An interdisciplinary team of researchers at the UCLA Jonsson Comprehensive Cancer Center has developed a medicated patch that can deliver immune checkpoint inhibitors and cold plasma directly to tumors to help boost the immune response and kill cancer cells.
The thumb-sized patch has more than 200 hollow microneedles that can penetrate the skin and enter the tumor tissue.
The cold plasma is delivered through the hollow structure, destroying cancer cells, which facilitates the release of tumor-specific antigens and boosts an immune response.
The immune checkpoint inhibitors – antibodies that block checkpoint proteins, which interferes with immune system function and prevents the immune system from destroying cancer cells -are also released from the sheath of microneedles to boost the T cell-mediated anti-cancer effects.
In the study, which is published in the Proceedings of the National Academy of Sciences, the UCLA researchers found that delivering the two therapies to mice with melanoma using the patch enabled the immune system to better attack the cancer, significantly inhibiting the growth of the tumor and prolonging the survival of the mice.
The team also found that the therapy not only inhibit the growth of the targeted tumor, but it also could inhibit the growth of tumors that had spread to other parts of the body.
“Immunotherapy is one of the most groundbreaking advances in cancer treatment,” said study senior author Zhen Gu, professor of bioengineering at the UCLA Samueli School of Engineering and member of the Jonsson Cancer Center.
“Our lab has been working on engineering new ways to apply or deliver drugs to the diseased site that could help improve the effectiveness of cancer immunotherapy, and we found the patch to be a quite promising delivery system.”
The study is also the first to demonstrate that cold plasma can be effective in synergizing cancer immunotherapy. Plasma, which is usually hot, is an ionized gas that comprises more than 99% of the universe.
Here, cold plasma is generated by a small device operating at atmospheric pressure and room temperature. Therefore, cold plasma can be applied directly to the body – internally or externally.
“This study represents an important milestone for the field of plasma medicine,” said co-senior author Richard Wirz, professor of mechanical and aerospace engineering at UCLA Samueli.
“It demonstrates that the microneedle patch can realize the plasma delivery while also working with the drug to improve the effectiveness of cancer therapy.”
“Plasma can generate reactive oxygen species and reactive nitrogen species, which are a group of chemical species that can destroy cancer cells,” said Guojun Chen, who is the co-first author of the study and a postdoctoral fellow in Gu’s laboratory.
“Those cancers can then release tumor-associated antigens, which can enhance immune response to kill cancers,” said Zhitong Chen, who is the other co-first author and a postdoctoral fellow in Wirz’s lab.
The team tested the cold plasma patch on mice with melanoma tumors. The mice that received the treatment showed an increased level of dendritic cells, which are a specific type of white blood cells that alert the immune system of a foreign invader and initiate a T cell-mediated immune response.
The group of mice also showed delayed tumor growth compared to the untreated group and 57% were still alive at 60 days, while mice in other control groups had all died.
“This treatment strategy can potentially go beyond cancer immunotherapy,” said Gu, who is also a member of the California NanoSystems Institute at UCLA. “Integrated with other treatments, this minimally invasive method can be extended to treat different cancer types and a variety of diseases.”
The patch will have to go through further testing and approvals before it could be used in humans. But the team members believe the approach holds great promise.
Cancer immunotherapy is a promising strategy that activates the body’s immune system to fight tumors. Recent decades have witnessed numerous advances in this field.
Today, several powerful approaches including cancer vaccines 1–3, immune checkpoint blockade 4–6, and adoptive cell transfer 7–9, have achieved significant increases in antitumor immunity and patient survival in clinical trials.
These approaches have their own strengths and limitations, but active immunization by cancer vaccines is considered a key tool for effective cancer immunotherapy, and holds great promise for personalized cancer treatment 10, 11.
Cancer vaccines aim to activate and amplify tumor-specific T-cell immunity, allowing effector CD8+ T cells to seek, capture and eradicate cancer cells. Diverse types of antigens including viral vectors, bacterial strains, recombinant proteins, whole tumor lysates, nucleic acids, and synthetic peptides have been used for rational vaccine design 3, 12–14.
Unfortunately, a few antigens such as tumor lysates, nucleic acids, proteins and peptides suffer low immunogenicity 15, 16, owing to their low efficiency, degradation, or to lower uptake by antigen-presenting cells (APCs), thus eliciting insufficient vaccine-specific T-cell responses on their own.
Thus, cancer vaccines are usually used in combination with adjuvants or delivery systems 16–21 that can assist the activation of APCs such as dendritic cells (DCs), protect antigens from degradation, and improve their uptake by DCs, to prolong their duration in vivo and enhance their drainage to lymph nodes, whereby, they provoke a much stronger antigen-specific T-cell immune response.
Whereas, tumor immunosuppression can downregulate the activation of T-cells, inhibit T-cell infiltration in tumors and thereby decrease cancer-specific cytotoxic T-cell numbers or even cause T-cell anergy or exhaustion 4, 22.
In this regard, immune checkpoint blockade using monoclonal antibodies or small molecule drugs against programmed cell death protein-1 (PD-1), indoleamine 2,3-dioxygenase (IDO), or cytotoxic T lymphocyte antigen-4 (CTLA-4) signaling pathways has shown promising clinical antitumor activity in melanoma 5, 6.
Nevertheless, this approach suffers from low objective response rate, systemic toxicity, and unavailability to a growing range of malignancy types such as pancreatic and colorectal cancer.
In principle, engineered biomaterials including nanoparticles and microcapsules can encapsulate and deliver various immune-stimulatory cargoes such as antigens, cytokines and antibodies in a spatiotemporally controlled manner, either to facilitate antigen uptake by APCs, promote the stimulation of immune cells, to increase T-cell response, or remodel the tumorous microenvironment, to enhance immune checkpoint blockade 28–33.
For example, synthetic polymeric nanoparticles 34 and lipoprotein-mimicking nanodiscs 12 has been developed to generate strong antigen-specific cytotoxic T-cell responses and inhibit the growth of several types of tumors. Nanoparticle-based toll-like receptor (TLR) agonist delivery for macrophage polarization or DC activation can also enhance the efficiency of cancer immunotherapy 35–37.
Macroscale drug delivery systems such as mesoporous silica micro-rod scaffolds, implants and injectable hydrogels also could enhance the immunogenicity of cancer vaccines 38–45, stimulate the activation of host dendritic cells (DCs) and T-cell response, and delay tumor growth. Likewise, various biomaterials have also shown great promise for enhancing immune checkpoint blockade 26, 46–48.
Biomaterials-based immunomodulation may be a key strategy to significantly improve the antitumor T-cell response either by increasing vaccine immunogenicity or by reducing tumor immunosuppression, and combining vaccines with the inhibition of tumoral immunosuppression may further improve immunotherapy efficiency, and is worthy of further study.
Herein, we developed a self-assembled mPEG-b-poly(L-alanine) hydrogel to encapsulate a tumor vaccine comprised of tumor cell lysates (TCLs) and granulocyte-macrophage colony-stimulating factor (GM-CSF), which has been identified as a potent stimulator for the recruitment, phenotype modulation and proliferation of DCs, and has undergone clinical testing as a vaccine adjuvant 49, 50.
These were combined with dual immune checkpoint inhibitors to synergistically modulate T-cell immunity and inhibit the tumor immunosuppression. The sustained presentation of the tumor vaccine is supposed to persistently recruit and activate DCs directly in vivo, which then primes the tumor-specific effector CD8+T-cell response.
Meanwhile, extended release of inhibitors including anti-PD-1 and anti-CTLA-4 antibodies from the hydrogel enables the blockage of PD-1 and CTLA-4 pathways, reducing the production of regulatory T-cells (Tregs) in tumor.
Collaboratively, such a hydrogel-based combinatorial immunotherapy is expected to significantly augment tumor-infiltrating CD8+ T-cells, and consequently, increasing the efficiency of immunotherapy against B16F10 melanoma and 4T-1 tumors.
More information: Guojun Chen el al., “Transdermal cold atmospheric plasma-mediated immune checkpoint blockade therapy,” PNAS (2020). www.pnas.org/cgi/doi/10.1073/pnas.1917891117