Novel Immunotherapy for Brain-Metastatic Breast Cancer
Abstract
We will address the overarching challenge of reducing deaths due to breast cancer that has spread to and grown in the brain, also known as brain-metastatic breast cancer (BMBC), while eliminating or reducing the need for the highly toxic current therapies, such as whole-brain irradiation. We hypothesize that our new therapeutic vaccine combined with a novel vaccine booster will work synergistically with previously developed immune drugs that have not been effective as single agents against BMBC. More specifically, that our therapeutic vaccine (alpha-DC1s loaded with HER2 and HER3, two antigens important for brain-metastatic process) combined with a novel combinatorial adjuvant that promotes the vaccination-induced effector cells to tumor lesions (chemokine modulation; CKM) will show therapeutic synergy and facilitate clinical efficacy of checkpoint blocking drugs (PD-1 blockers, such as Keytruda or Opdivo). Our comprehensive immunotherapy approach is made uniquely possible by the complementary preclinical and clinical expertise of the Dr. Kalinski (Initiating Principal Investigator [PI]) and Dr. Czerniecki (Partnering PI). We have already demonstrated safety and obtained early efficacy data of each the elements of the proposed treatments and several of their combinations in preclinical studies and early-phase clinical trials, in breast and brain cancers. Guided by these data, we developed the current therapeutic approach for patients with BMBC, including patients with its disseminated form (leptomeningeal disease, LMDz) who lack effective treatment options. We will target three specific aims: In Specific Aim 1, we will demonstrate antitumor activity of alpha-DC1-HER2/HER3 vaccines combined with systemic (i.v.) CKM and PD-1 blockade in patients with parenchymal BMBC. We will carefully monitor our patients for safety and treatment tolerability (which is expected to be high, based on our past experience) and evaluate the clinical efficacy, measured by objective response rate (irORR). In parallel correlative mouse and studies, we will determine if the paradigms derived from this trial are also relevant for disseminated brain cancer (LMDz), which will inform the final design of the trial in LMDz. In Specific Aim 2, we will perform a Phase Ib trial in LMDz to test the clinical and local longitudinal immunologic activity of alpha-DC1-Her2/Her3 vaccine in combination with CKM. Guided by the results of Specific Aim 1, we will finalize the design of the clinical trial of DC1-Her2/Her3 vaccine and CKM (either i.v. or local infusion; possible inclusion of PD-1 blockade) for patients with LMDz. The efficacy of treatment will be evaluated by measuring patients’ survival, with stringent monitoring for potential side effects. In Specific Aim 3, we will identify blood and tumor markers of the clinical benefit of alpha-DC1/CKM treatment, identify factors that limit its effectiveness, and develop relevant countermeasures. We will compare the biomarkers in patients’ blood, biopsy-accessible peripheral tumor lesions, and cerebrospinal fluid (CSF; patients with LMDz typically have implanted intrathecal catheters to control their disease) harvested before, during, and after immunotherapy, to identify the molecular correlates of the clinical benefit. We will also identify any molecular mechanisms that may limit the clinical effectiveness of the combination treatments and develop the relevant countermeasures to assure the optimal tumor control. Impact: Currently, there are no curative treatments for BMBC. The current treatments include surgery or radiotherapy (whole-brain radiation or gamma knife), which are associated with significant toxicity, but do not prevent recurrence and death. The proposed immune therapy can provide new effective and safe treatments for these patients who currently have a very grim prognosis.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910674
Entities
People
- Pawel Kalinski
Organizations
- United States Army