Cutting the brakes: CRISPR/Cas9 knockout shows promise for gastrointestinal cancer treatment
Knocking out an immune checkpoint gene demonstrated therapeutic promise for combating gastrointestinal (GI) tumors.
A recent study conducted by researchers at the University of Minnesota (USA) has shown promising signs of safety and potential effectiveness for a CRISPR/Cas9 gene-editing technique for GI cancers. By deactivating a key factor that prevents T cells from recognizing and attacking tumors, the researchers have modified tumor-infiltrating lymphocytes (TILs) to enhance their ability to identify and eliminate cancer cells.
Insights into the genomic drivers and other factors that contribute to cancer have transformed the approaches and techniques used to treat patients, including immunotherapies that target immune checkpoints – regulatory mechanisms closely linked to cancer development and progression. However, many patients with GI cancers have not yet benefited from these advancements. According to Emil Lou, a GI oncologist at the University of Minnesota Medical School and principal investigator of the study, “stage IV colorectal cancer [a form of GI cancer] remains a largely incurable disease.”
The researchers emphasized the need to extend the efficacy of immunotherapy to more patients while addressing resistance to existing immune checkpoint inhibitors. These inhibitors work by blocking checkpoint proteins that prevent the immune system from attacking cancer cells.
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To address this challenge, researchers utilized CRISPR/Cas9 gene editing to knockout the CISH gene, which encodes the cytokine-inducible SH2-containing protein. This protein is a novel intracellular immune checkpoint target and a founding member of the suppressors of cytokine signaling (SOCS) family of E3 ligases, which are a large group of enzymes that play a critical role in T-cell activation. By knocking out the CISH gene in TILs, the researchers enhanced immune cell activity by removing the inhibition of cytokine signaling. This increased sensitivity to cytokines results in a stronger antitumor immune response, enhances TIL functionality, reduces T-cell exhaustion and improves persistence in the tumor microenvironment. These modifications to TILs enhanced recognition and attack of cancer cells.
To evaluate the safety and anti-tumor effectiveness of knocking out CISH, researchers conducted a first-in-human, single-center Phase I trial involving twelve patients aged 18 to 70. These patients had end-stage metastatic gastrointestinal epithelial cancers and had at least one lesion suitable for TIL generation, as well as at least one measurable lesion to assess disease response.
The patients received an autologous CISH knockout TIL infusion. After follow-up, six out of the twelve patients had stable disease by day 28, while four patients continued to show stable disease at the 56-day mark. Remarkably, one patient had a complete response that lasted for over 21 months. The researchers noted that there were no serious adverse side effects reported, except expected effects such as tiredness, loss of appetite and hematological events due to preparative chemotherapy and the effects of interleukin-2 – a cytokine used in immunotherapy to activate T cells and natural killer cells.
The findings from this study suggest that the CISH knockout TIL infusion demonstrated effective anti-tumor activity, offering a promising strategy to help the immune system fight against advanced GI cancers.
“We believe that CISH is a key factor preventing T cells from recognizing and eliminating tumors,” said Branden Moriarity, an associate professor at the University of Minnesota. “Because it acts inside the cell, it couldn’t be blocked using traditional methods, so we turned to CRISPR-based genetic engineering.”
Not only did the study produce encouraging results, but the researchers successfully delivered over 10 billion modified TILs without adverse side effects – demonstrating for the first time the exciting potential for scalable and safe genetically engineered TIL-based therapies.
“This trial brings a new approach from our research labs into the clinic and shows potential for improving outcomes in patients with late-stage disease,” remarked Lou.
