Published in the UK June 2020 . Primary observation is field for targeting
macrophages therapeutics is is in infancy and wide open ie Macrophage
Therapeutics noted as one of only 4 companies and Navidea who has already demonstrated success in 2 primary obstacles.....
Macrophages are extraordinary cells. Not just for their phagocytic
capacity, which is also shared by a few other cells, but also for their
ability to dynamically adapt their function to intervene in unfolding
For most cells, differentiation (specialization) from their
progenitors (parent cells) is a one-way street – their roles become
fixed as they terminally differentiate. In contrast, macrophages can
switch between entirely different phenotypes.
Most macrophages start their 2-week life in bone marrow as monocytes.
Following release into the blood, monocytes invade tissues and
differentiate to early-stage macrophages which are then polarized into a
wide spectrum of phenotypes, with M1-types and M2-types roughly at
opposite poles of the spectrum. M1 macrophages are pro-inflammatory and
M2 macrophages are involved in tissue remodelling. The local
microenvironment, including reactive oxygen species and cytokines
released by other cells, influence the macrophage’s polarization.
Circulating macrophages carried in the blood will home particularly
towards sites of injury or infection polarizing to M1-types.
Subsequently, once the infection has cleared, the recruited macrophages
can transform, re-polarizing themselves to M2-types to orchestrate wound
healing. Macrophages are the sappers of the cell world: seeking out and
fighting invaders, removing unwanted cells and then constructing new
tissues. Viewing macrophages in vitro with a time-lapse video,
the mobility, industry and energy of these cells, continuously probing,
looking for work, is impressive.
In addition to circulating macrophages, it is now known that there
are many tissue-resident macrophages which originate within the tissues
themselves, rather than in bone marrow. These tissue-resident
macrophages help with tissue homeostasis – the maintenance of tissue
All that macrophage talent is difficult to control. This ability of a
macrophage to adapt to its environment produces vulnerabilities as well
as capabilities: macrophages have a dark side. They are the cells
primarily responsible for releasing cytokine storms which arise, for
example, in sepsis and following treatment with certain drugs (such as
high-dose IL-2 used for therapy of malignant melanomas and renal cell
cancers). In many cases, these cytokine storms can be fatal. Macrophages
also underlie many autoimmune diseases,
attacking the body’s own cells. For example, they are involved in the
pathogenesis of rheumatoid arthritis and inflammatory bowel disease.
Cancer is another arena where things can go horribly wrong for the
macrophage. Once inside an advanced tumour, these law-enforcers of the
cell world can be subverted.
In the very early stages of cancer, macrophages will attack and
remove cancer cells. Most nascent cancers are actually snuffed out in
the early stages of their development by this mechanism. Macrophages,
therefore, play an important role in protecting us from cancer. However,
cancer wages a campaign of attrition against the macrophages in three
Firstly, some cancer cells acquire mutations which provide a way to
evade immune surveillance. These cells will then outgrow adjacent cancer
cells to become dominant. This “immune-editing”, eventually allows
entire tumours to avoid macrophage attack. Specific mechanisms that
enable this immune-escape have
been uncovered. To stop engulfment by macrophages, cancer cells express
large numbers of the CD47 “don’t eat me” antigen on their surface. This
is an antigen that helps reign in and limit macrophages’ appetite for
normal cells. Cancers “learn” that making lots of this CD47 protein can
protect them. At least 20 companies are developing therapies that target
the CD47 axis including Forty Seven, recently acquired by Gilead for $4.9Bn.
Secondly, cancer cells also develop mechanisms to force macrophages
to polarize into pro-tumour M2-like phenotypes. Not only do these M2
cells fail to attack cancer cells, but they also quell the activity of
other immune cells. For example, M2 macrophages secrete cytokines that
suppress other immune cells and they also secrete large amounts of
PD-L1, which suppresses cytotoxic T cells.
Finally, macrophages are co-opted to actively assist tumours, acting as a chaperone to
cancer cells during metastasis and helping them break out from the
tumour into the circulatory system. Macrophages then accompany the
circulating cancer cells in clusters travelling as bodyguards to invade
new metastatic sites.
All of these macrophage activities and behaviours, that go right to
the heart of many diseases, have naturally attracted the attention of
medical researchers. There is reason to believe that some of their
efforts will be successful if the track record of therapies that target
other immune cells, such as cytotoxic T cells is a guide. Most of these
existing therapies, including PD-L1 inhibitors, CAR-T cells and IL-2
therapy, enable cytotoxic T cells to function against cancer and have
made huge impacts on specific tumour types.
The particular attributes of macrophages (availability of their
progenitors in bone marrow and blood, phagocytosis and ongoing
recruitment to tumours as well as sites of injury or infection), suggest
it may be possible to develop a Macrophage-Mediated Molecular Trojan
Morse (MAMMOTH) therapeutic strategy. However, there are significant
obstacles to this. Difficulties associated with any MAMMOTH strategy
- Developing an efficient mechanism to load a drug – macrophages are famously difficult to transduce.
- If phagocytosis is used as a loading mechanism, can the nanoparticle withstand the phagolysosome and secrete its cargo intact?
- Monocytes and macrophages can’t proliferate, so generating enough macrophages for therapy can be a challenge.
- Heterologous transplant of macrophages from a donor individual require engineering of the cells to render them non-immunogenic.
Companies developing macrophage-based or macrophage-targetted therapeutics for cancer include:
Research interest around macrophages in disease is increasing; 70%
more papers in the field were published in 2019 compared to 2009. More
specifically, research interest in the use of macrophage-mediated drug
delivery systems is growing. If the versatility of macrophages can be
harnessed to effectively deliver drugs to the site of disease, we could
witness a surge in availability of treatments available for a wide range
of diseases, many of which currently have no effective,