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Tuesday, 21 January 2020

Cancer: discovery of new cell receptor could revolutionize T-cell therapies



Some current cancer therapies involve the use of genetically engineered T cells to destroy cancer cells. These particular white blood cells are able to recognize and neutralize any intruder in the body. However, these therapies are extremely restrictive and must be fully personalized due to the variability of the HLA receptor, allowing T cells to detect cancer cells. However, the discovery of a new invariant cellular receptor, which can neutralize different types of cancer, could revolutionize this therapy.



The researchers behind the discovery note that the tests are still in their infancy, as they have only been performed on mice and human cells in the laboratory, not yet in living patients. But the preliminary results, published in the journal Nature Immunology , are promising and suggest that we may be on the verge of significant progress in T-cell therapies.

T cells are a type of white blood cell involved in the functioning of our immune system. When activated when they come into contact with defective or foreign cells in the body, they attack them, which helps us fight infection and disease.


T-cell therapies and HLA receptor variability

In T-cell therapy - the most common form of which is called CAR-T (for chimeric T cells of antigen receptors), scientists divert and increase this natural function of T cells to direct them to tumor cells in particular.

In CAR-T treatments, doctors extract T cells from patients' blood and genetically modify them in the laboratory to allow them to identify and specifically target cancer cells. The edited T cells are then multiplied in the laboratory before being administered to patients.

Diagram explaining the functioning of a CAR-T anticancer therapy. Credits: cancer.gov

Some of the limitations of the CAR-T technique are that edited T cells are only able to recognize a few types of cancer, and the whole therapy has to be personalized for different patients because of a T cell receptor (TCR) called “ human leukocyte antigen ”(HLA). HLA is what allows T cells to detect cancer cells, but it varies from person to person. And this is where this new discovery comes in.

MR1 receiver: an invariant and more suitable receiver

In the new study, led by biologists from Cardiff University in the UK, the researchers used CRISPR-Cas9 to discover a new type of TCR in T cells: a receptor molecule called MR1.

MR1 works similarly to HLA in terms of detecting and recognizing cancer cells, but one big difference is that, unlike HLA, it does not vary - which means that it could potentially form the basis of therapy for T cells that would work for a much wider range of people.

Diagram showing how new genetically engineered T cells use the MR1 receptor to identify and kill cancer cells. Credits: University of Cardiff

Preliminary laboratory experiments involving MR1 are indeed promising, even if the researchers point out that the results must be reproduced safely in clinical trials before they can confirm that it is a treatment suitable for humans.

In laboratory tests using human cells, T cells equipped with MR1 killed the multiple cancer cell lines tested (lung, melanoma, leukemia, colon, breast, prostate, bone and ovaries) that did not share common HLA. Tests on mice with leukemia - in which the animals were injected with MR1 cells - revealed signs of cancer regression and led the mice to live longer than the control mice.


Towards a new T cell therapy?

At the moment, we do not yet know how many types of cancer a technique based on this receptor could treat. That said, the first results certainly suggest that a varied range could be sensitive to it. If these types of effects can be replicated in humans - something scientists hope to start testing this year - T-cell therapies could take a big step.

To this end, the team's next step - in addition to organizing future clinical trials - will be to learn more about the mechanisms that allow MR1 to identify cancer cells at the molecular level.


Bibliography:

Genome-wide CRISPR–Cas9 screening reveals ubiquitous T cell cancer targeting via the monomorphic MHC class I-related protein MR1

Michael D. Crowther, Garry Dolton, Mateusz Legut, Marine E. Caillaud, Angharad Lloyd, Meriem Attaf, Sarah A. E. Galloway, Cristina Rius, Colin P. Farrell, Barbara Szomolay, Ann Ager, Alan L. Parker, Anna Fuller, Marco Donia, James McCluskey, Jamie Rossjohn, Inge Marie Svane, John D. Phillips & Andrew K. Sewell

Nature Immunology (2020)

doi:10.1038/s41590-019-0578-8

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