Cancers
are notorious for secreting chemicals that confuse the immune system
and thwart biological defenses. To counter that effect, some cancer
treatments try to neutralize the cancer’s chemical arsenal and boost a
patient’s immune response, though attempts to do both at the same time
are rarely successful.
Now,
researchers have developed a novel system to simultaneously deliver a
sustained dose of both an immune-system booster and a chemical to
counter the cancer’s secretions, resulting in a powerful therapy that,
in mice, delayed tumor growth, sent tumors into remission, and
dramatically increased survival rates. The researchers, led by Tarek
Fahmy of Yale University, reported their findings in the journal Nature Materials.
The
nanotechnology-based immunotherapy incorporates two well-studied drugs
into nanolipogels (NLGs), a new drug transport technology that Dr. Fahmy
and his colleagues designed. The NLGs are nanoscale, hollow,
biodegradable spheres, each one capable of accommodating large
quantities of chemically diverse molecules. The spheres appear to
accumulate in the leaky vasculature, or blood vessels, of tumors,
releasing their cargo in a controlled, sustained fashion as the sphere
walls and scaffolding break down in the bloodstream.
For
the recent experiments, the NLGs contained two components: an inhibitor
drug that counters a particularly potent cancer defense called
transforming growth factor-? (TGF-?), and interleukin-2 (IL-2), a
protein that rallies immune systems to respond to localized threats.
“You
can think of the tumor and its microenvironment as a castle and a
moat,” says Dr. Fahmy. “The castles are cancerous tumors, which have
evolved a highly intelligent structure—the tumor cells and vasculature.
The moat is the cancer’s defense system, which includes TGF-?. Our
strategy is to dry-up that moat by neutralizing the TGF-?. We do that
using the inhibitor that is released from the nanolipogels. The
inhibitor effectively stops the tumor’s ability to stunt an immune
response.”
At
the same time, the researchers boost the immune response in the region
surrounding the tumor by delivering IL-2, a cytokine protein that
stimulates protective cells, in the same drug delivery vehicle. “The
cytokine can be thought of as a way to get reinforcements to cross the
dry moat into the castle and signal for more forces to come in,” adds
Dr. Fahmy. In this case, the reinforcements are T cells. By
accomplishing both treatment goals at once, the body has a greater
chance to defeat the cancer.
The
current study targeted both primary melanomas and melanomas that have
spread to the lung, demonstrating promising results with a cancer that
is well-suited to immunotherapy and for which radiation, chemotherapy,
and surgery tend to prove unsuccessful, particularly when metastatic.
The researchers did not evaluate primary lung cancers in this study.
One
problem with current metastatic melanoma immunotherapies is the
difficulty managing autoimmune toxicities when the treatment agents are
administered throughout the body. The novel nanolipogel delivery system
used to administer IL-2 and an immune modulator for blocking the
cytokine TGF-? will hopefully bypass systemic toxicities while providing
support to enable the body to fight off the tumor at the tumor bed
itself.
Critical
to the treatment’s success is the ability to package two completely
different kinds of molecules—large, water-soluble proteins like IL-2
and tiny, water-phobic molecules like the TGF-? inhibitor-into a single
package. To accomplish this task, the NGL consists of two
simple-to-manufacture, yet highly functional parts. The outer shell of
each NLG is made from an FDA-approved, biodegradable, synthetic lipid
that the researchers selected because it is safe, degrades in a
controlled manner, is sturdy enough to encapsulate a drug-scaffolding
complex, and easily forms a spherical shell.
Each
shell surrounds a matrix made from biocompatible, biodegradable
polymers that the engineers had already impregnated with the tiny TGF-?
inhibitor molecules. The researchers then soaked those near-complete
spheres in a solution containing IL-2, which gets entrapped within the
scaffolding, a process called remote loading. The end result is a
nanoscale drug delivery vehicle that appears to fit the narrow
parameters necessary for successful treatment. Each NLG is small enough
to travel through the bloodstream, yet large enough to get entrapped in
leaky cancer blood vessels.
Source: National Cancer Institute
