Eliminating Ex Vivo Manipulation and Viral Transfection of T Cells in CAR T-Cell Immunotherapy of B-Cell Malignancies Using Ultrasound-Based Gene Delivery
Abstract
Topic Areas: Relevance to Immunotherapy and Lymphoma. Military Relevance Focus Area: Gap in cancer prognosis, treatment and impact on the health and well-being of military beneficiaries. Scientific objective and rationale of the proposed project: Blood cancer, including acute lymphoblastic leukemia (ALL) and lymphoma, is the most common type of cancer in children. It affects certain cells, called B cells, which play an important role in recognition and defense of the body from infection. The scientific objective of this project is to develop a simple method to improve the current treatment of such diseases in terms of quality of life during treatment, safety, cure rate, ease of manufacture, and cost. Immunotherapy is a cancer treatment that uses the patient s own immune system to help fight cancer. Among all treatments currently available to cure B cell malignancies, such as ALL, immunotherapy is the most promising and growing field where the key parts of patient s immune system, called T cells, are modified to be used as living drugs once re-injected. T cells need to have special molecules on their surface to recognize and destroy cancer cells. The introduction of this new receptor, called chimeric antigen receptor (CAR), is made possible using a virus that transmits new DNA into T cells. This is done in a laboratory outside the patient s body, and the genetically modified T-cells are re-injected back into the patient to find the malignant B cells and kill them. Aside from having to do this outside body, there are additional drawbacks. The laboratory needs to be sophisticated and sterile, the process is labor intensive, high cost, and adds significant delay (several weeks) before the patient can be treated. In addition, the normal T cells in the patient have to be destroyed using chemotherapy before the engineered cells can be transfused back into the patient s blood. Overall, despite remarkable successes in early-stage clinical trials, this therapy remains aggressive, often presents complications, and has several safety concerns. In a simple but powerful approach, we will use low pressure ultrasound (US) on microbubbles that circulate in blood and are targeted to the normal T cells and carry the CAR gene to deliver it directly to the T cells. The ability to initiate B cell killing shortly after treatment without T cell depletion would be a major advance. Ultimate Applicability of the Research: What types of patient will it help and how? Cancer diagnosis and treatment can be very hard on a child and his/her parent. Therapy is needed to minimize physiological as well as emotional suffering. Current immunotherapy can make infections more likely so a child under treatment needs to be away from anyone who may be sick. Our alternative approach would be minimally invasive with minimal discomfort to the child that can be repeated as many times as needed, without risks or complications. Potential clinical application, benefits, risk? Immunotherapy of B-cell malignancies will be possible in a simple manner, without the need for cell harvesting, viral transfection, and likely T-cell depletion. A likely major benefit of our approach is the ability repeat the treatment as many times as needed without risks or complications. Prospective time it may take to achieve a clinically relevant outcome? As our strategy combines two existing U.S. Food and Drug Administration (FDA)-approved technologies in an innovative way, it should allow us rapid translation to the clinic if successful. Likely contributions of this study to advancing the field of cancer research and/or patient care? The simplicity of our US-based approach -- inject target MBs carrying the desired gene and applying US to a large vessel to directly transfect T cells -- will also increase the opportunities to explore treating other liquid and potentially solid malignancies to improve survival and quality of life of cancer patients
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710401
Entities
People
- Caroline De Gracia Lux
Organizations
- United States Army
- University of Texas Southwestern Medical Center