Three of the Foundation’s research award programs announced newly funded projects for the second quarter of the year. The Cancer Immunotherapy Program selected a project that will study a new method using a combination of focused ultrasound and immunotherapy for treating recurrent ovarian and cervical cancer. The Veterinary Program funded a study to determine “time to metastasis” as an initial index of focused-ultrasound-induced systemic antitumor immune effect. The External Awards Program selected two projects that use mechanical ablation to treat brain tumors and pancreatic tumors, and one project that seeks to develop a “needle-less nerve block” technique that would noninvasively deliver pain medication for local anesthesia. Each project is described below.
Title: Activating Specific Cytotoxic T-cells by HIFU and Systemic Immunotherapy in Treatment of Recurrent Ovarian and Cervical Cancer in a Syngeneic Animal Model
PI: Nelson Teng, MD
Institution: Stanford University
Program: Immunotherapy, preclinical
Abstract: Ovarian/cervical carcinoma are recognized as cancers with low neo-antigen load, where the tumor antigens are known to be sequestered from immune cells. We propose that HIFU induced localized hyperthermia and cavitation will render the tumor immunologically non-silent, releasing tumor neo-epitopes, while concurrent immune checkpoint blockade (anti-PD-L1) will enhance the immune response to those neoepitopes by disinhibition of cytotoxic T-cells. Thereby, both treatment modalities combined would be superior to each of them alone. Combination therapy will be tested in a syngeneic animal model with ovarian cell line OV2944-HM-1 and cervical TC-1. Survival, tumor load and clonal expansion of tumor-specific T-cells will serve as endpoints. Abscopal effect at contralateral sites will also be tested. A tumor-targeting novel antibody developed in Teng Lab will be added for achieving complete survival. Novel mAb55.5 targets a tumor-specific carbohydrate-antigen on hematologic and epithelial cancers. Preliminary results suggest mAb55.5 helps generate a proinflammatory protective anti-tumor environment. Epithelial ovarian cancer is the most lethal gynecologic malignancy due to late diagnosis and eventual drug resistance. Cervical cancer is the most common gynecologic malignancy in the world with the high mortality in developing countries. The recent advent of immune-oncology has led to major improvements in the treatment of multiple cancers, but not gynecologic cancers. Success of immunotherapy is dependent on the exposure of neo-antigens to immune cells. The combined use of HIFU, checkpoint therapy, and mAb55.5 will achieve all goals needed for successful oncotherapy, neo-antigen presentation (HIFU), disinhibition of anergic T-cells (<PD-L1) in a pro-inflammatory tumor environment (mAb55.5).
Title: Treating Veterinary Cancer Patients with Focused Ultrasound
PI: Ashish Ranjan, PhD
Institution: Oklahoma State University
Program: Veterinary
Abstract: The annual cancer incidence, tumor type, and sites in canine patients are comparable to human cancer. Specifically, canine oral squamous and non-squamous masses are often well-established when detected in the oral cavity, and they metastasize aggressively. In preliminary studies, we achieved promising local remission rates of canine oral cancers with focused ultrasound (FUS). Additionally, we found that FUS treatment removed the tumor-mediated immunosuppression in murine melanoma by expanding CD4+ and CD8+ T cells, and polarized macrophages to the tumor-suppressing M1 phenotype. Building on our promising preliminary data, in this project, we will perform a pilot dog clinical trial to determine “time to metastasis” as an initial index of the systemic antitumor immune effect of FUS by immunopathological and radiological means, informing feasibility for human trials.
Title: Neuronavigation Coupled Histotripsy in the Canine Brain
PI: Stephen Frey, PhD
Institution: McGill University and Rogue Research
Program: External Awards
Abstract: Brain tumor incidence in dogs is significant, and available treatments such as surgery, chemotherapy, and radiotherapy are costly to owners and do not guarantee long survival periods. Cavitation-based histotripsy is an alternative noninvasive treatment that has demonstrated successful transcranial ablation of ex vivo tissue through the skull of the animal. We plan to use a frameless neuronavigation system to guide histotripsy treatments in the brains of anesthetized dogs. This technique will allow for targeting of brain masses with millimeter precision without the negative effects of invasive surgery, increasing the chances for survival, and significantly reducing the post-recovery period.
Title: Development of Novel Porcine Models of Orthotopic Pancreatic Cancer for FUS and Histotripsy Tumor Ablation Applications
PI: Irving Coy Allen, PhD
Institution: Virginia-Maryland College of Veterinary Medicine
Program: External Awards
Abstract: Despite significant progress in the fight against pancreatic cancer, survival rates are dismal, and the prognosis remains bleak with less than 7% of patients living longer than five years following diagnosis. There is a dire need for new treatment strategies and preclinical models to evaluate emerging therapeutic approaches. This interdisciplinary proposal will evaluate histotripsy, a nonionizing and nonthermal ultrasound ablation method that destroys tissue through the precise control of acoustic cavitation, as a unique tumor ablation strategy in a novel orthotopic pig model of pancreatic cancer.
Title: The Needle-less Nerve Block: Targeted Non-Invasive Analgesia with Ultrasonic Uncaging of Local Anesthetics
PI: Raag Airan, MD
Institution: Stanford University
Program: External Awards
Abstract: An ideal approach to both diagnose and treat pain without opioids would be to noninvasively ‘beam’ a local anesthetic to a suspected pain generator. For instance, in patients with acute or chronic pain, this technique could be used to anesthetize a spinal nerve and thereby interrogate which site(s) contribute most to the patient’s pain. This could then inform the delivery of a longer-lasting therapeutic dose or, complementarily, a permanent intervention such as focused ultrasound ablation. Here, we propose to develop exactly such a technology to noninvasively apply local anesthetics to suspected pain generators using targeted drug uncaging from ultrasound-sensitive nanoparticles.