Gastrointestinal cancer refers to malignant conditions of the gastrointestinal tract (GI tract) and accessory organs of digestion. This includes
Oesophageal Cancer Liver Cancer Stomach Cancer Gallbladder & Biliary Tract Cancer Pancreatic Cancer Gastro-Intestinal Stromal Tumour (GIST) Neuroendocrine Tumours (NETs) Colorectal Cancer Small Bowel Cancer Anal Cancer
Treatment options may include surgery, radiation therapy, chemotherapy, laser therapy, and electrocoagulation. Other treatment options, such as targeted therapy, are being studied in clinical trials.
GI cancer is the most common form of cancer, affecting both men and women. Around 28,900 Australians are diagnosed with it each year and 38 Australians die of it each day.
A Phase I/II Trial in Patients With Metastatic Gastrointestinal Epithelial Cancer Administering Tumor-Infiltrating Lymphocytes in Which the Gene Encoding CISH Was Inactivated Using the CRISPR/Cas9 System
Emil Lou, MD, PhD Division of Hematology, Oncology and Transplantation, University of Minnesota
A clinical trial to assess the safety and efficacy of genetically-engineered, neoantigen-specific Tumor Infiltrating Lymphocytes (TIL) in which the intracellular immune checkpoint CISH has been inhibited using CRISPR gene editing for the treatment of Gastro-Intestinal (GI) Cancer.
Tumor Infiltrating Lymphocytes (TIL) have shown efficacy in certain cancers, principally in melanoma. Efficacy in more common solid tumors has been demonstrated via the selection of cancer neoantigen-specific TIL. Combination checkpoint inhibitor therapy has also been employed in an attempt to enhance the efficacy of these cell therapies. Genetic engineering of T cells to further increase anti-tumor activity is now possible.
CISH (Cytokine-induced SH2 protein) is a novel intra-cellular immune checkpoint and an important negative regulator of T-cell signaling and function. The inhibition of CISH in mouse anti-tumor lymphocytes results in a marked increase in the ability of these lymphocytes to mediate tumor regression following administration to tumor bearing mice.
Additionally, data in genetically-engineered, neoantigen-specific human T cells in which CISH was inhibited, showed enhanced TCR functional avidity and increased ability of these T cells to detect cancer specific mutations and mount robust polyfunctional cytokine immune responses against their cognate cancer antigens. Thus, these T cells appear to have a significant advantage in inducing anti-tumor responses compared to wild-type anti-tumor lymphocytes.
The researchers have developed and optimized a CRISPR/Cas9 based strategy for precise and efficient genetic engineering in primary human T-cells without sacrificing cell viability or function.
Thus, in this protocol, the researchers propose to inhibit the gene encoding the intra-cellular checkpoint target CISH in lymphocytes from patients with metastatic cancers that are selected for anti-tumor activity in order to evaluate the safety and efficacy of genetically engineered T cell therapy for solid tumors in the setting of novel checkpoint inhibition.