Dr. Ashish Ranjan is an Associate Professor and the Kerr Chair in Oklahoma State University’s College of Veterinary Medicine. He is a veterinarian scientist who studies how focused ultrasound can noninvasively treat cancer and non-healing wounds in dogs and cats.
Beyond providing a range of focused ultrasound—based cancer treatment, Dr. Ranjan’s group has been engineering nanoparticles and focused ultrasound equipment. The team’s nanoparticles can be customized for use with various disease models and focused ultrasound systems, and their novel focused ultrasound device may one day be used in veterinary practices across the globe. We recently interviewed Dr. Ranjan to learn more about how using focused ultrasound to treat pets may also be advancing medicine for their owners.
Focused Ultrasound Work
When and how did you become interested in focused ultrasound?
I was always interested in noninvasive or minimally invasive cancer therapy. During my three-year visiting fellowship in Brad Wood’s laboratory at the National Institutes of Health (NIH), we utilized focused ultrasound—induced hyperthermia to release chemotherapeutics from temperature-sensitive liposomes in solid tumors. The resulting publications from our work garnered much scientific interest and have now been widely cited, because they were among the early studies demonstrating the application of focused ultrasound for targeted chemotherapy. These works spurred my interest in the focused ultrasound treatment modality.
What are your areas of interest?
Our group primarily studies the use of focused ultrasound with nanoparticles for improving chemo-immunotherapy outcomes in solid tumors. Specifically, we are interested in understanding the role of focused ultrasound—induced alterations of tumor immune microenvironment on local and systemic clearance of malignant disease. We are also using it to treat non-healing bone infections and soft tissue wounds. Because non-healing wounds are typically infected with drug-resistant bacteria, we study the role of focused ultrasound in reversing or reprogramming the wound microenvironment to make it more responsive to antibiotics.
Why do you make your own nanoparticles?
When I completed my PhD in nanomedicine, I gained a wealth of experience in the various types of nanoparticles and their applications for different disease models. Making our own nanoparticles allows us to tailor the particles to the indication, the disease model, and the focused ultrasound system. As we change parameters, we synthesize nanoparticles that best work in that specific environment. This allows us to address problems from the focused ultrasound perspective, and it is especially helpful in cancer immunotherapy. We call this “device-directed nanomedicine,” because it allows us to have more control, be more specific, and – potentially – develop intellectual property that can be commercialized. Making nanoparticles also provides an opportunity to collaborate with other groups that use them.
What mechanisms and clinical indications do you study?
We use many focused ultrasound mechanisms, including ablation, hyperthermia, drug delivery, immunotherapy, and histotripsy. For cancer, our initial focus was on drug delivery; but more recently, we have been transitioning to immunotherapy induced by histotripsy. We have been changing the microenvironment to make tumors more responsive to immunotherapy. In fact, after a successful preclinical study, we are in the process of initiating a new clinical trial using histotripsy for enhancing immunotherapy in canine patients.
Which focused ultrasound systems are you currently using?
We currently use a dry-type, ultrasound-guided Alpinion system in the veterinary hospital for procedures on cats and dogs with cancer. For murine studies, we use the wet-type Alpinion system.
Furthermore, we are designing, building, and testing a novel robotic high-intensity focused ultrasound (HIFU) system in the lab. It is still early stages, but we intend for it to become a system that can be safely, easily, and economically used in veterinary settings across the country. Its first applications will be for treating skin cancer and head and neck cancers. Initially, it will use anatomic co-registration for guidance because many superficial tumors and oral cancers can be adequately visualized with pretreatment CT or MRI. Later we may add ultrasound guidance. Complicated tumors, such as thyroid tumors that return after surgery and spread to the lymph nodes and lungs, do require the advanced imaging guidance that only MRI can provide.
What is the overall goal of your work?
In the upcoming years, we would like to demonstrate the feasibility of focused ultrasound for canine and feline cancer therapy. In particular, we seek to provide clinical evidence that focused ultrasound with nanoparticles alters the tumor microenvironment and that augmented immunotherapy outcomes can tremendously advance its use in human cancer patients.
What are your funding sources?
I have received two research grants from the Focused Ultrasound Foundation. Our newest funding from the NIH will support the upcoming canine clinical trial. We have also received grants from the Oklahoma Center for the Advancement of Science and Technology (OCAST), Petco, and others. Our current grants are:
- NIH/R01 (Selected for R37 MERIT Award), “Focused ultrasound enhanced calreticulin-nanoparticle for immune primed melanoma immunotherapy,” $1,655,985, 2019–2024 (extendable until 2026)
- PETCO, “Development of non-invasive cancer immunomodulation,” $500,000, 2019–2021
- OCAST, “Magnetic hyperthermia combined antimicrobial targeting of bone pathogens,” $135,000, 2017–2020
- Focused Ultrasound Foundation, “High intensity focused ultrasound—mediated targeting of solid tumors and hygroma in client-owned dogs,” $200,000, 2018–2020
- NIH R01, “Translation of temperature-sensitive liposomes and image-guided drug delivery in pediatric oncology,” $3,414,869 (paid consultant), 2015–2020
- Oklahoma Applied Research Support, “Minimally invasive animal sterilization,” $310,000, 2019–2021
- Celsion Corporation, “Role of Thermodox in cancer immunotherapy,” $112,500, 2019–2020
- Kerr Endowed Chair, “Enhancing biomedical research,” $30000-50,000/year, 2015–present
Who are your team members?
Our team includes veterinarians, immunologists, biomedical engineers, and chemists. The complementary expertise of these members has been key to our research productivity, and we plan to continue to strengthen our group in the upcoming years.
Who are your internal and external collaborators?
We are currently collaborating with Drs. Jack Hoopes and Steven Fiering at Dartmouth in the areas of canine medicine and immunology. We have had a standing collaboration with Rajiv Chopra, PhD, and his group at the University of Texas Southwestern. Together we published the first work that demonstrated that focused ultrasound could deliver antibiotics from nanoparticles into soft tissues.
We appreciate working with other groups because it allows us to learn from one another and avoid repeating mistakes. In general, the focused ultrasound community is small, so the more that we all communicate the better. Collaborating also allows us to expand into new areas of research and keeps us from being isolated.
Beyond the partnerships that we had already developed, our veterinary clinical trials have allowed us to form new collaborations with medical oncologists. For example, we are in the process of developing a memorandum of agreement with Dr. Chandan Guha from the Albert Einstein College of Medicine for faculty exchange and clinical trials in both human and veterinary patients. This exciting partnership will allow us both to expand our focused ultrasound capabilities and translate nanomedicine for clinical use.
What can you tell us about your past, ongoing, or upcoming clinical trials?
We are initiating a new clinical trial in canine cancer patients that will use histotripsy for enhancing immunotherapy. The study will be conducted with the Alpinion system. It should be an exciting project because we saw a distinct difference in immunomodulation when we switched from ablation to histotripsy in our preclinical mice work. These patients will have either melanoma or head and neck cancer.
We have also designed a clinical trial to use our nanoparticles with focused ultrasound. The United States Department of Agriculture (USDA) and NIH are currently in discussion on the regulatory aspects because it is a gene therapy trial. We are hoping the issues are resolved in the upcoming year so that this study can be initiated.
How many veterinary patients have you treated since the start of your focused ultrasound program?
So far, we have treated 17 patients. The Focused Ultrasound Foundation directly supported several of those treatments.
Do you have an interesting, unique, or especially memorable clinical research story to share?
The cancer remission that we had with our very first canine case was incredibly satisfying. This patient story was highlighted on the Focused Ultrasound Foundation’s website.
What are your greatest achievements? Any major disappointments?
Becoming an early translator of focused ultrasound technology for canine cancer treatments has been quite soothing, and I feel proud of it. The ultimate prize will be when we eventually see the use of the technologies for day-to-day patient treatment. We have been quite blessed with funding and impactful publications. Like any research group engaged in this area of work, we do experience setbacks (e.g., grants not making the cut or experiments failing), but I look at them as great learning experiences to build on.
What do you see as impediments to your success?
This is a difficult question. It can be challenging when desired results are not attained in patient or preclinical studies. It throws you back and can stifle project speed. I also feel that there is a lot to learn about the optimal focused ultrasound treatment conditions. Finally, the groups that fund biomedical research could be more supportive of focused ultrasound—related mechanistic studies.
What is your research wish list?
In the near future, we would like to demonstrate focused ultrasound’s potential for immunotherapy with nanoparticles. Additionally, we would like to show the benefits of our robotic system for veterinary treatment of superficial tumors.
Has the Foundation played a role in your work?
In addition to funding two of our studies, the Foundation will sometimes refer pet owners to me who reach out to them for help. One case that recently arose is from a dog owner in California. The dog has a mast cell tumor that has progressed to other regions, so it is no longer a candidate for surgery, and we are hoping to evaluate it for focused ultrasound treatment. I also periodically discuss our research with Dr. Kelsie Timbie. She has played an important role in our research program, and we greatly appreciate her enormous support.
Do you have any upcoming follow-up funding opportunities?
We are currently speaking to several foundations, including the Focused Ultrasound Foundation, to create a center for research excellence in focused ultrasound therapy in the College of Veterinary Medicine at Oklahoma State University. We also will continue to purse NIH funding opportunities to support bench to bedside research from my laboratory.
What comes next?
Demonstrating the immunoadjuvant properties of the focused ultrasound in canine patients would be pioneering work, and we are working on it.
Do you have any interesting images to use in our feature?
Below are two photos depicting the clearance of oral ameloblastoma using focused ultrasound in a canine patient. The second image shows recovery after two weeks without complications.
Sethuraman SN, Singh MP, Patil G, et al. Novel calreticulin-nanoparticle in combination with focused ultrasound induces immunogenic cell death in melanoma to enhance antitumor immunity. Theranostics. 2020;10(8):3397-3412.
Gorbet M-J, Ranjan A. Cancer immunotherapy with immunoadjuvants, nanoparticles, and checkpoint inhibitors: Recent progress and challenges in treatment and tracking response to immunotherapy. Pharmacol Ther. 2020;207:107456.
Singh MP, Sethuraman SN, Ritchey J, et al. In-situ vaccination using focused ultrasound heating and anti-CD-40 agonistic antibody enhances T-cell mediated local and abscopal effects in murine melanoma. Int J Hyperth Off J Eur Soc Hyperthermic Oncol North Am Hyperth Group. 2019;36(sup1):64-73.
Wardlow R, Sahoo K, Dugat D, Malayer J, Ranjan A. High Intensity Focused Ultrasound (HIFU) Heating Improves Perfusion and Antimicrobial Efficacy in Mouse Staphylococcus Abscess. Ultrasound Med Biol. 2018;44(4):909-914.
VanOsdol J, Ektate K, Ramasamy S, et al. Sequential HIFU heating and nanobubble encapsulation provide efficient drug penetration from stealth and temperature sensitive liposomes in colon cancer. J Control Release Off J Control Release Soc. 2017;247:55-63.
Wardlow R, Bing C, VanOsdol J, et al. Targeted antibiotic delivery using low temperature-sensitive liposomes and magnetic resonance-guided high-intensity focused ultrasound hyperthermia. Int J Hyperth Off J Eur Soc Hyperthermic Oncol North Am Hyperth Group. 2016;32(3):254-264.
Maples D, McLean K, Sahoo K, et al. Synthesis and characterisation of ultrasound imageable heat-sensitive liposomes for HIFU therapy. Int J Hyperth Off J Eur Soc Hyperthermic Oncol North Am Hyperth Group. 2015;31(6):674-685.
Bing C, Nofiele J, Staruch R, et al. Localised hyperthermia in rodent models using an MRI-compatible high-intensity focused ultrasound system. Int J Hyperth Off J Eur Soc Hyperthermic Oncol North Am Hyperth Group. 2015;31(8):813-822.
Ranjan A, Jacobs GC, Woods DL, et al. Image-guided drug delivery with magnetic resonance guided high intensity focused ultrasound and temperature sensitive liposomes in a rabbit Vx2 tumor model. J Control Release Off J Control Release Soc. 2012;158(3):487-494.
Negussie AH, Yarmolenko PS, Partanen A, et al. Formulation and characterisation of magnetic resonance imageable thermally sensitive liposomes for use with magnetic resonance-guided high intensity focused ultrasound. Int J Hyperth Off J Eur Soc Hyperthermic Oncol North Am Hyperth Group. 2011;27(2):140-155.
Focused Ultrasound Veterinary Researchers Receive Funding at Oklahoma State University October 2019
2nd Quarter 2019 Research Awards Aimed to Address Difficult Medical Problems June 2019
Focused Ultrasound Study for Pets Funded by Petco Foundation, Blue Buffalo May 2019
2018 Symposium Program Highlights October 2018
Symposium Showcases Latest Advances in Noninvasive Therapy for Brain Disorders, Cancer, and Other Major Diseases October 2018
Research Roundup October 2018
Research Roundup May 2018
New Foundation Program Funds Veterinary Clinical Trials April 2018
Canine Patient Profile: Oreo April 2018
Third Quarter Research Awards September 2017