Innovative dual approach: CD40 agonist and mFOLFIRINOX combination therapy in metastatic pancreatic cancer

Pancreatic cancer is one of the most lethal types of cancer in the world (1). Most patients already have metastasized disease at the time of diagnosis, making curative treatment infeasible (2). Systemic chemotherapy with (modified) FOLFIRINOX (mFOLFIRINOX; 5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) or gemcitabine plus nab-paclitaxel is the standard treatment regimen for patients with advanced disease (3-5). However, these treatment regimens frequently result in significant toxicity and limited prognosis. As a result, innovative therapeutic approaches are necessary for managing metastatic pancreatic cancer.

Immunotherapeutic treatment strategies have gained significant interest over the past decade and significantly improved the survival of several cancer types. However, results in pancreatic ductal adenocarcinoma (PDAC) remain limited due to the relatively low tumor mutation burden, resulting in limited tumor-associated antigen (TAA) presentation and immune activation, as well as an immunosuppressive tumor microenvironment (TME) (6). The TME consists of various factors that promote tumor growth and help the tumor evade recognition by the host’s immune system. Immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs), M2-like tumor-associated macrophages (TAMs), and regulatory T cells (Tregs) are present in the TME of PDAC. Additionally, a dense desmoplastic stroma acts as a physical barrier, inhibiting the infiltration of effector T cells while promoting tumor growth. An innovative approach targeting the TME and stimulating antigen presentation has great potential.

In the phase Ib-II OPTIMIZE-1 study, an innovative dual approach is utilized by combining a human anti-CD40 agonist IgG1 antibody mitazalimab with mFOLFIRINOX chemotherapy in chemo-naive patients with metastatic PDAC (7). CD40 is a cell surface molecule on various antigen-presenting cells (APC) such as B cells, dendritic cells (DCs), macrophages, and fibroblasts. Upon binding to its ligand CD40-L (also known as CD154), primarily present on activated T cells, it can license DCs to cross-present tumor antigens to T-cells. Additionally, it induces stromalysis by upregulating matrix metalloproteases produced by TAMs and allows T-cell infiltration (8,9). Hence, it has both T-cell-dependent and independent working mechanisms.

Using an anti-CD40 agonistic antibody has shown promising results in pre-clinical and clinical settings (10,11). In a phase I study, patients with various advanced solid malignancies were treated with mitazalimab, and displayed stable disease in 37% of the patients (10). One patient with renal cell carcinoma had a partial response for 5.6 months, and 36.8% of the patients had stable disease, which was persisting for more than 6 months in nine patients. However, combination strategies with an anti-CD40 agonist may offer greater therapeutic potential. Combining an anti-CD40 agonistic antibody with an immune checkpoint inhibitor (ICI) is hypothesized to have a synergistic effect that could overcome resistance to anti-PD-1. In a Phase II study, patients with advanced melanoma received sotigalimab (APX005M) in combination with the ICI nivolumab (an anti-PD-1 antibody) following confirmed disease progression on anti-PD-1 (12). An objective response rate (ORR) of 15% was found. However, the median duration of response exceeded 26 months.

Since chemotherapy’s cytotoxic properties can result in the release of TAAs, which in turn are taken up by APCs and processed to present them to T-cells, combination therapy of a CD40 agonist with chemotherapy is also hypothesized to have synergistic effects and be beneficial (9). Additionally, CD40-activated macrophages deplete tumor stroma and increase PDAC sensitivity to chemotherapy (8,13). When combined with a CD40 agonist, gemcitabine plus nab-paclitaxel increases T-cell enrichment and more active and proliferative T-cells in both TME and circulation. Furthermore, an increase in mature DCs, a decrease in tumor-promoting M2-like macrophages, and a reduction in fibrosis are also observed (8,14-17). However, until recently, no clinical trials used a CD40 agonist with mFOLFIRINOX, the chemotherapy regimen known for achieving the best progression-free and overall survival in PDAC.

Patients with metastatic PDAC enrolled in the OPTIMIZE-1 study were treated with 450 or 900 µg/kg mitazalimab in combination with mFOLFIRINOX (7). Mitazalimab was administered one week before mFOLFIRINOX as a priming dose, followed by additional doses two days after each mFOLFIRINOX administration in a 14-day treatment cycle. The primary endpoints were determining the recommended phase II dose (RP2D) and assessment of clinical activity using the ORR. As secondary endpoints, the safety of the mitazalimab and mFOLFIRINOX combination therapy, several clinical outcomes, assessment of anti-drug antibodies, and pharmacokinetic parameters were determined. These endpoints are important for assessing the clinical effectiveness of the combination treatment and pave the way for future clinical advancements. Additionally, exploratory immune monitoring was conducted to study the immune-modulating effects of the mitazalimab and mFOLFIRINOX combination therapy and to determine whether this treatment induces an anti-tumor immune response. The treatment was safe, and the RP2D was established at 900 µg/kg mitazalimab. The primary study endpoint was met with a confirmed ORR of 40% among the 57 evaluable patients, compared to 31.6% ORR observed with mFOLFIRINOX alone (3). The 1-year progression-free survival (PFS) rate and 1-year overall survival (OS) rates were 34% and 59%, respectively, which is more favorable than the 1-year PFS rate and 1-year OS rate of 12.1% and 48.4%, respectively, with mFOLFIRINOX monotherapy found by Conroy et al. (3). These findings suggest that adding mitazalimab to mFOLFIRINOX could enhance its therapeutic effectiveness in metastasized PDAC. However, it is challenging to interpret survival rates in phase I/II trials due to the limited number of patients, lack of randomization, and potentially short follow-up durations. If the immune monitoring data demonstrate anti-tumor immune activity, this combination treatment suggests a synergy between the TME and immune modulation by mitazalimab, along with the cytotoxic effects of mFOLFIRINOX leading to tumor antigen release. Subsequently, this promising approach warrants validation in larger randomized controlled trials.

A limitation in this study is the need for serial biopsies in order to evaluate the induced anti-tumor immune response. The authors found an increase in CD38⁺ NKT cells in the blood after starting therapy, which can be a positive sign that the immune system is being activated against the tumor. This increase is likely due to the activation of APCs and subsequent cytokine production by CD40. However, elevated levels of immune activation markers in the blood do not necessarily indicate that these immune cells are actively infiltrating the tumor. For an effective antitumor response, tumor-infiltrating immune cells are often essential, as immune activation in the blood may be triggered by non-specific factors, such as infections, inflammation, or other conditions that modulate the immune system. Therefore, serial biopsies could have confirmed whether the immune response following therapy was specifically targeting the tumor, rather than representing a systemic, non-tumor-specific reaction.

Apart from CD40 agonists, various modulatory agents are studied in clinical trials, combined with chemotherapy, to reduce the tumor-facilitating properties of the microenvironment in patients with pancreatic cancer. Marimastat is an orally administered matrix metalloproteinase (MMP) inhibitor, resulting in extracellular matrix (ECM) degradation. Marimastast was investigated in combination with gemcitabine in advanced PDAC (18). Although the combination was well tolerated, no significant differences in overall response rates or PFS were found compared to gemcitabine monotherapy. Pegvorhyaluronidase alfa (PEGPH20) is a novel pegylated recombinant human hyaluronidase. It is developed as an anticancer therapy to degrade tumor hyaluronan, a major stromal ECM component, thereby remodeling the TME. However, in combination with gemcitabine/nab-paclitaxel, once more, no improvement in OS or PFS was found in a phase III, randomized, double-blind, placebo-controlled study in patients with metastatic PDAC (19). The Hedgehog (Hh) signalling pathway suppresses the immune system, promotes an immunosuppressive TME, and activates cancer-associated fibroblasts (CAFs), contributing to tumor growth and metastasis. In PDAC, this pathway is overexpressed. Preclinical studies showed that combining Hh inhibitors with chemotherapy improved outcomes in animal models (20,21). Unfortunately, adding the Hh inhibitor vismodegib to gemcitabine or to gemcitabine with nab-paclitaxel did not improve the ORR, PFS, or the OS in patients with metastatic PDAC (22,23). While transforming growth factor-β (TGF-β) signalling can have tumor-suppressive effects in early stages, it predominantly contributes to creating a favorable TME for pancreatic cancer growth, invasion, and metastasis. This makes the TGF-β pathway a critical target for therapeutic interventions in pancreatic cancer (24). The TGFBR1-inhibitor galunisertib was also explored in PDAC patients as monotherapy and in combination with gemcitabine. Unfortunately, adding galunisertib to gemcitabine failed to improve survival significantly (25).

In addition to the agents mentioned above, various modulatory agents affecting the immune TME are also being investigated (6). This includes vaccine strategies to deliver TAAs, ICI that release the “brake” on the immune system and oncolytic viruses to induce a local interferon response and strong T-cell influx. These agents target immune cells within the TME, reducing their immunosuppressive properties and enhancing their sensitivity to immunotherapy.

However, several challenges remain when using (immune)modulatory agents. The heterogeneous patient population and the complex immune landscape in PDAC necessitate further investigation. Long-term follow-up is needed to understand potential late-onset toxicities fully. Furthermore, future studies should explore biomarkers for treatment response to better tailor this combination therapy to individual patients.

The clinical results of the OPTIMIZE-1 study show promise in the fight against metastasized PDAC. The trial was well designed and included patients in a reasonable period. The translational research behind this study is of high scientific quality. Including patients in a clinical trial across many hospitals (multi-center trials) presents several challenges and limitations. Ensuring consistent and accurate data collection across multiple sites is challenging, and protocol deviations could affect the validity of the results. The complete immune analysis after treatment will provide insight into the anti-tumor immune response. The combination of CD40 agonist mitazalimab with mFOLFIRINOX paves the way for improving the efficacy of current therapies through immune modulation and modulation of the TME. While additional research is needed to validate these findings in a randomized trial, the study offers hope for patients battling this challenging disease.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-162/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-162/coif). C.H.J.v.E. reports consulting fees from AIM ImmunoTech. The other 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.

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