Beyond PD1: An Immunotherapeutic Strategy to Stimulate and Enable Both T-Cell and B-Cell Responses in Immunosuppressive and Nonmutated Metastatic Breast Cancer
Abstract
The body’s own immune system has been recently shown to be an effective therapy against cancer. Cancer cells are now known to be adept at suppressing immune responses, and new drugs (called “immune checkpoint blockade” or ICB antibodies) block this cancer immunosuppression, thus allowing immune cells to successfully eradicate cancer cells. Cancer cells utilize the natural “brakes” of immune to slow down the anticancer response and ICB effectively “cut the brakes” allowing immune responses to eradicate cancer cells. Recent clinical trials of ICB antibodies targeting T-cells (cells that attack other cells, including cancer cells) checkpoint using PD-1 and PD-L1 blocking antibodies have shown great promise, as these molecules are highly expressed in tumors, functioning as critical “brakes” on the body’s immune responses. These newly approved drugs (ICB antibodies) block their ability to function as immune “brakes” and have shown promise in many cancers, including some forms of breast cancer (BC). Unfortunately, in most cancers, only a small fraction (10%-20%) of tumors in patients shrink in response to these PD-1/PD-L1 ICB antibodies. So why aren’t the immune systems of more BC patients more effective in attacking their tumors? Apparently cutting the brakes on T cells alone is often not sufficient to allow immune systems to eliminate tumors. That is why most scientists now believe that the immune system must first be stimulated to attack the tumor through targeting proteins on the tumor called “antigens” (activation), and then the inhibit the breaks of the killer immune T cells attacking the tumor (enabling T-cell effectors). Some evidence suggests that activation occurs when tumors are recognized by the immune system, especially when they have lots of DNA mutations, which encode for different building blocks (amino acids) in their proteins. These substitute amino acids represent foreign looking antigens (so-called neo-epitopes) that can be recognized by their immune systems when presented (looking “different”). Most BCs do not have large numbers of mutations, which is why many scientists think T-cell ICBs are not effective in enabling immune effector cells to cure most BCs (thus, only 20% of some types of BCs are responsive to T-cell ICBs alone). So one problem for most BCs is a lack of immune activation to mutated DNA encoding peptides. We have overcome this by developing a novel vaccine that triggers immune responses against the non-mutated proteins that drive BC, such as HER-2. Additionally, while T-cells represent one arm of the immune system, another equally important arm is made up of B-cells. These cells produce antibodies, which bind to cells and enable their killing by other immune cells that possess specialized receptors (Fc) that recognize these cell-bound antibodies. For some cancers, such as HER2+ BC, antibodies against HER2 (i.e., Trastuzumab) are used as drugs to treat cancer through binding to tumor cells and activating these Fc-effector cells. We have demonstrated that Trastuzumab works through this mechanism to stimulate Fc-effector cells to kill cancer cells. Notably, these cells also possess a braking system that we found was critical in generating anti-tumor immune responses, and recent clinical trials have shown that tumor-targeting antibody therapies are much more effective when utilized with this different class of ICBs that cut the brakes of Fc-effector cells (enabling Fc-effectors). However, most if not all efforts in BC immunotherapy are focused on stimulating T cell responses, without any consideration for B cell responses and antibody engagement of Fc-effector cells as a means to treat cancer. As an alternative to waiting for one’s immune system to attack BC, we propose to use cancer vaccines, which could be now be made highly effective by the use of both T-cell and Fc-cell ICBs. We have developed a HER2 vaccine, which “activates” the immune system to fight cancers, and tes
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010346
Entities
People
- Zachary C Hartman
Organizations
- Duke University
- United States Army