Researchers at Houston Methodist have invented a nanodevice that delivers immunotherapy medications directly to a tumor in a single, sustained-release dose, dramatically reducing treatment-related side effects.
Conventional immunotherapy, which involves systemic treatment administration, often results in significant side effects while failing to produce a sufficient antitumor immune response. Delivering immunotherapy medications intratumorally—directly within the tumor—has the potential to solve this problem, producing a more efficient antitumor response without the toxicity that results from exposing the whole body to immunotherapy drugs.
"We're in the middle of an exciting time in medicine, because if we can get [this device] to work, you decrease the toxicities to the patient," commented E. Brian Butler, MD, Chair of the Department of Radiation Oncology at Houston Methodist and co-senior author of the study, which has been published in the Journal of Controlled Release. "This offers the opportunity of treating locally and getting the systemic response without all the side effects."
What distinguishes the researchers' approach from other intratumoral delivery methods that are currently in development is the implantable nanodevice, which can be placed inside the tumor in a single, simple procedure and is capable of sustaining drug delivery over a lengthy period of time. In contrast, many of the other intratumoral delivery methods require repeated injections into the tumor and, in some cases, repeated invasive procedures.
"Our implant releases the drug in a constant manner until the entire amount is completely gone from the reservoir," stated the device's inventor, Alessandro Grattoni, PhD, Chair of the Department of Nanomedicine at the Houston Methodist Research Institute and co-senior author of the study. "Since it can deliver the immunotherapy by itself for weeks to potentially months, we would only need to place the device inside the tumor once and then the drug would be released autonomously for that long period of time."
In addition to working as a sustained release system, the researchers' nanofluidic-based device, called the nanofluidic drug-eluting seed (NDES), functions as a fiducial marker that can enable accurate delivery for image-guided radiation.
The NDES is inserted into the tumor using a minimally invasive trocar method similar to that used for brachytherapy seed insertion. Its constant and sustained drug delivery without need for injections or other clinical intervention results from physical and electrostatic nanoconfinement, which regulate the drug's diffusion.
The researchers tested the NDES on triple-negative breast cancer (TNBC), a rare type of breast cancer that lacks effective treatment options and is more capable of inducing an immune response than other breast cancer subtypes. In a mouse model of TNBC, NDES-mediated intratumoral release of the agonist monoclonal antibodies OX40 and CD40 activated local and systemic antitumor immune response and inhibited tumor growth compared with control mice. In addition, the mice treated with NDES-delivered CD40 demonstrated minimal liver damage, unlike those treated systemically.
"In this study we demonstrated in mice that our intratumoral delivery of immunotherapy was equally effective compared to systemic immunotherapy treatment," commented Dr. Grattoni. "The difference was that the systemic immunotherapy showed significant side effects, while our device delivered the same effective treatment without side effects. We were, in fact, able to completely eliminate side effects, which was very surprising to us."
Next, the researchers plan to combine NDES-delivered immunotherapy with radiation therapy in mouse models to see if it can surpass the results of systemically-delivered immunotherapy, rather than equaling them.
"We are hoping to go to patients within three years," stated Dr. Grattoni. "We would definitely improve on what is out there currently and what other groups are already studying."
For More Information
Chua CYX, Jain P, Susnjar A, et al (2018). Nanofluidic drug-eluting seed for sustained intratumoral immunotherapy in triple negative breast cancer. J Control Release, 285:23-34. DOI:10.1016/j.jconrel.2018.06.035