An RNA sequencing analysis (Andersson et al.) using blood samples (a subset of patients from this phase-1 study) aimed to study the peripheral pharmacodynamic activity (18). Mitazalimab (intravenous dose at 600 and 900 µg/kg) induced transient peripheral transcriptomic alterations (PTA), which were mainly attributed to immune activation. Particularly, the PTA showed a decrease in effector cells [e.g., natural killer cells (NKCs) and CD8⁺ T-cells] and B-cells peripherally, with the remaining cells (e.g., DC, NKC and monocytes, B-cells) showing PTA consistent with activation. Another phase 1, dose-escalation study (REACtiVe-2) evaluated 16 metastatic PDAC patients with an autologous DC vaccine (MesoPher) with mitazalimab after modified FOLFIRINOX (mFOLFIRINOX) treatment (19). Patients with history of previous immunotherapy or malignant ascites were excluded. MesoPher (25×10⁶ DCs) was co-administered with mitazalimab (300, 600, or 1,200 µg/kg). Primary end points of safety and tolerability were met. One transient DLT with grade 3 fever was observed. MesoPher/mitazalimab induced a systemic increase in activated and vaccine-specific T-cell responses. Increased T-cell infiltration and decreased collagen deposition were observed in post-treatment tumor biopsies. No objective radiological response was observed, but 50% (n=8) showed stable disease after 3 administrations.

The first open-label, multi-center phase-2 clinical study (OPTIMIZE-1) evaluated the safety and clinical efficacy (primary endpoint, ORR) of intravenous mitazalimab at the recommended dose, in combination with mFOLFIRINOX in PDAC patients with metastasis who have not previously been treated with chemotherapy (20,21). Phase-1b (dose-determining stage) study determined mitazalimab 900 µg/kg as the recommended dose in phase-2 rather than 450 µg/kg. Patients received an initial day (D)1 priming dose of mitazalimab, followed by a 2-week regimen starting with mFOLFIRINOX (D8) and mitazalimab (D10). It was terminated under the condition of disease progression, unacceptable toxicities, or consent withdrawal. Full analysis only included those phase-1b or phase-2 patients had received mitazalimab (900 µg/kg) and had completed ≥2 treatment cycles. Thus, the full analysis included 57 patients (phase-1b, n=6; 51 phase-2, n=51). OPTIMIZE-1 reported that the safety profile and promising activity of the combination of mitazalimab and mFOLFIRINOX. At the median follow-up period of 18.2 months, the confirmed ORR was 42.1% [PR, n=24; complete response (CR), n=1]. Including unconfirmed responses, the ORR reached 54.4%. The disease control rate was 78.9%. The most common adverse events (grade ≥3) included neutropenia, hypokalemia, thrombocytopenia, and anemia. The safety profile of this combined regimen was similar to that of mFOLFIRINOX. The treatment was generally manageable with no treatment-related mortality reported. In the updated report (a median follow-up, 33 months), this combination regimen met the primary end point by showing a long-lasting effect in line with trends showed from previous reports, with a final ORR of 54.4% (42.1% confirmed). The median duration of response, PFS, OS, and 30-month OS rate was 12.6 months, 7.8 months, 14.9 months, and 21%, respectively (22). Multi-omic analyses of tumor and blood specimens showed that better survival was associated with a baseline tumor-intrinsic gene signature including transcripts related to fibrosis. Furthermore, increased frequencies of immune cell (including activated myeloid, B-cells, and T-cells) after mitazalimab administration correlate with better outcomes, supporting mitazalimab’s contribution to anti-tumor activity. This may define potential patient subgroups that derive the greatest benefit from this combination regimen and supports the use of mitazalimab as a therapeutic agent to remodel the TME, aiming to enhance the efficacy of mFOLFIRINOX. With this promising phase-2 study’s result of mitazalimab in advanced PDAC, a well-planned large-scale phase-3 randomized study is urgently needed to evaluate its safety and efficacy of this new combination treatment strategy against the current standard of treatment. Identification of subgroup of patients most likely to benefit from this treatment is needed also. Future research should also focus on how to effectively reprogramme the immune-cold TME via immunotherapy strategies.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Pancreatic Cancer. The article has undergone external peer review.

Peer Review File: Available at https://apc.amegroups.com/article/view/10.21037/apc-26-0019/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://apc.amegroups.com/article/view/10.21037/apc-26-0019/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Lai ECH, Ung AKY. Update on management of pancreatic cancer: a literature review. Chin Clin Oncol 2024;13:41. [Crossref] [PubMed]
2. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Pancreatic Cancer. 2026. Available online: https://seer.cancer.gov/statfacts/html/pancreas.html
3. Rahib L, Smith BD, Aizenberg R, et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014;74:2913-21. [Crossref] [PubMed]
4. Park W, Chawla A, O'Reilly EM. Pancreatic Cancer: A Review. JAMA 2021;326:851-62. [Crossref] [PubMed]
5. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013;369:1691-703. [Crossref] [PubMed]
6. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817-25. [Crossref] [PubMed]
7. Golan T, Hammel P, Reni M, et al. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N Engl J Med 2019;381:317-27. [Crossref] [PubMed]
8. George B, Kudryashova O, Kravets A, et al. Transcriptomic-Based Microenvironment Classification Reveals Precision Medicine Strategies for Pancreatic Ductal Adenocarcinoma. Gastroenterology 2024;166:859-871.e3. [Crossref] [PubMed]
9. Suresh DS, Salcedo-Noriega MF, Vaish U, et al. Cytokine circuitry in pancreatic cancer: Targets for overcoming immune checkpoint inhibitor resistance in PDAC. Cytokine Growth Factor Rev 2026;88:124-37. [Crossref] [PubMed]
10. Zhou Y, Richmond A, Yan C. Harnessing the potential of CD40 agonism in cancer therapy. Cytokine Growth Factor Rev 2024;75:40-56. [Crossref] [PubMed]
11. Beatty GL, Chiorean EG, Fishman MP, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 2011;331:1612-6. [Crossref] [PubMed]
12. Byrne KT, Betts CB, Mick R, et al. Neoadjuvant Selicrelumab, an Agonist CD40 Antibody, Induces Changes in the Tumor Microenvironment in Patients with Resectable Pancreatic Cancer. Clin Cancer Res 2021;27:4574-86. [Crossref] [PubMed]
13. Padrón LJ, Maurer DM, O'Hara MH, et al. Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: clinical and immunologic analyses from the randomized phase 2 PRINCE trial. Nat Med 2022;28:1167-77. [Crossref] [PubMed]
14. Mangsbo SM, Broos S, Fletcher E, et al. The human agonistic CD40 antibody ADC-1013 eradicates bladder tumors and generates T-cell-dependent tumor immunity. Clin Cancer Res 2015;21:1115-26. [Crossref] [PubMed]
15. Deronic A, Nilsson A, Thagesson M, et al. The human anti-CD40 agonist antibody mitazalimab (ADC-1013; JNJ-64457107) activates antigen-presenting cells, improves expansion of antigen-specific T cells, and enhances anti-tumor efficacy of a model cancer vaccine in vivo. Cancer Immunol Immunother 2021;70:3629-42. [Crossref] [PubMed]
16. Irenaeus SMM, Nielsen D, Ellmark P, et al. First-in-human study with intratumoral administration of a CD40 agonistic antibody, ADC-1013, in advanced solid malignancies. Int J Cancer 2019;145:1189-99. [Crossref] [PubMed]
17. Moreno V, Perets R, Peretz-Yablonski T, et al. A phase 1 study of intravenous mitazalimab, a CD40 agonistic monoclonal antibody, in patients with advanced solid tumors. Invest New Drugs 2023;41:93-104. [Crossref] [PubMed]
18. Andersson H, Sobti A, Jimenez DG, et al. Early Pharmacodynamic Changes Measured Using RNA Sequencing of Peripheral Blood from Patients in a Phase I Study with Mitazalimab, a Potent CD40 Agonistic Monoclonal Antibody. Cells 2023;12:2365. [Crossref] [PubMed]
19. Kucukcelebi S, van 't Land FR, van der Burg SH, et al. REACtiVe-2: phase I evaluation of dendritic cell vaccination and agonistic CD40 therapy following (m)FOLFIRINOX in metastatic pancreatic cancer. Nat Commun 2025;16:10609. [Crossref] [PubMed]
20. Van Laethem JL, Borbath I, Prenen H, et al. Combining CD40 agonist mitazalimab with mFOLFIRINOX in previously untreated metastatic pancreatic ductal adenocarcinoma (OPTIMIZE-1): a single-arm, multicentre phase 1b/2 study. Lancet Oncol 2024;25:853-64. [Crossref] [PubMed]
21. Van Laethem JL, Geboes K, Borbath I, et al. CD40 agonist mitazalimab with mFOLFIRINOX in untreated metastatic pancreatic cancer: Biomarkers associated with outcomes from OPTIMIZE-1. Cell Rep Med 2025;6:102407. [Crossref] [PubMed]
22. Alligator announces final 30-month OPTIMIZE-1 results highlighting the potential of mitazalimab in metastatic pancreatic cancer. 2025. Accessed September 24, 2025. Available online: https://tinyurl.com/3845ve3c