T-cells with the new TCR were shown, in the lab, to kill lung, skin, blood, colon, breast, bone, prostate, ovarian, kidney and cervical cancer cells, while ignoring healthy cells. The researchers injected T-cells able to recognise MR1 into mice bearing human cancer and with a human immune system. This showed encouraging cancer-clearing results which the researchers said was comparable to the now NHS-approved CAR-T therapy in a similar animal model.
The Cardiff group were further able to show that T-cells of melanoma patients modified to express this new TCR could destroy not only the patient’s own cancer cells, but also other patients’ cancer cells in the laboratory, regardless of the patient’s HLA type.
CAR-T and T-Cells
T-cell therapies for cancer – where immune cells are removed, modified and returned to the patient’s blood to seek and destroy cancer cells – are the current hottest thing in cancer treatments. The most widely-used therapy, known as CAR-T, is personalized to each patient but targets only a few types of cancers and has not been successful for solid tumors, which make up the vast majority of cancers.
T-cell therapies have been making slow progress because each type of cancer needs specific modifications that require their own clinical trials.
Cardiff researchers have now discovered T-cells equipped with a new type of T-cell receptor (TCR) which recognises and kills most human cancer types, while ignoring healthy cells.
How does this new TCR work?
Conventional T-cells scan the surface of other cells to find anomalies and eliminate cancerous cells – which express abnormal proteins – but ignore cells that contain only “normal” proteins.
The scanning system recognizes small parts of cellular proteins that are bound to cell-surface molecules called human leukocyte antigen (HLA), allowing killer T-cells to see what’s occurring inside cells by scanning their surface.
HLA varies widely between individuals, which has previously prevented scientists from creating a single T-cell-based treatment that targets most cancers in all people.
But the Cardiff study, published today in Nature Immunology, describes a unique TCR that can recognise many types of cancer via a single HLA-like molecule called MR1.
Human leukocyte antigen (HLA)-independent, T cell–mediated targeting of cancer cells would allow immune destruction of malignancies in all individuals. Here, we use genome-wide CRISPR–Cas9 screening to establish that a T cell receptor (TCR) recognized and killed most human cancer types via the monomorphic MHC class I-related protein, MR1, while remaining inert to noncancerous cells. Unlike mucosal-associated invariant T cells, recognition of target cells by the TCR was independent of bacterial loading. Furthermore, concentration-dependent addition of vitamin B-related metabolite ligands of MR1 reduced TCR recognition of cancer cells, suggesting that recognition occurred via sensing of the cancer metabolome. An MR1-restricted T cell clone mediated in vivo regression of leukemia and conferred enhanced survival of NSG mice. TCR transfer to T cells of patients enabled killing of autologous and nonautologous melanoma. These findings offer opportunities for HLA-independent, pan-cancer, pan-population immunotherapies.
SOURCES- University of Cardiff, Nature Immunology
Written By Brian Wang, Nextbigfuture.com