Chimeric Antigen Receptor T Cell Therapy Targeting ICAM-1 in Gastric Cancer

Abstract

Cancer therapy utilizing adoptive transfer of chimeric antigen receptor (CAR) T cells has demonstrated remarkable clinical outcomes in hematologic malignancies. However, CAR T cell application to solid tumors has had limited success, partly due to the lack of tumor-specific antigens and an immune-suppressive tumor microenvironment. From the tumor tissues of gastric cancer patients, we found that intercellular adhesion molecule 1 (ICAM-1) expression is significantly associated with advanced stage and shorter survival. In this study, we report a proof-of-concept study using ICAM-1-targeting CAR T cells against gastric cancer. The efficacy of ICAM-1 CAR T cells showed a significant correlation with the level of ICAM-1 expression in target cells in vitro . In animal models of human gastric cancer, ICAM-1-targeting CAR T cells potently eliminated tumors that developed in the lungs, while their efficacy was more limited against the tumors in the peritoneum. To augment CAR T cell activity against intraperitoneal tumors, combinations with paclitaxel or CAR activation-dependent interleukin (IL)-12 release were explored and found to significantly increase anti-tumor activity and survival benefit. Collectively, ICAM-1-targeting CAR T cells alone or in combination with chemotherapy represent a promising strategy to treat patients with ICAM-1 + advanced gastric cancer.

Helicase-like transcription factor-deletion from the tumor microenvironment in a cell line-derived xenograft model of colorectal cancer reprogrammed the human transcriptome-S-nitroso-proteome to promote inflammation and redirect metastasis

“…In this study, the proinflammatory mediator S100A8/A9 in combination with species-specific expression of proinflammatory cytokines IL6 (mouse) and IL8 (human) established a pro-metastatic primary tumor niche in the Hltf -deleted TME. Changes in CDX gene expression further promoted metastasis as ICAM-1 increases cancer cell invasion/intravasation into the microvasculature [ 49 ] and mediates peritoneal carcinomatosis [ 50 ] HP promotes colorectal cancer cell motility [ 51 ] and SERPINA3 promotes tumor cell migration and invasion [ 52 ]. Decreased HGF may be partly responsible for reduced liver metastasis in this model [ 53 ].…”

The Role of CAR-T Cells in Peritoneal Carcinomatosis from Gastric Cancer: Rationale, Experimental Work, and Clinical Applications

“…Another group targeted ICAM-1 and compared intraperitoneal injection versus tail vein injection. They observed a significantly higher tumor response with intraperitoneal delivery [47].…”

“…ICAM is found more frequently in advanced stages, such as lymph-node metastases and systemic metastases [46]. In mice, the use of ICAM in CAR-T cell therapy has shown a strong capacity for tumor elimination and can also act on distant tumors [47].…”

CAR T cells in solid tumors: challenges and opportunities

“…Colorectal NKG2D [54], EP-CAM [55], HER2 [56], GUCY2C [57], TAG-72 [58], CD46 [58] Liver CEA [59], Glypican3 [60], AFP [61] Gastric Mesothelin [62], ANTXR1 [63], MUC3A [63], Trop2 [64], Claudin18.2 [66], NKG2D [28], HER2 [65,66], FR-α [67] Pancreatic MUC1 [68], Mesothelin [69], αvβ6 [70], CEA [71], PSCA [71], FAP [71], CD47 [72], HER2 [73], NKG2D [74] Renal CAIX [75] Melanoma GD2 [76], GSPG4 [77], Glypican3 [78], HER2 [79] Cervix αvβ6 [80], L1-CAM [81] Neuroblastoma GD2 [82,83], CD56 [84], Glypican 2 [85], CD171 [86] Glioblastoma EGFRvIII [87], HER2 [88], B7-H3 [89], NKG2D [90], CAIX [91], αvβ3, IL13Rα2 [92] Ovarian Mesothelin [62,93], αvβ6…”

“…Based on other studies, using clau-din18.2-CAR T cells [74], NKG2D-CAR T cells [75], folate receptor 1 (FOLR1)-CAR T cells [76], and HER2-CAR T cells [77] can be considered as a novel therapeutic approach for gastric cancer therapy. In a recent study, Jung et al showed that ICAM-1 CAR T cells alone or in combination with chemotherapeutic agent paclitaxel or CAR T cells modified IL-12 release, as a promising approach which greatly improves ICAM-1 high -advanced gastric cancer patients [78].…”