Enhancement of Natural Killer Cell Function for Therapeutic Targeting and Elimination of Metastatic Breast Cancer
Abstract
Rationale: For many years (e.g., first FDA approval for ipilumumab (Yervoy), an immunostimulatory antibody to enhance lymphocytes, against melanoma was in 2011), we did not recognize that our immune system regulates the initiation, progression, and spread of cancer. Now scientific and clinical evidence strongly supports the critical role for both early and later immune responses controlling cancer growth. However, for reasons that remain unknown, the majority of breast cancers do not have an ongoing immune response that can be amplified by cell immunotherapies (when your own immune cells fight cancer). One option for these patients is to genetically reengineer the patient’s immune cells to target the cancer cells. These cells are known as CAR-cells based upon their expression of a chimeric antigen receptor (CAR), which gives the ability to potentially anti-cancer lymphocytes to see a defined protein expressed by the tumor cells and eliminate these cells. Many new immunotherapeutic treatments are making a significant impact on the treatment of blood cancers, but as yet these approaches have not been tested in breast cancer. Furthermore, several types of breast cancer (hormone-insensitive) appear resistant and unresponsive to all therapies examined thus far. In particular, like most cancers, spread (metastasis) is what kills the patient. Natural Killer (NK) cells are subsets of lymphocytes (approximately 10% to 18.5% of the total lymphocytes) known for their ability to trigger cell death very selectively in target cells, particularly in settings of oncogenesis or viral infection. They thus hold great promise for cancer immunotherapy as they do not attack healthy self-tissues and have proven fewer toxicities than conventional therapies. Objective: Genetic engineering techniques, such as CAR-engineering, have the potential to restore or augment NK natural functionality. This technique was initially pioneered in T cells by using a patient’s own blood T cells (autologous). They are modified to express CAR systems, which allow them to recognize and kill tumor cells more efficiently. Although this approach is now FDA-approved and clinically adopted for certain cancers, T cells still offer potential toxicities, challenges, and transplantation concerns that are slowing down upscaling trials towards industrial production and generation of products that could be used off-the-shelf. We will investigate whether allogeneic (derived from a donor different than the patient to be treated) CAR NK cells can be offered as a therapeutic intervention to breast cancer, with a particular focus on hormone-insensitive cancers (so-called triple-negative breast cancer), currently representing approximately 10%-15% of all diagnosed breast cancers, presenting patients with the worst prognosis due to their aggressiveness. Applicability: This project will address the overarching challenges of “Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival” (as prioritized by the Department of Defense Breast Cancer Research Program (BCRP)’s mission) and “Eliminate the mortality associated with metastatic breast cancer.” Enhancing CAR NK cell therapy addresses both of this criterion: successful CAR NK cell therapy of blood cancers has recently been associated with high rates of therapeutic responses (>90%), and are not associated with the side-effect profile of CAR T cell therapies or conventional treatments such as chemotherapy and radiotherapy. Moreover, the fact that it is an immune-based therapy makes it ideally suited to treating metastatic disease; this project has the capacity to help patients who have failed conventional therapies and therefore have a worse overall prognosis. A major benefit of this approach is that it will develop novel strategies for the production of an immune system-derived off-the-shelf therapy to target cancer, allowing for ongoing long-term protection. Therefore, we
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110017
Entities
People
- Fernando Souza-Fonseca-Guimaraes
Organizations
- United States Army
- University of Queensland