Scientists retool CAR T cells to serve as `micropharmacies' for cancer
drugs
These souped-up versions may help overcome some limitations of existing
CAR T cells.

Date:
December 30, 2021
Source:
Memorial Sloan Kettering Cancer Center
Summary:
Immunotherapies called chimeric antigen receptor (CAR) T cells use
genetically engineered versions of a patient's own immune cells
to fight cancer. These treatments have energized cancer care,
especially for people with certain types of blood cancers. Now,
scientists have developed new CAR T cells that can do something
their predecessors cannot: Make drugs.



FULL STORY ========================================================================== Immunotherapies called chimeric antigen receptor (CAR) T cells use
genetically engineered versions of a patient's own immune cells to
fight cancer. These treatments have energized cancer care, especially
for people with certain types of blood cancers. Now, scientists at
Memorial Sloan Kettering Cancer Center's Sloan Kettering Institute (SKI)
have developed new CAR T cells that can do something their predecessors
cannot: Make drugs.


========================================================================== Standard-issue CAR T cells are designed in the lab to recognize specific markers on cancer cells. When these CAR T cells are given back to a
patient, they proliferate and go on the attack, acting as a kind of
"living drug." Despite their usefulness for treating blood cancers,
there are several limitations of current CAR T models. One is that the
CAR T cells can only kill cancer cells that contain the marker they are designed to recognize. But it is not uncommon for cancer cells to stop
making this marker and thus to "escape" from the therapy.

A second problem is that CAR T cells can become "exhausted" -- and
even inhibited by the cancer cells themselves. Lastly, existing CAR
T cells work well only against blood cancers that the CAR T cells can
easily reach. Against dense solid tumors in the lung or breast, they
are mostly powerless.

To overcome these hurdles, a team of SKI researchers has designed an
entirely new type of CAR T cell that acts as a "micropharmacy": It can
deliver a toxic drug payload directly to a tumor, killing both tumor
cells that contain the cancer marker as well as those cancer cells nearby
that do not. What's more, the engineered cells can produce the drug even
after they become exhausted, and the drug is not suppressed by the cancer.

"We call them SEAKER cells," says physician-scientist David A. Scheinberg, Chair of the Molecular Pharmacology Program in SKI who also directs
the Center for Experimental Therapeutics. "SEAKER stands for Synthetic Enzyme-Armed KillER cells. These cells combine the target-seeking power
of immune cells with the ability to locally generate a potent anticancer
drug for double effect." The cancer-fighting molecule is one that SKI
Chemical Biology Program Chair Derek Tan -- Dr. Scheinberg's collaborator
on the project -- discovered previously while developing antibiotics. The molecule, called AMS, is so powerful that it cannot be injected directly
into an animal's bloodstream. But when it is produced locally just at
the site of a tumor, it is effective at safely killing cancer cells in
mice. The scientists have not yet tested the technology in people.



========================================================================== Details about the SEAKER platform, which the scientists say has
applicability to both cancer and other diseases, were published on
December 30, 2021, in Nature Chemical Biology.

A Unique Drug-Delivery Approach The idea of using CAR T cells to
deliver additional therapeutic agents isn't brand new. Several research
groups have shown it's possible to get them to make immune proteins
like antibodies and cytokines. But getting CAR T cells to produce a small-molecule cancer drug is a trickier prospect.

"Human cells cannot normally make this type of compound," Dr. Tan says.

To find a work-around, the team devised a clever approach. They linked
the cancer drug to another chemical that "masks" its function. Then,
they genetically engineered the T cells to make an enzyme that cuts the
masking molecule from the drug.



==========================================================================
"In contrast to small-molecule drugs, human cells are very good at making enzymes, so CAR T cells are able to produce it effectively," Dr. Tan adds.

When the inactive version of the drug, called a prodrug, is injected into
the bloodstream, it circulates through the body. The enzyme produced by
the CAR T cells acts like a scissor, releasing the active part of the
prodrug at the site of the tumor.

The scientists tested their SEAKER cells on both cancer cells growing
in a dish and in mouse models. In both cases, the SEAKER cells performed
better than regular CAR T cells at killing the cancer cells.

The SKI team also showed that their SEAKER cells work with several
different prodrugs and several different cleaving enzymes -- hence
their referring to this technology as a "platform." A Risky Bet That
Paid Off The scientists emphasize the "high risk, high reward" nature
of their research.

"It's one of the wildest ideas I've ever worked on," Dr. Tan says. "It's
very exciting that we got it to work." Thanks to seed funding from
MSK's Center for Experimental Therapeutics and philanthropy, they were
able to take a risk and eventually get the idea off the ground. Later,
the National Institutes of Health (NIH) provided additional funding.

Dr. Tan adds that this project is a good example of how the pursuit of noncancer-related basic science at MSK can spawn new discoveries with
relevance to cancer.

'SEAKING' Out Cancer and Other Diseases Now that the scientists have shown
that their SEAKER cells work in mice, there has been a lot of interest in
the approach. In fact, a company called CoImmune has already licensed the technology from MSK to develop the CAR T cell technology for human trials.

"There is an opportunity to better understand the limitations of CAR
T cells and specifically engineer new treatment options that have the
potential to address challenges with eliminating tumor masses and
toxicity," says Charles Nicolette, PhD, chief executive officer of
CoImmune. "This exciting collaboration positions us to evaluate this
completely novel approach that may provide a new treatment option for
patients with solid tumors." "The collaboration with CoImmune is exciting because we need a company to take this on to scale up and manufacture
a standardized product," Dr. Scheinberg adds.

Another part of the appeal of the SEAKER technology is that it has more
than one possible application.

"You could imagine it being used to produce drugs to fight other
conditions, such as autoimmune diseases and infections," Dr. Scheinberg
says.

But for now, the focus of the MSK researchers and CoImmune will be
on cancer.

Dr. Scheinberg speculates that a clinical trial in cancer is about two
to three years away.

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


========================================================================== Journal Reference:
1. Thomas J. Gardner, J. Peter Lee, Christopher M. Bourne, Dinali
Wijewarnasuriya, Nihar Kinarivala, Keifer G. Kurtz, Broderick
C. Corless, Megan M. Dacek, Aaron Y. Chang, George Mo, Kha
M. Nguyen, Renier J.

Brentjens, Derek S. Tan, David A. Scheinberg. Engineering CAR-T
cells to activate small-molecule drugs in situ. Nature Chemical
Biology, 2021; DOI: 10.1038/s41589-021-00932-1 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/12/211230130928.htm

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