Four strategies for targeting tumor-associated macrophages

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Four strategies for targeting tumor-associated macrophages

Four strategies for targeting tumor-associated macrophages.  Tumor-associated macrophages (TAMs) are one of the key factors affecting tumor progression, metastasis and recurrence.

TAMs mainly originate from monocyte precursor cells in the circulatory system. In addition, resident macrophages in the tumor microenvironment can also differentiate into tumor-associated macrophages under corresponding stimulation.

In solid tumors, macrophages represent the main immune cell population. Macrophages have plasticity, making them polarized toward M1 or M2 under the stimulation of corresponding cytokines. The M1 phenotype promotes inflammation/anti-tumor, while the M2 phenotype is anti-inflammatory/promotes tumor development.

M1 and M2 tumor-associated macrophages (Reference 1)

Strategy 1: Clear TAM

CSF1R blocking antibodies and inhibitors

CSF1 receptor (CSF1R), expressed on circulating monocytes and tissue macrophages, controls the survival, proliferation, differentiation and chemotaxis of such cells. The CSF1/CSF1R signal axis is overexpressed in many tumors and is associated with poor prognosis. Monoclonal antibodies or small molecule inhibitors can block CSF1R signaling and have shown effectiveness in preclinical models, successfully depleting TAM and increasing the percentage of T cells in the tumor.

Drugs under development

RG7155(emactuzumab)

Roche research and development, combined with Atezolizumab clinical phase 1 has been completed. NCT02323191, A Study of Emactuzumab andAtezolizumab Administered in Combination in Participants With Advanced SolidTumors, Phase 1

IMC-CS4

Lilly’s research and development, a phase 1 clinical study of pancreatic cancer is in progress. NCT03153410, Pilot Study With CY, Pembrolizumab, GVAX, and IMC-CS4 (LY3022855) in Patients With BorderlineResectable Adenocarcinoma of the Pancreas

FPA008

Five Prime Therapeutics research and development. In 2015, BMS and Five Prime Therapeutics began to cooperate, O drug combined with FPA008 to treat advanced tumors (NCT02526017, NCT03335540, etc.).

Small molecule inhibitor

PLX3397 (pexidartinib/pexidartinib)

The small molecule CSF1R inhibitor developed by Daiichi Sankyo has been approved by the FDA for use in synovial giant cell tumors that have failed chemotherapy or have recurred.

The clinical use of antibodies and small molecule drugs has caused serious adverse events, such as fatigue, weakness, anemia, nausea, facial and periorbital edema, lupus erythematosus, and liver toxicity, which may be caused by off tumor.

In addition, these antibodies and inhibitors can not only selectively act on M2 type inhibitory TAM, and therefore also affect the anti-tumor activity of M1 type TAM. Therefore, tumor-selective and M2 selective elimination antibodies need to be considered for future development.

M2 selective removal

Recently, the scavenger receptor CD163 (M2 type TAM marker) antibody specifically eliminates M2 tumor-associated macrophages, and it has been shown in mouse models to promote the anti-tumor activity of M1 type TAM and T cells (Reference 2).

Strategy 2: Suppress TAM recruitment

CCL2/CCR2

Primary tumors express CCL2 and CC2R and recruit TAM. Therefore, blocking CCL2-CCR2 can inhibit TAM recruitment. Blocking antibodies and small molecules, pre-clinical data have shown effectiveness, but the results of clinical studies are frustrating.

Centocor Research & Development, Inc.’s carlumab (CCL2 antibody) failed to inhibit tumor growth because the tumor cells compensatoryly increased the expression of CCL2 after one week of treatment (Reference 3).

The clinical study of FOLFIRINOX and Pfizer PF-04136309 (CCR2 inhibitor) in advanced pancreatic cancer (NCT01413022) resulted in a decrease in the number of circulating and intratumoral CCR2 monocytes. The treatment was well tolerated, and half of the patients had objective tumor responses. In the FOLFIRINOX group, no objective reaction was observed. On the contrary, the combination of PF-04136309 with paclitaxel and gemcitabine shows safety issues in metastatic pancreatic cancer and has no therapeutic advantage compared to standard treatments. The reason is that other chemokines, cytokines and growth factors participate in this process to make up for the lack of CCL2/CCR2.

Other chemokines

CXCL12/CXCR4 and CCL20/CCR6 are alternative options that can successfully target cancer to prevent the accumulation of TAM. The CXCR4 antagonist AMD3100 (plerixafor) can also inhibit tumor growth by antagonizing the immunosuppressive mechanism. Several clinical studies are underway.

Dual antagonists targeting two chemokine receptors at the same time are a strategy that may lead to more effective TAM targeting. The dual CCR2/CCR5 antagonist BMS-813160 is actually being combined with O drugs or standard chemotherapy to treat pancreatic cancer, lung cancer, kidney cancer and hepatocellular carcinoma (NCT03496662, NCT03767582, NCT04123379, NCT02996110).

It is necessary to accurately select chemokine targeting agents so as not to affect the recruitment of other immune cells, such as natural killers (NK) and T cells, which is the basis for the effectiveness of immunotherapy.

Strategy 3: Promote TAM phagocytic activity

Directly or indirectly induce pro-inflammatory factors, such as IFN, IL4, IL6, IL13, VEGF, GM-CSF, CSF-1, Ang-2, CCL2 and other chemokines, which can promote the polarization of TAM to M1 and produce anti-tumor effects .

CD47/SIRPa

It is known that CD47/SIRPa transmits a “don’t eat me” signal to macrophages, so CD47 and SIRPα blocking antibodies have become a new hot spot. The pharmacological inhibition of CD47 signal by antibodies Hu5F9-G4 and CC-90002 or the engineered fusion protein SIRPa-Fc (TTI-621) can effectively enhance the phagocytosis of tumor cells. Many manufacturers around the world have deployed monoclonal antibodies, double antibodies, and fusion proteins for this target. Many articles have elaborated on them, so I will not repeat them in this article.

CD47-SIRPa and tumor immunity (Reference 4)

CD40

CD40 monoclonal antibody (selicrelumab, Roche R&D code RO7009789) is another method to reprogram TAMs to the M1 phenotype and enhance phagocytosis. It is currently being tested in phase I clinical trials of several solid tumors in combination with standard chemotherapy or immunotherapy ( NCT02304393, NCT03424005, NCT03193190, NCT03555149).

CD40-CD40L and tumor immunity (Reference 5)

TLR

Activation of TLRs by bacterial products or viral nucleic acids can induce immune responses and induce the M1 phenotype of macrophages. Using TLR3, TLR7, TLR8 and TLR9 ligands, encouraging results have been obtained in mouse tumor models such as melanoma and breast cancer.

The TLR7 agonist imiquimod is approved for the local treatment of squamous and basal cell carcinomas, and is reported to be safe in the treatment of melanoma and metastatic breast cancer skin lesions, enhancing the accumulation of immune cells.

Poly-I:C stimulates TLR3 to effectively repolarize TAMs in melanoma and is currently being evaluated as a cancer vaccine to improve the anti-tumor immune response of advanced tumors.

The scavenger receptor Marco is highly expressed in TAMs in patients with melanoma and breast cancer and has been found to be associated with a poor prognosis. An antibody that specifically targets the Marco receptor can redirect TAMs to the M1 phenotype and, together with anti-CTLA-4 immune checkpoint inhibitors, increase the anti-tumor immune response.

Small molecule inhibitor

Some small molecule inhibitors exert anti-tumor effects by reprogramming macrophages. Inhibition of PI3K induces a pro-inflammatory response through M1 TAMs and recruits CTLs into the tumor to prevent tumor growth. PI3K inhibitor combined with anti-PD1 checkpoint inhibitor treatment improves the response and overall survival rate of mice.

Apparent genetics

Another promising strategy is the repolarization of TAM at the epigenetic or genetic level. For example, the histone deacetylase inhibitor TMP195 can induce the M1 phenotype of TAMs and induce their accumulation and phagocytic activity in the microenvironment of breast tumors.

Strategy 4: Target TAMR

TAMR is an acronym for Tyro3, ​​Axl and MerTK, and is expressed in tumors and various immune cells. These receptors have multiple roles in cell fate, proliferation, migration, and regulation of tissue homeostasis and inflammation.

The most famous ligands of TAMR are Gas6 and protein S, which act as adaptors to connect the phosphatidylserine apoptosis signal to TAMR target cells, thereby facilitating the phagocytosis of macrophages. The activated downstream signaling pathway converges on the PI3K/Akt axis, and participates in TAM activation and polarization to the M2 phenotype, thereby limiting the inflammatory response, promoting the production of immunosuppressive cytokines, preventing immune cell activation, and solid tumors thereby avoiding death. Therefore, blocking TAMR signals may be a promising immunotherapy strategy. At present, small molecule inhibitors, ADC drugs, CAR-T, fusion proteins, etc. are all under development (see the table below, Reference 6).

Summary

Tumor-associated macrophages are the most important immune cells in the tumor microenvironment and have strong plasticity.

Clearing TAM, preventing TAM recruitment, and inducing M1 polarization to promote phagocytosis, targeting TAM are four common strategies. Of course, each strategy now has its limitations, such as the non-selectivity of removing TAM and off tumor toxicity.

The development of highly selective drugs in the future will help promote the further development of anti-tumor immunotherapy targeting TAM.

(source:internet, reference only)

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