By Erica Langan
Conventional cancer treatments such as chemotherapy and radiation focus on introducing harmful substances to the body in order to kill cancer cells (and whatever other healthy human cells happen to be in the line of fire). But wouldn’t it be amazing to harness the body’s own ability to fight foreign entities to kill cancer?
Just as the human immune system has the power to fight off foreign invaders that enter the body, it is also capable of targeting and destroying our own cells that become cancerous. However, cancer cells are very talented at evading this response, in part by suppressing the activity of specialized immune cells within the microenvironment of the tumor. Evolution has equipped some immune cells with checkpoint proteins that promote passivity instead of aggressiveness, providing an emergency “off switch” that can be harnessed by the body to restrict the overall magnitude of immune activity and prevent the unnecessary destruction of healthy, normal tissue. When each of these proteins on immune cells binds to a specific complementary protein found only on certain other cells, the immune cells are instructed not to attack that specific cell. By expressing these complementary proteins, many cancer cells manipulate this checkpoint protein mechanism to avoid detection and destruction by the immune system.
An important example of this system is the PD1/PDL1 protein combination. Programmed cell death protein 1 (PD1) is a checkpoint protein found on cytotoxic T cells that attenuates their responsiveness upon binding to its complementary protein, PDL1. Since many tumor cells express PDL1, they can avoid assault by these white blood cells which represent an important component of the anti-cancer immune response. To prevent this from happening, a type of cancer treatment called immune checkpoint blockade (ICB) therapy introduces special anti-PDL1 (α-PDL1) antibodies that prevent interactions between PD1 and PDL1, leaving cancer cells exposed and targetable by the immune system.
This therapy has demonstrated great efficacy for the treatment of some cancers but has some important shortcomings. A major issue is that the α-PDL1 antibodies often bind to the wrong tissues. PDL1 is also expressed by muscle, pancreatic, liver, vascular endothelial, and other cells, and using ICB therapy in these regions could cause the immune system to attack healthy human tissue. This problem is referred to as the “on-target but off-tumor” effect.
In an effort to address the issues with conventional ICB therapy, Dr. Dangge Wang from the Chinese Academy of Sciences in Shanghai, China and colleagues have engineered nanoparticles that selectively deliver α-PDL1 antibody to tumors. The nanoparticle, which contains α-PDL1 antibody, is specially designed to be activated by a certain protein produced in high quantities in tumors, which helps to avoid the on-target but off-tumor effect.
This nanoparticle is uniquely capable of remaining stable in the bloodstream during circulation while also accumulating at the tumor site. In combination with photodynamic therapy (a type of cancer therapy that uses a specific wavelength of light to activate agents that kill cancer cells), these engineered nanoparticles were successful in reducing the immunosuppressive nature of the tumor microenvironment. They were able to successfully prevent interactions between PDL1 expressed by tumor cells and PD1 expressed by immune cells, increasing the infiltration of the tumor by cytotoxic T cells. The nanoparticles improved the antitumor immune response, inhibited metastasis (the spread of tumors to other regions of the body), and even promoted long-term immune memory in mouse models of melanoma and lymphatic metastatic breast cancer. The researchers showed that this nanoparticle technology works better than normal ICB therapy alone or normal ICB therapy in combination with other treatments like chemotherapy and radiation.
However, additional work is still needed to improve this therapeutic method. Wang et al. hope to modify the nanoparticle design to enable the treatment of a greater variety of tumors. They explain that medical instruments could be refined to improve the photodynamic therapy that accompanies delivery of the nanoparticles, and other therapeutics (like radioisotopes or chemotherapeutics) could be integrated into this nanoplatform for more efficient and specific drug delivery.
The success of these engineered nanoparticles is promising, and Wang et al. believe that they could be used in conjunction with other ICB drugs to potentially both improve efficacy and reduce the side effects of targeted immunotherapy for cancer.
Wang D, Wang T, Yu H, et al. (2019) Engineering nanoparticles to locally activate T cells in the tumor microenvironment. Science Immunology, 4(37), 10.1126/sciimunol.aau6584. https://immunology.sciencemag.org/content/4/37/eaau6584
Image Attribution: “Killer_T_cells_surround_a_cancer_cell.” Date: August 2015. Description: Superresolution image of a group of killer T cells (green and red) surrounding a cancer cell (blue, center). When a killer T cell makes contact with a target cell, the killer cell attaches and spreads over the dangerous target. The killer cell then uses special chemicals housed in vesicles (red) to deliver the killing blow. This event has thus been nicknamed “the kiss of death”. After the target cell is killed, the killer T cells move on to find the next victim. Source: The National Institutes of Health. https://commons.wikimedia.org/wiki/File:Killer_T_cells_surround_a_cancer_cell.png