SP 5

TIL dynamics in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDA), is a devastating disease for which incidence and death rates are still almost equal. Surgical resection is the only treatment that offers perspectives for prolonged survival, but the recurrence rate is higher than 90% and tumors are highly chemoresistent.
Given the urgent need for new treatment modalities, our recent success in isolating tumor infiltrating lymphocytes (TILs) from primary PDA biopsies marks a promising starting point. Our plans for developing and implementing immunotherapeutic strategies focus on two approaches:

• Evaluation of the possibility of TIL therapy in PDA, involving the isolation of TILs from tumor biopsies, followed by ex vivo expansion and re-infusion into patients. Given the striking efficacy of this approach in patients with advanced metastatic melanoma who failed multiple prior treatments, this modality must also be explored in the treatment of PDA.

• Combination of gemcitabine, a chemotherapeutic drug commonly applied in patients with PDA, with immunostimulatory antibodies targeting the immune receptor CD40. Strong evidence for the synergistic action of chemo-immunotherapeutic regimens is available from pre-clinical mouse models, and more recently similarly promising findings have been reported in clinical studies. The change of TIL-dynamics in response to this therapy regimen will be investiagted.

The ultimate aim of these efforts is to work towards successful implementation of immunotherapeutic strategies in the treatment of PDAC in the clinic.

Keywords: tumor-infiltrating lymphocytes, immunotherapy, T-cell receptor repertoire, next-generation sequencing, pancreatic cancer, melanoma, vaccination, immuno-stimulatory antibodies