To date, extensive efforts to harness immunotherapeutic strategies for the treatment of pancreatic ductal adenocarcinoma (PDAC) have yielded disappointing results in clinical trials. These strategies mainly focused on cancer vaccines and immune checkpoint inhibitors alone or in combination with chemotherapeutic or targeted agents. However, the growing preclinical and clinical data sets from these efforts have established valuable insights into the immunological characteristics of PDAC biology. Most notable are the immunosuppressive role of the tumour microenvironment (TME) and PDAC’s characteristically poor immunogenicity resulting from tumour intrinsic features. Moreover, PDAC tumour heterogeneity has been increasingly well characterized and may additionally limit a “one-fits-all” immunotherapeutic strategy. In this review, we first outline mechanisms of immunosuppression and immune evasion in PDAC. Secondly, we summarize recently published data on preclinical and clinical efforts to establish immunotherapeutic strategies for the treatment of PDAC including diverse combinatorial treatment approaches aiming at overcoming this resistance towards immunotherapeutic strategies. Particularly, these combinatorial treatment approaches seek to concomitantly increase PDAC antigenicity, boost PDAC directed T-cell responses, and impair the immunosuppressive character of the TME in order to allow immunotherapeutic agents to unleash their full potential. Eventually, the thorough understanding of the currently available data on immunotherapeutic treatment strategies of PDAC will enable researchers and clinicians to develop improved treatment regimens and to design innovative clinical trials to overcome the pronounced immunosuppression of PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed at advanced stages and most anti-cancer therapies have failed to substantially improve prognosis of PDAC patients. As a result, PDAC is still one of the deadliest tumors. Tumor heterogeneity, manifesting at multiple levels, provides a conclusive explanation for divergent survival times and therapy responses of PDAC patients. Besides tumor cell heterogeneity, PDAC is characterized by a pronounced inflammatory stroma comprising various non-neoplastic cells such as myofibroblasts, endothelial cells and different leukocyte populations which enrich in the tumor microenvironment (TME) during pancreatic tumorigenesis. Thus, the stromal compartment also displays a high temporal and spatial heterogeneity accounting for diverse effects on the development, progression and therapy responses of PDAC. Adding to this heterogeneity and the impact of the TME, the microbiome of PDAC patients is considerably altered. Understanding this multi-level heterogeneity and considering it for the development of novel therapeutic concepts might finally improve the dismal situation of PDAC patients. Here, we outline the current knowledge on PDAC cell heterogeneity focusing on different stromal cell populations and outline their impact on PDAC progression and therapy resistance. Based on this information, we propose some novel concepts for treatment of PDAC patients.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with poor 5-year overall survival. This can be mainly explained by late diagnosis mostly at advanced stages, excluding primary tumor resection as putative curative treatment, and a profound therapy resistance. L1 cell adhesion molecule (L1CAM) is upregulated in PDAC cells and associated with different hallmarks of cancer contributing to tumor progression and therapy resistance. Using L1CAM as tumor associated antigen, two antibody drug conjugates (ADC) targeting L1CAM were developed with different toxins as payload. Both L1CAM-ADC led to a L1CAM specific reduction in tumor cell growth of up to 60% in 2D PDAC cell models. A maximum therapeutic effect was observed when at least 50% of the PDAC cells expressed L1CAM. In 3D PDAC spheroids, MMAE conjugated L1CAM-ADC still showed strong therapeutic effects, while efficacy of SG3199 conjugated L1CAM-ADC was diminished. Co-culture of PDAC spheroids with pancreatic myofibroblasts did almost not impair L1CAM-ADC anti-tumor effects, while macrophages enhanced anti-tumor responses. Application of L1CAM-ADC as adjuvant or palliative treatment in clinically adapted PDAC mouse models exerted potent anti-tumor effects even with enhanced tumor burden. Adjuvantly applied, MMAE conjugated L1CAM-ADC efficiently reduced pancreatic relapses and peritoneal metastases, whereas SG3199 conjugated L1CAM-ADC less impacted pancreatic relapses, but almost completely eliminated liver and peritoneal metastases. In the palliative setting, both L1CAM-ADC reduced number and size of liver and peritoneal metastases. Overall, our results demonstrate strong anti-tumor effects of L1CAM-ADC underscoring their potential as immunotherapeutic approach in therapy of even advanced PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an immunosuppressive tumor microenvironment (TME) with pancreatic myofibroblasts (PMF) and macrophages being two prominent cell populations essentially impairing tumor responses to (immuno)therapies. L1 cell adhesion molecule (L1CAM) is upregulated in PDAC cells in primary and metastatic tissues and associated with tumor progression and therapy resistance. Using L1CAM as tumor-associated antigen, two bispecific antibodies (bsAB) targeting L1CAM and CD3 were developed in the IgG-(L)-ScFv format and their anti-tumorigenic activity was investigated in different preclinical PDAC models. In 2D models, both L1-bsAB exerted L1CAM-specific anti-PDAC cell activity when co-cultured with activated CD8+ T cells. Strong anti-PDAC cell effects along with elevated release of T cell effector molecules were also observed upon co-culture with peripheral blood mononuclear cells (PMBC) from healthy donors and PDAC patients. Of note, both L1-bsAB were also effective in 3D PDAC cell spheroids and neither impaired by PMF nor macrophages. Finally, application of L1-bsAB on organotypic tissue slice cultures from PDAC tissues comprising the entire complex TME also induced PDAC cell apoptosis and release of T cell effector molecules. Overall, our results highlight relevant anti-PDAC cell activity of L1-bsAB in immunosuppressive contexts supporting their potential as immunotherapeutic strategy for PDAC.