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Colette Bilynsky
The wonders of cellular therapies and immunotherapies have been often discussed here on Oncobites. But one of the challenges here is that these strategies are dependent on immune cells’ ability to reach tumors and still function. However, tumors will often try to evade and stop the immune system from targeting them using a variety of methods.
Tumors are made of a collection of both cancer cells and tumor-associated cells. These tumor associated cells are fibroblasts (cells that create the support proteins for tissues) and a variety of immune cells, like dendritic cells and macrophages. Macrophages in particular play an integral role in helping the tumors evade the immune system. In order to best respond to what is needed, macrophages “polarize” along a spectrum in response to signals within the body. Macrophages will polarize towards M1 (pro-inflammatory) in response to viruses and bacteria, which helps them recruit and activate other immune cells to stop the infection. At the other end of the spectrum, in the event of an injury or wound, macrophages will polarize towards an M2 (anti-inflammatory) type which helps these wounds heal and the surrounding tissue remodel. Cancer cells will influence the macrophages within the tumor to activate towards an M2 type, which suppresses the activity of other immune cells and helps the tumor itself grow and spread.
Because of their role within a tumor, macrophages have often been targeted as a potential cellular therapy. These therapies generally were macrophages activated outside of the body towards an M1 (pro-inflammatory) state. These activated macrophages would then be administered to the patient [1]. The major problem with this strategy is that the macrophages would end up reverting to an M2 activation once they reached the tumor because the tumor was still secreting signaling molecules that influenced the macrophages towards this anti-inflammatory state [1].
To solve this issue, cellular “backpacks” were created. Essentially, researchers in the Mitragotri group created tiny soft discs that stick to the macrophages. These backpacks kept the cells proinflammatory even as they reach the tumor [2]. The backpacks were made of polymers that naturally degrade within the body that are constructed in 4 distinct layers. The first is a cell-adhesive layer made of hyaluronic acid and poly(allylamine) hydrochloride which helped with its printing. Then there was a layer of polymer to provide structural support, then a layer of IFN-y (a signaling molecule that tells the macrophages to be M1) with another polymer to provide stability, and then finally another structural support layer. They found that the backpacks stuck to around 87% of the macrophages.
To test their ability to treat cancer, the researchers tested these backpack-laden macrophages on mice with breast cancer tumors. That cancer model was chosen because it is highly immunosuppressive, resistant to chemotherapy, and challenging to treat with CAR-T cell therapy. The mice that were treated with backpack-laden macrophages had significantly less tumor growth than controls, less metastatic tumors in the lungs, and significantly longer survival [2]. The researchers also confirmed that the backpack-laden macrophages kept their M1 activation when they reached the tumor, and they even influenced the macrophages within the tumor to adopt a more M1, anti-tumoral, activation state [2].
While this study focused on the backpack-laden macrophage’s ability to treat breast cancer, another group of researchers from the Batrakova lab demonstrated the potential of this strategy to treat brain cancers [3]. While their backpacks were made of different materials, they demonstrated that the backpack-laden macrophages could cross the blood-brain barrier in a mouse model. Their study was not cancer-focused, and instead focused on how this strategy could possibly treat neurodegenerative disorders like Parkinson’s and Alzheimer’s.
The Mitragotri group has used this backpack strategy on other cell types as well. They put backpacks on red blood cells to successfully treat lung metastasis in mice, decreasing the number of mets and increasing the survival of the mice treated with the backpack-laden red blood cells compared to controls [4]. The group has also put backpacks on monocytes to target inflamed tissue (seen in cancer, Alzheimer’s, Parkinson’s, and arthritis) [5]. They found that the backpack-laden monocytes could successfully target inflamed skin [5]. These backpack-laden monocytes have also been used to treat multiple sclerosis, which is an autoimmune condition without a cure [6].
Cellular therapies hold plenty of promise, even though CAR T cell therapy (perhaps the most well known example) only treats a very specific subset of cancers. This backpack strategy allows for the manipulation of cellular behavior without needing to genetically modify the cells like in CAR therapies. I’ll continue to watch these studies progress with excitement, and hope to see this strategy translated into something clinical so that patients can benefit.
Edited by Sakshi Dhavale
Works Cited:
OncoBites 
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