SEATTLE—The immune system is a key focal point in cancer. Given cancer's ability to constantly mutate to avoid immune cells or even engage such cells to protect tumors, harnessing or tweaking immune functions could hold the key to more effective treatments. The field of immuno-oncology is driven by interest in this approach, and recent news out of the Fred Hutchinson Cancer Research Center could provide a new tool for such efforts. The study, “Genetic programming of macrophages to perform anti-tumor functions using targeted mRNA nanocarriers,” was published in Nature Communications.
Some approaches for “recalibrating” the immune system entail training T cells to recognize certain proteins or enzymes on the surface of tumor cells, replicating those T cells in the lab, and then reintroducing the trained cells into the body. The Fred Hutch discovery offers a more specialized method of reprogramming immune cells that they say avoids toxicities seen in similar approaches.
Their method uses nanotechnology, specifically using “minuscule, dissolving polymer particles [that] can ferry genetic instructions that temporarily rewire certain immune-suppressing cells into cancer fighters without causing body-wide toxicities,” according to a press release authored by Sabrina Richards of the Fred Hutch News Service.
The cells in question are macrophages, a type of white blood cell. Macrophages are generally grouped as either M1 or M2 macrophages. As explained in the Nature Communications study, “Just like in healthy tissues, where macrophages have a remarkable ability for responding to environmental cues, TAMs are educated by the tumor microenvironment they experience. This produces multiple phenotypes that have a broad range of functions. TAM phenotypes can be described along a linear scale, where M1 and M2 phenotypes represent the two extremes (comparable to the TH1–TH2 classification)2,3. M1 macrophages are recognized as classically activated macrophages that can phagocytose pathogens. More importantly, these cells have anti-tumoral properties.”
“Unfortunately, other macrophages are polarized into the M2 phenotype,” the authors continue. “These decrease inflammation, encourage tissue repair, and provide pro-tumoral effects6. In established progressive tumors in humans, TAMs usually express an M2-like phenotype, and thus promote tumor progression, metastasis, and resistance to chemotherapy7,8,9. It is therefore of key interest in cancer research to create strategies that can reprogram TAMs from a pro-tumoral (M2-like) to an anti-tumor (M1-like) phenotype and thereby induce immune effects that can bring about tumor regression. However, as yet there are no methods that can enable physicians to rationally and selectively reprogram TAMs for therapeutic purposes.”
Previous efforts to do so, they note, have been “nonspecific and elicit systemic inflammation.”
Stephan and his team are looking to tackle this issue with a bioengineering twist. Their nanoparticles can be packed with genetic instructions to control cell functions, and they dissolve once in the cell.
“The nanoparticles are designed to be nonimmunogenic and not activate the immune system by themselves. They’re not designed to release a drug,” Stephan explained. “We’re programming the immune system from within.”
In this study, Stephan and Dr. Fan Zhang, a postdoctoral fellow on Stephan's team, focused on synthetic mRNA molecules—specifically, in vitro-transcribed mRNA—as the genetic instructions to be included. The mRNA nanoparticles contain instructions for the production of two macrophage-stimulating proteins, which, as noted in Richards' piece, “allows them to reprogram macrophages without touching their DNA.” Also included were molecules to ensure the nanoparticles would reach and be “eaten” by macrophages.
The team tested the nanoparticles in mice with ovarian cancer, administering them once a week via abdominal catheter for nine weeks—and the results were promising. Forty percent of mice saw complete clearance of tumors in the nanoparticle group, and mice in this group also lived an average of 142 days, compared to an average of 60 days for the control group. Mice with the mRNA-laden nanoparticles presented with increased populations of inflammatory macrophages, and also saw more T cells penetrate their tumors. When tested in mice with glioblastoma and metastatic melanoma, three intravenous infusions a week for three weeks led to comparable increases in survival times as those seen in the mice with ovarian cancer.
Stephan explained that immature macrophages are being intercepted before they can be coopted by the tumors, adding that “We are targeting these cells that the tumor wants to recruit and we make sure that they don't turn into suppressor cells, but they turn into the exact opposite.”
“We show that we can affect a lot of different immune cells, and we haven’t seen any of the toxicities that could be associated with treatments that modulate the immune system throughout the body, such as checkpoint inhibitors,” he said.
While this has obviously yet to be translated into humans, the team did demonstrate that nanoparticles with mRNA that encodes human proteins were also capable of reprogramming the macrophages.
The authors report that there could be potential for using this nanoparticle approach in combination with other treatments, saying “Although we will test IRF5/IKKβ NPs as a monotherapy first, our platform could ultimately reveal its full potential when used in synergy with existing immunotherapies, (e.g., T cell therapies, cancer vaccines, or checkpoint blockade inhibitors) by creating a therapeutic window for patients, thus stimulating a stronger overall immune response … Considering the substantial role TAMs play in cancer proliferation, angiogenesis, invasion, and metastasis44, we suspect that our platform could be used to its best advantage as a companion therapeutic for patients that are refractory to other treatments such as immune checkpoint inhibitors, cancer vaccines, T cell therapies, or antibody approaches.”
Moving forward, this technology will be licensed exclusively to Tidal Therapeutics, a Fred Hutch spinoff company, of which Stephan is a scientific founder. Plans are underway for a Phase 1 trial of these nanoparticles in women with ovarian cancer.
“My expectation is that we can prolong the survival of these patients [with ovarian cancer] without any additional side effects,” Stephan said. “It’s a therapy that is designed to be selective and not destructive.”