Cocktail treatment with EGFR-specific and CD133-specific chimeric antigen receptor-modified T cells in a patient with advanced cholangiocarcinoma

Abstract

Background: Cholangiocarcinoma (CCA) is one of the most fatal malignant tumors with increasing incidence, mortality, and insensitivity to traditional chemo-radiotherapy and targeted therapy. Chimeric antigen receptor-modified T cell (CART) immunotherapy represents a novel strategy for the management of many malignancies. However, the potential of CART therapy in treating advanced unresectable/metastatic CCA is uncharted so far.

Case presentation: In this case, a 52-year-old female who was diagnosed as advanced unresectable/metastatic CCA and resistant to the following chemotherapy and radiotherapy was treated with CART cocktail immunotherapy, which was composed of successive infusions of CART cells targeting epidermal growth factor receptor (EGFR) and CD133, respectively. The patient finally achieved an 8.5-month partial response (PR) from the CART-EGFR therapy and a 4.5-month-lasting PR from the CART133 treatment. The CART-EGFR cells induced acute infusion-related toxicities such as mild chills, fever, fatigue, vomiting and muscle soreness, and a 9-day duration of delayed lower fever, accompanied by escalation of IL-6 and C reactive protein (CRP), acute increase of glutamic-pyruvic transaminase and glutamic-oxalacetic transaminase, and grade 2 lichen striatus-like skin pathological changes. The CART133 cells induced an intermittent upper abdominal dull pain, chills, fever, and rapidly deteriorative grade 3 systemic subcutaneous hemorrhages and congestive rashes together with serum cytokine release, which needed emergent medical intervention including intravenous methylprednisolone.

Conclusions: This case suggests that CART cocktail immunotherapy may be feasible for the treatment of CCA as well as other solid malignancies; however, the toxicities, especially the epidermal/endothelial damages, require a further investigation.

Trial registration: ClinicalTrials.gov NCT01869166 and NCT02541370 .

Keywords: CART cocktail immunotherapy; CD133; Cholangiocarcinoma; EGFR.

Figures

Fig. 1

Changes of tumor lesions in sequential PET-CT examinations in the period of CART-EGFR cell infusion. a PET-CT examination illustrated hepatic hilar malignancy before surgery. b PET-CT examined after the completion of radiotherapy with illustration of a new metastatic hypermetabolic lesion in the hepatic caudate lobe and enlarged soft tissue and retroperitoneal lymph node metastases. c PET-CT assessment 6 weeks after the infusion of CART-EGFR cells showed a more than 80% shrinkage of metastatic lesions in the hepatic hilar region and caudate lobe. d Routine examination by PET-CT showed a persistent PR status 4 months after the CART-EGFR cell infusion. e PET-CT detected multiple new SUV abnormal lesions in the omentum majus, peritoneum, and abdominal cavity 8.5 months after the first cycle of CART-EGFR cell infusion. f The examination of PET-CT detected newly emerged metastases in the bottom of the pelvis, right liver lobe, and left supraclavicular lymph node as well as enlargement of previous tumor lesions in the abdomen 4 weeks after the combination of anti-PD-1 antibody and CART-EGFR

Fig. 2

Change of CA199 in the course of CART cocktail immunotherapy

Fig. 3

Transgene copy number of CAR DNA in PB throughout the treatment process

Fig. 4

The levels of IL-6 and CRP during and after the infusion of CART-EGFR and CART133 cells

Fig. 5

Outcome of CART133 cell infusion. (a) With the guidance of PET, tumor lesions were labeled on the images presented by computed tomography (CT) scans before the infusion of CART133 cells (red arrow). (b) CT images showed remarkable shrinkage or even disappearance of some metastases in the peritoneum and abdominal cavity (red arrow) and an abscess in the right liver. (c) CT scan detected an approximate 40 × 70 mm new metastatic lesion under the abdominal wall and suspected metastases in the abdominal cavity 4.5 months after the CART 133 immunotherapy (red arrow)

Fig. 6

Epidermal and endothelial damages caused by the infusion of CART cells. a Lichen striatus-like skin rashes appeared and worsened after the CART-EGFR therapy with the illustration of pathological changes such as the loss of partial epidermis, vacuolar degeneration of basal cells, and infiltration of numerous T lymphocytes in the epidermis and its appendages. b Diffused pinpoint hemorrhages and congestive rashes occurred on her neck, right upper arm, chest, left abdomen, and retropharyngeal mucosa after the CART133 cell infusion