Nanotechnology has the potential to make immunotherapy/chemotherapy combinations dramatically effective, even against aggressive tumors.
Nanotechnology has the potential to make immunotherapy/chemotherapy combinations dramatically effective, even against aggressive tumors, according to researchers at the University of Arizona Health Sciences.
Looking to find out more, BioSpace sat down with Jianqin Lu, B.Pharm., Ph.D., assistant professor of pharmaceutics and pharmacokinetics in the UArizona College of Pharmacy’s department of pharmacology and toxicology and associate member of the UArizona Cancer Center.
In preclinical studies, Lu and his team developed a nanocarrier and attached a chemo drug to it. This platform enables the chemotherapy drug camptothecin to synergize immune checkpoint blockade (ICB) therapies, delivering 23 times more chemotherapy to the tumor than freely-circulating forms of the chemotherapy with good tolerability. This resulted in a 5-fold reduction in tumor size. Notably, this approach appears effective against both mild and aggressive cancers.
This breakthrough, which was detailed recently in Nature Nanotechnology, is designed for cancer patients for whom current immunotherapies are ineffective. That includes 96% of all colorectal cancer patients.
“This is a game-changing and paradigm-shifting technology for chemotherapy,” Lu said. “It not only can enhance the therapeutic efficacy but also can minimize the systemic toxicities associated with chemotherapeutic agents, thus markedly improving the survival rate and the quality of life for cancer patients during the course of cancer treatments.”
Lu’s goal was to make immunotherapy and immuno/chemotherapies effective for more cancer patients. Checkpoint inhibitors have enormous potential to treat cancer, but they also have severe limitations, he pointed out. Namely, ICB therapies aren’t effective for many types of cancers. Likewise, chemotherapy has been used for decades and sometimes can switch immune-cold tumors to immune-hot tumors so they can be treated by immune checkpoint inhibitors.
The combination is interesting to many researchers, but it has challenges, too. ICB therapies combined with chemotherapy agents, such as camptothecin, for example, are potent anti-cancer agents but are unstable, poorly soluble in water and have serious side effects.
To overcome those limitations, Lu and his team turned to a nano-scaled delivery platform because of its established history of improving drug movement, therapeutic efficacy and toxicity.
More specifically, they attached camptothecin to sphingomyelin (a naturally-occurring lipid found on the surface of cells) to create nanovesicles called camptothesome-stabilized-camptothecine. These nanovesicles “elicit potent granzyme-B- and perforin-mediated cytotoxic T lymphocyte (CTL) responses,” the researchers wrote. They contain an immune checkpoint inhibitor that targets indoleamine 2,3-dioxygenase (IDO1), which is a key checkpoint. When combined with other inhibitors targeting PD-L1 and PD-1, the ensuing blockade thus eradicates the subcutaneous MC38 adenocarcinoma in a way that enables the immune system to remember the challenge and respond, thereby preventing tumor recurrence. Thus, efficacy is improved and toxicity is reduced.
In rodent models, the nanotherapeutic deeply penetrated the tumor and released its chemotherapy. “Our nanotherapeutic platform improved the blood circulation half-life (one of the key parameters in pharmacokinetics) of free chemotherapy by 51-fold and delivered 23.3-fold more drug into the tumor site. These improvements resulted in about 5-fold more tumor reduction than that of free chemotherapy,” Lu said.
It also “increased the maximum tolerated dose of chemotherapy by 23-fold,” he continued. “At the maximum tolerated dose, our nanotherapeutic did not cause any noticeable toxicity, while free chemotherapy showed severe toxicities for normal tissues, such as damage to liver and kidney tissues, and decreased immune cells.” Importantly, camptothesomes combined with ICB and folate targeting achieved complete metastasis remission in clinically relevant advanced orthotopic CT26-Luc tumors and late-stage B16-F10-Luc2 melanoma, according to the paper.
This novel nanotherapeutic platform also outperforms the tumor efficacy of ONIVYDE® (irinotecan liposome injection), a standard therapy for colorectal cancer.
Lu said this nanotherapeutic platform appears to be a first-of-its-kind delivery system and can be generalized to work with a variety of therapeutics. Consequently, this could be a means of enlarging the pool of patients for whom immunotherapy may become effective.
The next step is to conduct human trials. Lu and his team are working with oncologists at the University of Arizona Cancer Center in the hopes of launching a Phase I clinical trial to learn whether the nanotherapeutic platform has a demonstrable clinical impact. Meanwhile, “We are in the process of establishing a start-up company,” he said. “We welcome any interested pharmaceutical companies and/or venture capital to help us achieve the goal earlier.”
