Anticancer T-cell therapy has a lot in common with lock picking, a painstaking business that often ends in frustration. Every cancer, like every lock, presents a unique challenge. But what if there were such a thing as an anticancer T cell that worked as though it carried a skeleton key? Imagine it: a T cell equipped with a T-cell receptor (TCR) that bypasses obstructions and engages a shared mechanism, that is, a mechanism common to the locks presented by different kinds of cancer.
A skeleton key–like TCR hasn’t been found on ordinary T cells. However, one has been discovered on the keychain of another kind of T cell, the mucosal-associated invariant T (MAIT) cell. Unlike ordinary anticancer T cells, which fumble over molecular locks involving the human leukocyte antigen (HLA) system, MAIT cells have a TCR that works with another cell surface display system, the monomorphic MHC class I-related protein, MR1.
The new discovery, which comes from scientists based at Cardiff University, raises the possibility of developing pan-cancer, pan-population cancer immunotherapies. “We hope this new TCR may provide us with a different route to target and destroy a wide range of cancers in all individuals,” said Cardiff’s Andrew Sewell, PhD, a professor of infection and immunity. “Previously nobody believed this was possible.”
The usual target of anticancer T-cell therapies is the HLA system, which varies widely between individuals. The MR1 system, however, does not vary in the human population—meaning it is a hugely attractive new target for immunotherapies.
“Current TCR-based therapies can only be used in a minority of patients with a minority of cancers,” he continued. “Cancer-targeting via MR1-restricted T cells is an exciting new frontier—it raises the prospect of a ‘one size fits all’ cancer treatment, a single type of T cell that could destroy many different types of cancers across the population.”
Sewell is the senior author of an article (“Genome-wide CRISPR-Cas9 screening reveals ubiquitous T cell cancer targeting via the monomorphic MHC class I-related protein MR1”) that appeared in Nature Immunology. According to this article, the MR1-targeting TCR from MAIT cells “recognized and killed most human cancer types … while remaining inert to noncancerous cells.”
“An MR1-restricted T cell clone mediated in vivo regression of leukemia and conferred enhanced survival of NSG mice,” the article’s authors wrote. “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.”
T cells equipped 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. To test the therapeutic potential of these cells in vivo, the researchers injected T cells able to recognize MR1 into mice bearing human cancer and with a human immune system.
This showed “encouraging” cancer-clearing results, which the researchers said were comparable to those obtained using a conventional chimeric antigen receptor (CAR) T-cell therapy in a similar animal model. The Cardiff group also showed 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.
In currently approved T-cell therapies for cancer, immune cells are removed, modified, and returned to the patient’s blood to seek and destroy cancer cells. The most widely used version of this therapy, the CAR T-cell therapy, is personalized to each patient. It targets only a few types of cancers, and it has not been successful for solid tumors, which make up the vast majority of cancers.
The current limitations of CAR T-cell therapy could be overcome by T-cell therapies incorporating the newly discovered MR1-targeting TCR, suggested Cardiff’s Oliver Ottmann, MD, professor and head of hematology. To help realize this possibility, the Cardiff team performed experiments to determine the precise molecular mechanism by which the new TCR distinguishes between healthy cells and cancer.
“Unlike mucosal-associated invariant T cells, recognition of target cells by the TCR was independent of bacterial loading,” reported the authors of the Nature Communications article. “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.”
In other words, the researchers believe the TCR may work by sensing changes in cellular metabolism that cause different metabolic intermediates to be presented at the cancer cell surface by MR1.
The Cardiff group hopes to trial this new approach in patients toward the end of this year following further safety testing. Sewell stressed that a vital aspect of this ongoing safety testing was to further ensure killer T cells modified with the new TCR recognize cancer cells only.
“There are plenty of hurdles to overcome,” Sewell noted. “However, if this testing is successful, then I would hope this new treatment could be in use in patients in a few years’ time.”
