Study shows engineered natural killer immune cells can directly kill tumor cells

According to a new study published in the eLife journal, researchers have successfully designed natural killer immune cells that destroy head and neck tumor cells in mice and also decrease the immune-suppressing myeloid cells that enable tumors to escape the immune response.

Natural Killer Cell

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It is believed that the engineered cell therapy can be used as an alternative method for treating cancer in those patients in whom earlier immunotherapy based on T-cell activation did not work. Scientists from the U.S. National Institutes of Health (NIH) in Bethesda, Maryland, have reported these findings.

In the recent past, treatments known as CAR-T cell therapy or T-cell therapy have been approved for treating blood cancers, and several other therapies are being developed for other types of cancer.

But these T-cell therapies depend on the potential to manipulate an individual’s own T cells to express a chimeric antigen receptor (CAR) that are known to target cancer cells. This procedure of manipulating an individual’s T cells is not only costly but also arduous.

High-affinity natural killer cells, or haNKs for short, are promising, “off-the-shelf” cell therapies that do not depend on reprogramming an individual’s own immune cells.

The same kinds of cells could be created in large quantities and can perhaps be donated to anyone. However, immune-suppressing myeloid cells present in the tumor microenvironment continue to be an obstacle for effective immunotherapy, such as haNK cell-based treatments.

To tackle this issue, scientists from the NIH’s National Institute on Deafness and Other Communication Disorders (NIDCD) and also from the National Cancer Institute have used CAR-expressing haNKs that target a molecule known as programmed death ligand 1 (PD-L1).

PD-L1 is a familiar culprit that is abundantly produced by cancer cells and immunosuppressive myeloid cells to weaken the immune system.

The research team, headed by Clint Allen, the study’s senior author and Principal Investigator, Section on Translational Tumor Immunology, NIDCD, tested the engineered PD-L1 haNKs versus normal haNKs against mouse and human head and neck cancer cells.

The researchers discovered that human and mouse tumor cells were destroyed to a greater extent by the haNKs expressing the PD-L1 CAR when compared to haNKs without the CAR. Moreover, this ability was sustained even if they had already been subjected to cells carrying PD-L1 before. This finding is significant because natural killer cells become “exhausted” after destroying the target cells.

In mice affected by head and neck tumors, the haNK cell-based therapy effectively cured the animals in 30% of cases and reduced the tumor growth in the remaining ones, without causing any toxicity. Therapies based on haNKs also lowered the numbers of PD-L1-carrying immunosuppressive myeloid cells inside the tumor, without having any impact on other kinds of immune-boosting white blood cells.

To further study whether this impact on the immune cells also took place in patients, the researchers incubated white blood cells from individuals affected by advanced head and neck cancer with the PD-L1 haNK cells.

As observed in the mice, the researchers noted that PD-L1-carrying immunosuppressive myeloid cells were considerably decreased following treatment with the PD-L1 haNK cells.

This indicates that the therapy can directly destroy tumor cells and also eliminate the immunosuppressive myeloid cells that inhibit the function of traditional immunotherapies.

Such findings indicate that haNK cells expressing a PD-L1 CAR could overcome certain drawbacks of traditional immunotherapy that depends on the activation of T-cells and can possibly be used in those patients who are believed to be insensitive to immunotherapy treatments, or have failed to respond to these treatments.

The scientists stated that the subsequent steps would be to test this treatment in a clinical setting to study the safety of PD-L1 haNKs in individuals with recurring or advanced cancer, and to observe if integrating haNK cell therapy with other types of immunotherapies that activate T cells can improve the response to treatments.

Source:
Journal reference:

Robbins, Y., et al. (2020) Tumor control via targeting PD-L1 with chimeric antigen receptor modified NK cells. eLife. doi.org/10.7554/eLife.54854.

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