KRAS-targeted T-cell therapy shrinks pancreatic cancer tumors by 72%
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KRAS-targeted T-cell therapy shrinks pancreatic cancer tumors by 72%.
Pancreatic cancer is the deadliest type of common cancer. Not only are many patients at an advanced stage when symptoms appear, but neither chemotherapy nor immune checkpoint inhibitors have very limited efficacy against it.
Using autologous T-cell therapy targeting the KRAS G12D mutant expressed by cancer cells, a patient who had received multiple prior treatments achieved deep and durable Tumor shrinks.
The New England Journal of Medicine published two review articles dedicated to the study, and renowned scholar Eric Topol also tweeted that it was a groundbreaking study.
Nearly 90% of pancreatic cancers carry KRAS mutations, of which KRAS G12D mutation is one of the most common KRAS mutations, and it is also the most common KRAS mutation in pancreatic cancer, occurring in 41% of patients.
Therefore, targeting the KRAS G12D mutation is an attractive anticancer strategy. Currently, several companies are developing small-molecule inhibitors targeting KRAS G12D.
In this study, the researchers used T cell receptor (TCR) cell therapy.
TCR can recognize tumor antigens presented on the cell surface by HLA proteins of cancer cells.
In this study, the researchers genetically engineered T cells from pancreatic cancer patients in vitro to express two different TCRs that recognize the G12D mutation-containing polypeptide presented by the HLA-C*08:02 molecule.
These two TCRs can not only accurately identify polypeptides containing the G12D mutation, but also do not respond to wild-type KRAS, so that they can precisely target pancreatic cancer cells with KRAS G12D mutation.
TCR cell therapy targeting KRAS G12D polypeptide (Image source: Reference [1])
Patients treated with this therapy had previously received chemotherapy, surgery, radiation, and tumor-infiltrating lymphocyte (TIL) therapy, but all of these treatments progressed and developed metastases in the lungs.
After receiving TCR cell therapy, the patient achieved partial remission, and the volume of visceral metastases decreased by 72%.
After 6 months of treatment, the genetically engineered T cells accounted for 2% of the patients’ circulating peripheral blood T cells. The patient’s remission was maintained at 6 months.
Image source: Reference [1]
Cell therapy represented by CAR-T has achieved excellent efficacy in the treatment of hematological cancers, however, it still faces multiple challenges in the treatment of solid tumors.
This study shows that targeting the KRAS G12D mutation using TCR cell therapy can mediate tumor regression in metastatic pancreatic cancer, the researchers said.
This therapeutic strategy warrants continued evaluation in clinical trials for the treatment of patients with KRAS G12D-expressing pancreatic and other cancers.
References:
[1] Leidner at al., (2022). Neoantigen T-Cell Receptor Gene Therapy in Pancreatic Cancer. NEJM, DOI: 10.1056/NEJMoa2119662
[2] Eric Topol. Retrieved June 1, 2022, from https://twitter.com/EricTopol/status/1532105835425411072
KRAS-targeted T-cell therapy shrinks pancreatic cancer tumors by 72%
(source:internet, reference only)
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