To overcome the poor prognosis of cholangiocarcinoma (CCA), highly targeted therapies, such as antibody-drug conjugates (ADCs), photodynamic therapy (PDT) with/without systemic chemotherapy, and experimental photoimmunotherapy (PIT), have been developed. Three preclinical trials have investigated the use of ADCs targeting specific antigens, namely HER2, MUC1, and glypican-1 (GPC1), for CCA. Trastuzumab emtansine demonstrated higher antiproliferative activity in CCA cells expressing higher levels of HER2. PDT is effective in areas where appropriate photosensitizers and light coexist. Its mechanism involves
photosensitizer excitation and subsequent reactive oxygen species production in cancer cells upon irradiation. Hematoporphyrin derivatives, temoporfin, phthalocyanine-4, talaporfin, and chlorine e6 derivatives have mainly been used clinically and preclinically in bile duct cancer. PIT is the most novel anti-cancer therapy developed in 2011 that selectively kills targeted cancer cells using a unique photosensitizer called “IR700” conjugated with an antibody specific for cancer
cells. PIT is currently in the early stages of development for identifying appropriate CCA cell targets and irradiation devices. Future human and artificial intelligence collaboration has potential for overcoming challenges related to identifying universal CCA cell targets. This could pave the way for highly targeted therapies for CCA, such as ADC, PDT, and PIT.
1. Introduction
The biliary tree is complicated and finely branched into the liver, which is anatomically classified into small intrahepatic (ϕ20–300 μm), large intrahepatic (300–800 μm), and extrahepatic (>800 μm) bile ducts, including the gallbladder
[1]. Its numerical bifurcations can cause difficulty in the detection of and approach to early biliary lesions, especially in the periphery, leading to a poor prognosis of cholangiocarcinoma (CCA), with a 5-year relative survival rate of 7–20%
[2,3,4][2][3][4]. To improve prognosis, novel therapeutic approaches to CCA are necessary.
There have been a number of clinical and basic studies on CCA regarding etiology, clinicopathology, molecular biology, and immunology that have clarified the characteristics and targeted points of CCA to some extent. Currently, there are six primary modalities of anticancer treatment for CCA: (1) surgical therapy; (2) chemotherapy; (3) radiotherapy, including brachytherapy and proton radiotherapy; (4) immunotherapy, including immune checkpoint inhibitor and chimeric antigen receptor (CAR) T-cell therapy, (5) phototherapy, and (6) combination therapy, such as antibody-drug conjugate (ADC) therapy (2 + 4), photodynamic therapy (PDT; 2 + 5), and photoimmunotherapy (PIT; 4 + 5). Surgical therapy has developed with the increase in skilled surgeons, high-resolution imaging modalities, and the introduction of portal vein embolization
[5]. Chemotherapy has been developed with an understanding of the biology and molecular mechanisms of CCA
[6]. Radiotherapy has also improved with internal small, sealed sources
[7,8][7][8] and proton beams
[9], mainly with palliative and supportive intent. Immunotherapy has evolved and improved with the advent of immune checkpoint inhibitors, such as durvalumab (a PD-L1 antibody)
[10] and CAR-T therapy
[11]. Among them, highly targeted therapies such as ADC, PDT, and PIT are attracting much attention for precision medicine because of their expected high effectiveness and low invasiveness.
To provide highly targeted therapies, previous researchers revealed that CCA abnormally expresses some possible antigens/targets or molecules on the cell surface, such as epidermal growth factor receptor (EGFR), HER2 (c-erbB-2), and vascular endothelial growth factor receptor (VEGFR)
[12].
In addition, recent genetic investigations of biliary tract cancer have revealed a range of genetic mutations and alterations specific to the primary cancer site. These include fibroblast growth factor receptor-2 (
FGFR2) fusion and
IDH1/2 in intrahepatic CCA (ICC);
HER2 (
erbB-2),
PRKACA, and
PRKACB in extrahepatic CCA (ECC: perihilar and distal CCA);
EGFR,
ERBB3, and
PTEN in gallbladder cancer; and
KRAS,
SMAD4, and
TP53 shared in ICC and ECC
[13,14][13][14]. Some of these genetic mutations are also common in pancreatic cancer, which is attributed to the adjacent embryologic relationship between the biliary tree and pancreas
[15]. These genetic variations often present challenges and emphasize the importance of implementing precision medicine approaches tailored to the specific cancer site.
2. Antibody-Drug Conjugate
2.1. Preclinical Studies of ADCs for CCA
There have been three preclinical trials of ADCs for CCA using murine models whose targeted antigens were human epidermal growth factor receptor 2 (
HER2) [23] [16], mucin 1 (
MUC1) [24] [17], and
glypican-1 (GPC1) [25][18] (
Table 1). HER2 is a member of the EGFR family. Protein dimers of HER2 with HER family receptors, such as EGFR, HER2, HER3, or HER4, accelerate cell proliferation and prolong cell survival. Amplification or overexpression of HER2 is predominantly associated with tumorigenesis in the breast (15–30%), stomach, and esophagus (10–30%)
[26,27,28][19][20][21]. HER2 overexpression is also observed in 4.8% (95% confidence interval [CI] 0–14.5%) of ICC, 17.4% (95% CI 3.4–31.4%) of ECC, 19.1% (95% CI 11.2–26.8%) of gallbladder cancer, and 27.9% (95% CI 0–60.7%) of ampullary carcinoma
[29][22]. Yamashita-Kashima et al. indicated that the anti-proliferative activity of the ADC trastuzumab emtansine (T-DM1) was higher in CCA cell lines with higher levels of HER2 expression and in proportion to HER2 status
[23][16]. Shinoda et al. showed that the cytotoxicity of lymphokine-activated killer cells (a heterogeneous population consisting of NK, NKT, and T cells) against CCA can be reinforced by staphylococcal enterotoxin A (SEA) conjugated with an antibody directed to MUC1 (MUSE11) in CCA cells
[24,30][17][23]. SEA is one of the superantigens that bind outside of the peptide-binding groove of MHC class II molecules and activate T cells expressing a certain Vβ type of T cell receptor
[31,32][24][25]. The transmembrane glycoprotein MUC1 is a mucin family member that can act as a lubricant, moisturizer, and physical barrier in normal cells. MUC1 is also an epithelial mucin antigen that is widely expressed in adenocarcinomas, such as those arising in the pancreas, stomach, ovaries, and bile ducts
[33,34,35][26][27][28]. Thus, the SEA-MUSE11 conjugate can work via the above-mentioned phase 4 mechanism alone.
Table 1. Targets for cholangiocarcinoma cells.
|
|
Preclinical Study |
Clinical Study |
Name |
Type |
ADC |
ADC-Payload |
PIT |
ADC |
ADC-Payload |
HER2 |
Receptor |
✓ |
Emtansine (DM1) |
✓ |
✓ |
Emtansine (DM1) Deruxtecan (DXd) |
EGFR |
Receptor |
|
|
✓ |
|
|
FGFR2 |
Receptor |
|
|
|
✓ |
Ixadotin |
MUC1 |
Secretion (mucin) |
✓ |
|
|
|
|
Glypican-1 (GPC1) |
Secretion (proteoglycan) |
✓ |
Monomethyl auristatin F (MMAF) |
|
|
|
CD133/ prominin-1 |
Secretion (glycoprotein) |
✓ |
Maleimidocaproyl-valine-citrulline-p-aminobenzoyl-MMAF (vcMMAF) |
|
|
|
TROP2 |
Secretion (glycoprotein) |
|
|
✓ |
|
|