Correcting the Anti-HER-2 CD4 Th1 Response in Breast Cancer Therapy to Prevent Recurrence
Abstract
The Problem: HER-2 directed therapies have improved survival for most patients; however, those with residual disease post-neoadjuvant therapy have increased risk of recurrence. It would also be of interest to induce more complete pathologic complete responses to neoadjuvant therapy. Lastly, reducing the need for toxic chemotherapy is a goal all patients tell me they welcome. Solution: We will attack all three of these issues so that we reduce mortality by preventing recurrence in those with high risk, increase pathologic complete response rate to HER-2 directed therapy, and reduce the need for adjuvant chemotherapy in patients with HER-2pos breast cancer. We will also develop an immune response test to identify patients at risk for recurrence and development of HER-2pos breast cancer. Overarching Challenges: Decrease mortality, prevent recurrence of dormant cells, and reduce the need for chemotherapy. How We Will Attack the Problem: We have assembled an All Star Team of Physicians and Immunologists with the largest experience in immune-based therapies directed against HER-2pos breast cancer. We have demonstrated that there is a loss of anti-HER-2 CD4 T helper cells in patients with HER-2pos breast cancer starting in ductal carcinoma in situ (DCIS) and continuing to severely depressed levels in T1a invasive tumors. This is not seen in patients with HER-2neg breast cancer. This loss of anti-HER-2 helper cells in general is not reversed by standard surgery, radiation, or chemotherapy or HER-2 directed therapy. However, we have found that those with the lowest levels of anti-HER-2 CD4 T cells experience diminished disease-free survival and much fewer odds of having a complete pathologic response to neoadjuvant therapy. The good news is we have documented in several clinical trials that we can reverse the loss of the anti-HER-2 T helper response by vaccinations using dendritic cell vaccines. In this application, we will assess whether restoring this anti-HER-2 CD4 T cell response can prevent recurrence and reduce mortality and even reduce the need for chemotherapy. We have studied what the CD4 T helper cells do to the breast cancer cells. The cytokines gamma interferon and tumor necrosis factor produced by the CD4 cells cause HER-2pos breast cells to undergo apoptosis and induce tumor senescence causing the tumor cells into an irreversible permanent growth arrest. If we combine HER-2 blocking agents trastuzumab (Herceptin) and pertuzumab (Perjeta) with the cytokines, there is a greatly augmented induction of apoptosis and senescence induction. We will study this further and take advantage of this in our clinical trial designs. Patients tell me in the office they don t want more chemotherapy, so we will bring them an immune-based program with little toxicity to restore their anti-Her-2 immune response. Specific Aims: Aim 1: We will conduct three clinical trials: (1) a Phase II multicenter trial using vaccines in patients with residual disease following neoadjuvant chemotherapy to prevent recurrence; (2) a Phase I/II study in patients with HER-2pos breast cancer combining vaccines with chemotherapy and HER-2 targeted therapies to increase pathologic complete responses; and (3) a Phase I/II clinical trial using vaccines combined with HER-2/HER-3 blockade and partial breast radiation in a neoadjuvant study in patients with T1 HER-2pos invasive breast cancer to avoid chemotherapy. Aim 2: Study the mechanism by which HER-2/HER-3 blockade and T helper cells cause breast cancer cells to die and go to sleep. Aim 3: Study the use of monitoring tests to detect effectiveness of vaccine and develop an immune test to predict risk patients of recurrence or primary breast cancer development of HER-2 breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610385
Entities
People
- Brian J. Czerniecki
Organizations
- H. Lee Moffitt Cancer Center & Research Institute
- United States Army