Although combining radiation therapy (RT) with immune checkpoint blockade (ICB) could activate an in situ vaccine effect, RT limits the tumor antigen presentation and cannot overcome suppressive mechanisms in the tumor microenvironment (TME), limiting the vaccine effect.
An article published in the journal Nature Communications presented a solution to overcome the above challenges by developing PIC multifunctional nanoparticles based on poly-(L-lysine) (PLL), CpG oligodeoxynucleotide (CpG), and iron oxide nanoparticles (ION). The designed nanoparticles served as radiation sensitizers, improved the tumor antigen presentation, increased the M1:M2 ratio of tumor-associated macrophages, and enhanced the stimulation of a type I interferon response combined with RT.
The therapy using the combination of RT, PIC nanoparticles, and ICB in immunologically “cold” murine tumor models improved the tumor response, increased the survival rate, and activated the tumor-specific immune memory. Utilizing the designed PIC nanoparticles in RT evoked the in situ vaccine effect, potentiated adaptive anti-tumor immunity, and augmented the response to ICB and other potential immunotherapies.
Role of Nanoparticles in Cancer Immunotherapy
Despite the success of cancer immunotherapy, patients with immunologically “cold” tumors are less likely to respond to ICB therapy. The “cold” tumors are characterized by limited immune cell infiltration and low neoantigen load. The in situ cancer vaccination converts a patient’s tumor into a nidus to present tumor-specific antigens and to stimulate and diversify anti-tumor T cell response. Thus, improving the response rates of immunologically “cold” tumors.
At least half of cancer patients receive RT at some point in their cancer treatment which helps in activating the in situ vaccine response. RT stimulates the immunogenic cell apoptosis, increases tumor infiltration by immune cells, and enhances the immune-mediated killing of tumor cells. Although RT may induce many favorable effects in the tumor microenvironment (TME), it may also lead to detrimental effects on cells due to a lack of specificity.
Due to the development of nanotechnology, nanomaterials with heavy metals showed promising radio-sensitization to enhance the favorable RT outcomes, such as gold and silver nanoparticles, which can efficiently absorb, scatter, emit radiation energy, and are easily eliminated by metabolism. Recently, cancer immunotherapy has emerged as a promising treatment, and immune checkpoint regulation has the potential property to improve clinical outcomes in cancer immunotherapy.
Multifunctional Nanoparticles to Potentiate the In Situ Vaccination Effect
The cancer immunotherapy resistant “cold” tumors are characterized by low tumor neoantigen load, few tumor-infiltrating effector T cells, and activation of immune suppressive mechanisms in TME. Previously conducted clinical studies confirmed the safe combination of RT and ICB in improving response and survival rate, particularly in patients with “cold” tumors.
Besides the above advantages, RT was also reported to cause detrimental local effects on the TME. To increase the capacity of RT in eliciting in situ vaccination, the combination of RT with the therapeutic agent was hypothesized to augment the effect of RT in activating T-cell immunity.
In the present work, PIC nanoparticles were designed to improve the in situ vaccine effect of RT, facilitate anticancer response against “cold” tumors, and increase their response to ICBs. The results suggested that this approach could offer an effective strategy that permits the use of off-the-shelf treatment in realizing in situ vaccine effect. Here a patient’s tumor is transformed into nidus to present tumor-specific antigens, stimulating and diversifying the anti-tumor T cell response against the patient’s cancer cells.
Additionally, combining anti-CTLA-4 with PIC nanoparticles and RT in situ vaccination showed greater tumor response, improving the survival rate and tumor-specific immune memory compared to RT or PIC nanoparticles or combined treatment. Moreover, the mouse model treated with PIC nanoparticles + RT or PIC nanoparticles + RT + anti-CTLA-4 did not show any hepatic, gastrointestinal, renal, or autoimmune toxicities, confirming the biosafety of the proposed strategy.
Conclusion
To summarize, the present work demonstrated that the designed PIC nanoparticles had the advantages of reproducibility and scalability. Following RT, the nanoparticles modulated the tumor-immune microenvironment, favoring the activation of an in situ vaccine effect.
Immunotherapies and ICBs are extensively used to treat cancer patients. However, the limiting response of “cold” cancers to these therapies was an issue of concern. The multifunctional PIC nanoparticles resolved the above issue by potentiating the vaccination effect and augmenting the response rate of “cold” cancers to ICBs.
Thus, the results confirmed the promising application of PIC nanoparticles in combination with ICB and RT and its translation to the preclinical and early phases of clinical trials in treating metastatic cancers.
News
Platelet-inspired nanoparticles could improve treatment of inflammatory diseases
Scientists have developed platelet-inspired nanoparticles that deliver anti-inflammatory drugs directly to brain-computer interface implants, doubling their effectiveness. Scientists have found a way to improve the performance of brain-computer interface (BCI) electrodes by delivering anti-inflammatory drugs directly [...]
After 150 years, a new chapter in cancer therapy is finally beginning
For decades, researchers have been looking for ways to destroy cancer cells in a targeted manner without further weakening the body. But for many patients whose immune system is severely impaired by chemotherapy or radiation, [...]
Older chemical libraries show promise for fighting resistant strains of COVID-19 virus
SARS‑CoV‑2, the virus that causes COVID-19, continues to mutate, with some newer strains becoming less responsive to current antiviral treatments like Paxlovid. Now, University of California San Diego scientists and an international team of [...]
Lower doses of immunotherapy for skin cancer give better results, study suggests
According to a new study, lower doses of approved immunotherapy for malignant melanoma can give better results against tumors, while reducing side effects. This is reported by researchers at Karolinska Institutet in the Journal of the National [...]
Researchers highlight five pathways through which microplastics can harm the brain
Microplastics could be fueling neurodegenerative diseases like Alzheimer's and Parkinson's, with a new study highlighting five ways microplastics can trigger inflammation and damage in the brain. More than 57 million people live with dementia, [...]
Tiny Metal Nanodots Obliterate Cancer Cells While Largely Sparing Healthy Tissue
Scientists have developed tiny metal-oxide particles that push cancer cells past their stress limits while sparing healthy tissue. An international team led by RMIT University has developed tiny particles called nanodots, crafted from a metallic compound, [...]
Gold Nanoclusters Could Supercharge Quantum Computers
Researchers found that gold “super atoms” can behave like the atoms in top-tier quantum systems—only far easier to scale. These tiny clusters can be customized at the molecular level, offering a powerful, tunable foundation [...]
A single shot of HPV vaccine may be enough to fight cervical cancer, study finds
WASHINGTON -- A single HPV vaccination appears just as effective as two doses at preventing the viral infection that causes cervical cancer, researchers reported Wednesday. HPV, or human papillomavirus, is very common and spread [...]
New technique overcomes technological barrier in 3D brain imaging
Scientists at the Swiss Light Source SLS have succeeded in mapping a piece of brain tissue in 3D at unprecedented resolution using X-rays, non-destructively. The breakthrough overcomes a long-standing technological barrier that had limited [...]
Scientists Uncover Hidden Blood Pattern in Long COVID
Researchers found persistent microclot and NET structures in Long COVID blood that may explain long-lasting symptoms. Researchers examining Long COVID have identified a structural connection between circulating microclots and neutrophil extracellular traps (NETs). The [...]
This Cellular Trick Helps Cancer Spread, but Could Also Stop It
Groups of normal cbiells can sense far into their surroundings, helping explain cancer cell migration. Understanding this ability could lead to new ways to limit tumor spread. The tale of the princess and the [...]
New mRNA therapy targets drug-resistant pneumonia
Bacteria that multiply on surfaces are a major headache in health care when they gain a foothold on, for example, implants or in catheters. Researchers at Chalmers University of Technology in Sweden have found [...]
Current Heart Health Guidelines Are Failing To Catch a Deadly Genetic Killer
New research reveals that standard screening misses most people with a common inherited cholesterol disorder. A Mayo Clinic study reports that current genetic screening guidelines overlook most people who have familial hypercholesterolemia, an inherited disorder that [...]
Scientists Identify the Evolutionary “Purpose” of Consciousness
Summary: Researchers at Ruhr University Bochum explore why consciousness evolved and why different species developed it in distinct ways. By comparing humans with birds, they show that complex awareness may arise through different neural architectures yet [...]
Novel mRNA therapy curbs antibiotic-resistant infections in preclinical lung models
Researchers at the Icahn School of Medicine at Mount Sinai and collaborators have reported early success with a novel mRNA-based therapy designed to combat antibiotic-resistant bacteria. The findings, published in Nature Biotechnology, show that in [...]
New skin-permeable polymer delivers insulin without needles
A breakthrough zwitterionic polymer slips through the skin’s toughest barriers, carrying insulin deep into tissue and normalizing blood sugar, offering patients a painless alternative to daily injections. A recent study published in the journal Nature examines [...]
