Novel nanotechnology triggers powerful therapeutic anti-tumor immune responses against multiple types of cancer

Novel nanotechnology triggers powerful therapeutic anti-tumor immune responses against multiple types of cancer

A study from Ludwig Cancer Research has developed a novel nanotechnology that triggers powerful therapeutic anti-tumor immune responses and demonstrated its effectiveness in mouse models of several types of cancer. Led by co-director Ralph Weichselbaum, researcher Wenbin Lin and postdoctoral fellow Kaiting Yang at the Ludwig Center in Chicago, the study describes the synthesis, mechanism of action and preclinical evaluation of the nanoparticle loaded with a drug that activates a protein central to efficiently induce anti-cancer immunity. The study, which overcomes significant technical barriers to target this protein stimulator of interferon genes, or STING, for cancer therapy, appears in the current issue of Nature Nanotechnology.

The nanoparticles developed by the Lin lab release a drug that targets macrophages and can activate powerful antitumor immune responses that extend survival in mice carrying a variety of tumors. In combination with radiation and immunotherapy, they even help control “cold tumors” that are otherwise almost completely insensitive to immune attacks.”

Chicago Center co-director Ralph Weichselbaum

STING is part of the cellular recognition system for DNA fragments produced by infections or cancer treatments that damage DNA, such as radiation therapy and some chemotherapies. Its activation promotes inflammation and drives immune cells such as macrophages and dendritic cells to process and present cancer antigens to T cells, helping to stimulate and direct the immune attack on tumors. Although STING is a valuable target for drug development, the drug-like molecules that can activate the molecular sensor – known as cyclic dinucleotides (CDNs) – have been plagued by problems such as poor bioavailability, low stability and high toxicity in the absence of any means to specifically target them to tumors.

To better target such drugs, Weichselbaum, Lin, Yang and colleagues encapsulated a type of CDN in self-assembling spherical particles called nanoscale coordination polymers. A single dose of the nanoparticles, called ZnCDA (due to the zinc ions in their core), suppressed tumor growth in two mouse models of colon cancer: a subcutaneously injected solid tumor and a model of liver metastases. ZnCDA also prolonged survival in a model of B-cell lymphoma, suppressed tumors in melanoma and prostate cancer models, and induced antitumor effects in a model of a type of lung cancer resistant to STING activators.

Nanoparticles injected into the blood tend to accumulate in tumors because their malformed blood vessels are leaky and tumors have poor drainage systems. However, the researchers found that ZnCDA accumulated in tumors at levels too high to be due to passive accumulation alone.

"The accumulation of ZnCDA also activates STING in the cells lining tumor blood vessels, and this disrupts the tumor vasculature, increasing its leakiness and increasing the accumulation of the nanoparticles," Lin said. “In a sense, the nanoparticles drive their own delivery to malignant tissues, limiting toxicity and increasing drug delivery efficiency.”

Macrophages in tumors exist in a biological gradient between two states or phenotypes: one, known as M1, in which they stimulate anti-tumor immune responses and attack cancer cells themselves—literally eating them up—or another (M2), in which they support the proliferation and survival of cancer cells.

"We found that ZnCDA is particularly well taken up by a subpopulation of macrophages, in which it switches on gene expression programs that both push them into the M1 state and promote their presentation of cancer antigens to T cells," Yang said.

The researchers also tested ZnCDA's therapeutic potential against two types of tumors, pancreatic cancer and glioblastoma. Both diseases are generally incurable and aggressive, characterized by cold tumors that are resistant to radiation therapy and all existing immunotherapies.

The researchers found that ZnCDA treatment made a mouse model of pancreatic cancer susceptible to anti-PD-L1 immunotherapy, thereby extending the survival of tumor-bearing mice. When radiation therapy was added to the regimen, the increase in survival was even more dramatic. The researchers also showed that ZnCDA could cross the blood-brain barrier and accumulate in gliomas, where it attracted T cells to tumors and, when combined with anti-PD-L1 immunotherapy, extended the survival of treated mice. Adding radiation therapy to the mix again extended survival.

With the proof of concept in hand, researchers are now ready to translate this nanotechnology for future clinical use.

Source:

Ludwig cancer research

Reference:

Yang, K., et al. (2022) Zinc-cyclic di-AMP nanoparticles target and suppress tumors through endothelial STING activation and tumor-associated macrophage resuscitation. Nature nanotechnology. doi.org/10.1038/s41565-022-01225-x.

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