A Perspective on Cell Therapy and Cancer Vaccine in Biliary Tract Cancers (BTCs)

Abstract

Biliary tract cancer (BTC) is a rare, but aggressive, disease that comprises of gallbladder carcinoma, intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma, with heterogeneous molecular profiles. Advanced disease has limited therapeutic options beyond first-line platinum-based chemotherapy. Immunotherapy has emerged as a viable option for many cancers with a similar unmet need. Therefore, we reviewed current understanding of the tumor immune microenvironment and recent advances in cellular immunotherapy and therapeutic cancer vaccines against BTC. We illustrated the efficacy of dendritic cell vaccination in one patient with advanced, chemorefractory, melanoma-associated antigen (MAGE)-positive gallbladder carcinoma, who was given multiple injections of an allogenic MAGE antigen-positive melanoma cell lysate (MCL)-based autologous dendritic cell vaccine combined with sequential anti-angiogenic therapy. This resulted in good radiological and tumor marker response and an overall survival of 3 years from diagnosis. We postulate the potential synergism of adding anti-angiogenic therapy, such as bevacizumab, to immunotherapy in BTC, as a rational scientific principle to positively modulate the tumor microenvironment to augment antitumor immunity.

Keywords: bevacizumab; biliary tract cancer; cell therapy; dendritic cell vaccine; immunotherapy; personalized medicine; review.

Figure 1

Carbohydrate Antigen (CA) 19-9 and neutrophil-to-lymphocyte ratio (NLR) of the patient during treatment.

Figure 2

Resolution of liver and lung metastasis in the patient after commencing dendritic cell (DC) vaccine and bevacizumab. (A) Positron emission tomography-computed tomography (PET-CT) done prior to any treatment in week 3 showing 0.5 cm lung metastasis. (B) PET-CT done in week 13 showing a reduction in size of lung metastasis that became unmeasurable. (C) PET-CT done prior to any treatment in week 3 showing a 2.3 cm liver metastasis. (D) PET-CT done in week 13 showing resolution of the liver metastasis.

Figure 3

Flow cytometry analysis of peripheral blood mononuclear cells (PBMCs) to identify percentages of monocyte CD14⁺HLADR⁻ cells, representative of the monocytic myeloid-derived suppressor cell (MDSC) population, CD4 and CD8 T-effector cells prior to treatment (week 3) after the first cycle of DC vaccine + anti-angiogenic combination (week 42 and during disease progression (week 89).

Figure 4

Plasma cytokine profile of Patient 7. Using the Luminex assay, it was observed that, while the plasma cytokine levels of interleukin (IL)-1a, IL-1b, IL-2, IL-6, IL-10, VEGF and fibroblast growth factor 2 (FGF2) were all higher than baseline reference ranges for healthy individuals pre-treatment [10]; they were found to be lowered during periods of treatment response compared to pre-treatment and disease progression time points.