Brachytherapy and intratumoral injection are two approaches that deliver cancer treatment via a catheter or needle that is placed directly into a tumor. Brachytherapy typically involves placement of catheters to deliver radioactive seeds into a tumor to provide targeted radiation therapy. Intratumoral injection is an emerging delivery method for immunotherapies and cell- or viral-based therapies. To date, these therapies have not been used in combination, but preclinical research by a team of Department of Human Oncology researchers and UW biomedical engineering students has demonstrated the feasibility of this approach.
The research team created and tested a multi-purpose catheter to deliver both therapies with a single catheter insertion. The idea was first conceptualized by DHO Assistant Professor, Dr. Zachary Morris. Interestingly, he reports, “The idea came to me during a dream one night while on vacation. I woke up and quickly sketched out a design on a pad of paper that I had on my nightstand.” It took two years of design and preclinical testing to turn that concept into a functional prototype.
“If we used a two-insertion approach where you have a standard catheter and injection via needle, it would mean twice the number of insertions, twice the risk of inadvertently hitting structures we’re trying to avoid, and increased risk for bleeding and infection,” says Justin Jagodinsky, an MD/PhD student in the Morris lab. “The benefit of this multi-purpose catheter approach is that it allows a single insertion, so we’re not likely to change the risk from catheter insertion while permitting combination of brachytherapy with local delivery of injectable agents.”
The multi-use catheter consists of an outer tube and an inner syringe tube that can be filled with the injectable agent. Testing with a water phantom showed that the catheter does not affect brachytherapy treatment planning dosimetry. In vitro and in vivo injection testing showed that the catheter was able to accurately deliver the injectable agent.
In vivo testing also demonstrated that intratumoral injection enables delivery of therapy with reduced toxicity. Mice given an intratumoral injection of cyclophosphamide, a chemotherapeutic with potential applications as an immunomodulator, showed no significant reduction in lymphocyte count (a measure of toxicity); whereas, those that received the same drug systemically had significant lymphocyte reduction.
Testing in mice also demonstrated that brachytherapy and intratumoral injection can be safely co-administered and provide clinical benefit. Brachytherapy combined with intratumoral injection of IL-2 (immunotherapy molecule) resulted in prolonged survival without any observed toxicity. (Toxicity of intravenous administration of IL-2 often limits its use in human patients.)
Although the diameter of this catheter is larger than that of a standard brachytherapy catheter, the larger size did not lead to more bleeding or increased time for wound healing.
The catheter also enabled the researchers to inject contrast agent into the tumor. This could allow for novel imaging techniques. For example, injecting contrast agent could enable researchers to measure how long an injected agent remains in a tumor. In the clinic, the ability to deliver an immunotherapy mixed with contrast agent could be used to monitor how the agent behaves over time. “This personalized imaging of the tumor and the injected agent could enhance patient care,” Jagodinsky says.
With any combined cancer therapy, timing is a critical factor, Jagodinsky says. “We envision delivering the injectable agent at about the same time as radiation. However, sometimes immunotherapy is more effective if given at a delayed interval after radiation.” To address this, the team has established additional collaborations to develop nanoparticles and microparticles that might allow for slow or delayed release of immunotherapies so these could be injected around the same time as brachytherapy.
The next step, Morris says, is to identify an industry partner to help manufacture the catheter. “We’re very optimistic about the potential benefits of combining brachytherapy with intratumoral injection of additional cancer therapies. Once we have a supply of these catheters, we are ready to immediately move forward with clinical testing.”