Engineered killer immune cells target tumors and their immunosuppressive allies

Date:
July 7, 2020
Source:
eLife
Summary:
Scientists have engineered natural killer immune cells that not
only kill head and neck tumor cells in mice but also reduce the
immune-suppressing myeloid cells that allow tumors to evade the
immune response.



FULL STORY ========================================================================== Scientists have engineered natural killer immune cells that not only kill
head and neck tumour cells in mice but also reduce the immune-suppressing myeloid cells that allow tumours to evade the immune response, according
to a new study in eLife.


==========================================================================
The engineered cell therapy could be used as an alternative approach
for treating cancer in patients for whom previous immunotherapy based
on the activation of T cells has failed. These findings are reported by researchers at the U.S. National Institutes of Health (NIH) in Bethesda, Maryland.

In recent years, treatments called T-cell therapy or CAR-T cell therapy
have been approved to treat blood cancers, and many others are now in development for other forms of cancer. However, these T-cell therapies
rely on the ability to reprogram a patient's own T cells to express a
chimeric antigen receptor (CAR) that targets tumour cells. This process
of reprogramming a patient's own T cells is expensive and laborious.

High affinity natural killer cells (haNKs) represent potential
'off-the-shelf' cell therapies that do not rely on reprogramming a
patient's own immune cells.

The same cells could be produced in mass and potentially given to
anyone. But the presence of immune-suppressing myeloid cells in the
tumour microenvironment remains a barrier to effective immunotherapy,
including haNK cell-based treatment.

To address this barrier, researchers from the NIH's National Institute on Deafness and Other Communication Disorders (NIDCD) and National Cancer Institute have utilised haNKs expressing a CAR that targets a molecule
called programmed death ligand 1 (PD-L1). PD-L1 is a well-known culprit
that cancer and immunosuppressive myeloid cells produce in high amounts
to dampen down the immune system.

Led by senior author Clint Allen, Principal Investigator, Section on Translational Tumor Immunology, NIDCD, the team tested the engineered
PD-L1 haNKs versus ordinary haNKs against human and mouse head and neck
cancer cells.

They found that the haNKs expressing the PD-L1 CAR kill mouse and human
tumour cells to a greater degree than haNKs without the CAR, and that
this ability was retained even if they had already been exposed to cells carrying PD-L1 before.

This is important because natural killer cells are known to become
'exhausted' after killing target cells.

In mice with head and neck tumours, the haNK cell-based therapy cured the
mice in 30% of cases and slowed the growth of tumours in the rest of the
mice, without causing toxicity. Treatment with haNKs also reduced the
numbers of immunosuppressive myeloid cells that carry PD-L1 within the
tumour, while having no effect on other immune-boosting white blood cells.

To investigate whether this effect on the immune cells also occurred
in patients, the team incubated white blood cells from people with
advanced head and neck cancer with the PD-L1 haNK cells. As they saw
in the mice, the immunosuppressive myeloid cells that carry PD-L1 were significantly reduced after treatment with the PD-L1 haNK cells. This
suggests that this treatment can both directly kill tumour cells and
remove the immunosuppressive myeloid cells that prevent conventional immunotherapies from working.

These findings suggest that haNK cells expressing a PD-L1 CAR may overcome
some of the limitations of conventional immunotherapy that relies on
T-cell activation, and could be used in patients who are predicted to
be insensitive to or have failed existing immunotherapy treatments. The researchers say the next steps would be to take this treatment into the
clinic to explore the safety of PD-L1 haNKs in people with advanced
or recurring cancer, and to see whether combining haNK cell therapy
with other immunotherapies that activate T cells can enhance treatment response.


========================================================================== Story Source: Materials provided by eLife. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. Yvette Robbins, Sarah Greene, Jay Friedman, Paul E Clavijo,
Carter Van
Waes, Kellsye P Fabian, Michelle R Padget, Houssein Abdul Sater,
John H Lee, Patrick Soon-Shiong, James Gulley, Jeffrey Schlom,
James W Hodge, Clint T Allen. Tumor control via targeting PD-L1
with chimeric antigen receptor modified NK cells. eLife, 2020;
9 DOI: 10.7554/eLife.54854 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/07/200707113302.htm

--- up 24 weeks, 2 hours, 39 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1337:3/111)