Efficacy of novel immunotherapeutic strategies targeting L1CAM in pancreatic cancer
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with a 5-year overall survival rate of less than 10%, due to late diagnosis mostly at advanced stages, excluding primary tumor resection as putative curative treatment, early metastasis and profound therapy resistance. A promising target for new therapeutic options is the L1 cell adhesion molecule (L1CAM) which is upregulated in PDAC cells in most PDAC tissues and associated with different hallmarks of cancer contributing to therapy resistance, immune evasion and tumor progression. This study analyzed the therapeutic efficacy of two antibody drug conjugates (ADC) targeting L1CAM with different toxins (monomethyl auristatin E (MMAE) and a pyrrolobenzodiazepine dimer (SG3199)) as payload and a bispecific antibody targeting L1CAM on tumor cells and CD3 on T cells in different preclinical PDAC models. Both L1CAM-ADC led to a L1CAM specific reduction in tumor cell growth of up to 60% in 2D PDAC cell models. 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. Both L1CAM-ADC strongly reduced number and size of liver and peritoneal metastases. L1CAMxCD3-bAB revealed strong targeting ability, correlated with antigen presentation on the respective target cells and exerted notable anti-tumor effects in a 3D PDAC spheroid model. Combinatory treatment with MYC-inhibitor (MYC-I) altered the presentation of immune checkpoint proteins at the cell surface of different immune cell populations including monocytes and T cells suggesting a more anti-inflammatory phenotype. These findings suggest that a combinatory treatment of L1CAMxCD3-bAB and immune checkpoint inhibitors may enhance treatment efficacy. Overall, this study highlights the potential of L1CAM as a target for immunotherapeutic therapies, with L1CAM-ADC demonstrating effective immunotherapeutic approach in therapy of even advanced PDAC.
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