Research led by University of Massachusetts Amherst scientists demonstrated that a nanoparticle (NP)-based vaccine can effectively prevent melanoma, pancreatic cancer, and triple-negative breast cancer in mice. The study showed that, depending on the cancer type, up to 88% of the vaccinated mice remained tumor-free, and the vaccine reduced—and in some cases completely prevented—cancer spread.
“By engineering these nanoparticles to activate the immune system via multi-pathway activation that combines with cancer-specific antigens, we can prevent tumor growth with remarkable survival rates,” said research lead Prabhani Atukorale, PhD, assistant professor of biomedical engineering in the Riccio College of Engineering at UMass Amherst. Atukorale is corresponding author of the team’s published paper in Cell Reports Medicine, titled “Super adjuvant” nanoparticles for platform cancer vaccination.”
The Atukorale Lab draws inspiration from how pathogens naturally stimulate the immune system. To mount a strong immune response, the body requires multiple “danger” signals triggered through different pathways. “In recent years, we have come to understand how important the selection of the adjuvant is because it drives the second signal that is needed for the correct priming of T and B cells,” said Atukorale.
Vaccines—regardless of the target disease—contain two primary components, the antigen and an adjuvant. The antigen is the piece of the disease-causing pathogen (in this study, cancer cells) that the immune system can be trained to target. The adjuvant is a substance that activates the immune system to recognize the antigen, treat it as a foreign intruder, and eliminate it. “Vaccines have two essential components: an antigen, which is uniquely expressed on the pathogen (or cancer cell), and an adjuvant, which activates the innate costimulatory signaling critical for priming an adaptive immune response,” the authors wrote.
However, just like oil and water, many of the most promising adjuvants for cancer immunotherapy do not mix well at the molecular level. “While vaccination has emerged in recent years as a powerful frontier in the development of effective cancer therapies by training adaptive immune cells to recognize and eliminate tumor cells, effective adjuvanticity has remained a hurdle,” the investigators further commented.
To overcome this, the Atukorale Lab has engineered a lipid-based “super adjuvant” nanoparticle that is capable of stably encapsulating and co-delivering two distinct immune adjuvants that activate immunity in a coordinated, synergistic way. “Our lipid-based NP platform co-encapsulates agonists of the stimulator of interferon genes (STING) and Toll-like receptor 4 (TLR4) pathways to promote synergistic production of type I interferons and other proinflammatory cytokines in innate antigen-presenting dendritic cells and macrophages,” they explained.
Previous research by the lab had shown that the novel nanoparticle-based drug design can shrink and clear cancer tumors in mice. The newly reported work has shown how it can also work preventively.
For their newly reported study, the team paired the nanoparticle system with well-characterized melanoma peptides (antigens), similar to how a flu shot typically contains parts of the inactivated flu virus. The formulation activated immune system T cells, priming them to recognize and attack this type of cancer. Three weeks later, the mice were exposed to melanoma cells.
The study results showed that 80% of the “super adjuvant”-vaccinated mice remained tumor-free and survived until completion of the study at 250 days. In comparison, all of the unvaccinated mice and mice vaccinated with traditional vaccine systems, non-nanoparticle formulations, developed tumors. None of these animals survived longer than 35 days.
The super adjuvant vaccine also protected against the spread of cancer to the lungs. When exposed to melanoma cells systemically, which mimics how cancer metastasizes, none of the nanoparticle-vaccinated mice developed lung tumors, while all of the mice in the other test groups did develop lung tumors.
Atukorale describes this as “memory immunity,” noting, “That is a real advantage of immunotherapy, because memory is not only sustained locally. We have memory systemically, which is very important. The immune system spans the entire geography of the body.”
Metastases across the board are the highest hurdle for cancer, said Atukorale. “The vast majority of tumor mortality is still due to metastases, and it almost trumps us working in difficult-to-reach cancers, such as melanoma and pancreatic cancer.”
The initial testing reported was conducted using a vaccine with well-characterized antigens that matched the type of cancer. However, developing antigens tailored to different cancers requires whole-genome sequencing or complex bioinformatics screening. For the second part of the study, the researchers used killed cancer cells derived directly from the tumor mass, called tumor lysate. After vaccination with the nanoparticle lysate vaccine, the mice were then exposed to melanoma, pancreatic ductal adenocarcinoma, or triple-negative breast cancer cells.
The researchers observed striking tumor rejection rates: 88% of mice for pancreatic cancer, 75% of mice for breast cancer, and 69% of mice for melanoma rejected tumors. All of these tumor-free, nanoparticle-vaccinated mice remained tumor-free when the researchers tested if the cancer would metastasize, given systemic exposure.
In their paper, the researchers wrote in summary, “Compared to empty NPs and free agonists, dual-adjuvant NPs administered with antigenic peptides or tumor cell lysate promote increased antigen processing and presentation, drain efficiently to nearby lymph nodes, increase polyfunctional tumor-specific T and B cells, and improve tumor-free outcomes upon vaccination and subsequent challenge with multiple aggressive tumor cells.”
This robust T-cell response is possible because of the particular nanoparticle design of the vaccine. “The tumor-specific T-cell responses that we are able to generate—that is really the key behind the survival benefit,” said Griffin Kane, PhD, a postdoctoral research associate at UMass Amherst and first author on the paper. “There is really intense immune activation when you treat innate immune cells with this formulation, which triggers these cells to present antigens and prime tumor-killing T cells.”
The researchers say that their nanoparticle design offers a platform approach that could be used across multiple cancer types. “Our studies demonstrating efficacy with antigenic peptides or tumor lysate highlight the advantages of biocompatible lipid-based systems and make the case for a modular platform approach for next-generation cancer vaccination,” they noted.
They envision that the platform could be applied to create both therapeutic and preventative regimens, particularly for individuals at high risk for cancer. This is an idea that Atukorale and Kane have turned into a startup called NanoVax Therapeutics. “The real core technology that our company was founded on is this nanoparticle and this treatment approach,” noted Kane. “This is a platform that Prabhani developed. The startup lets us pursue these translational efforts with the ultimate goal of improving patients’ lives.”
Atukorale and Kane next plan to extend this technology to a therapeutic vaccine and have already taken the initial de-risking steps in translation.