Engaging the Immune System to Kill Sarcoma: A Comparative Oncology Approach
Abstract
Overarching Challenges Addressed: Improving the efficacy of Immunotherapy and Transforming cancer treatment for sarcoma patients. Near-Term Impact and Applicability of the Research: For many years, the hope was to harness the patient’s own immune system to fight cancer. There were many attempts that failed, so hopes dimmed along with these many failures. Only in the past few years, it was discovered that bioengineered drugs composed of antibody fragments that simultaneously bind cancer target cells and cells of our own immune system could successfully engage the immune system with remarkable anti-cancer responses in patients who failed chemotherapy. These drugs have mostly been effective against blood-born tumors such as leukemia. These discoveries launched a new direction of the cancer research field. It is now believed that we can harness this technology so we can treat very difficult solid tumors such as those we see in those individuals diagnosed with sarcoma. This will be a more difficult challenge. In this proposal, we believe we are positioned to have major impacts on sarcoma immunotherapy. (1) We have improved the ability of genetically engineered drugs to bind by changing the antibody framework to that of llama antibody. (2) In the same drug, we incorporated a signal that dramatically expands the number of immune natural killer cells to kill the tumor. (3) Since the target that we intend to hit with antibody is extremely important in cancer, we have targeted a marker that is an extremely high-quality sarcoma target called B7-H3. B7-H3 is highly expressed on sarcoma cells and minimally expressed on non-target cells in the body. (4) In addition to the drug itself, the way we intend to study it is extremely important, and few centers have the means to accomplish it. We intend to combine our drug development program with our canine veterinary oncology program. We engineered our drug so it has the ability to recognize B7-H3 sarcoma in dogs and in humans. Dogs develop sarcoma far more frequently than humans, so we have many canine patients from our canine oncology clinic to study. By respectfully treating these canine patients, we will learn how best to dose animals to get the maximal anti-cancer response with the least amount of toxic side effects and what route of injection is best. (5) There is something else very special about our drug. It belongs to a new class of drugs that engage natural killer cells to kill cancer. Natural killer (NK) cells are white blood cells that have evolved to kill cancer cells. When people get cancer, it is because, in part, NK cells are blinded and are not performing their intended duties. Our drug is designed to assist NK cells and to engage them so they can better do their job as cancer killers. This proposal also will assess the effect of our drug on the dog’s immune system so that we can better understand whether the drug is working as intended. Since we already have designed, manufactured, and vialed our drug, these studies will immediately benefit dogs and dog owners. It will provide critical information since what we learn in dogs is applicable to humans and a future human clinical trial. Scientific Objective and Rationale: Our primary objective is to generate preclinical support for our NK cell-enhancing species, cross-reactive drug in a canine system that will benefit patients, most notably young adults. The potential benefit to dogs with sarcoma and their owners is not trivial, and is a secondary goal. Our rationale is multifaceted. (1) Since components of human and dog immunity are similar, companion dog therapy can be used to better understand new immunotherapies in a valuable large animal model of sarcoma, which cannot be replicated in mouse models. (2) Our drug targets B7-H3, a high-quality sarcoma target. B7-H3 is expressed on sarcoma and minimally expressed on normal tissue. Our drug is species cross-reactive since the anti-B7-H3 nan
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310583
Entities
People
- Daniel Vallera
Organizations
- United States Army
- University of Minnesota