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.