Advancing Immunotherapy in Breast Cancer: Local Reprogramming of Tumor-Associated Macrophages with Novel Biomaterials for Systemic Adaptive Anticancer Immunity
Abstract
Metastatic disease is the primary cause of mortality from breast cancer. Distributed disease initiates through the growth of one, or a few, tumor cells in a distant, unknown location that make the earliest stages of disease undetectable. Metastases grow to become detectable and cause the health consequences that lead to death. The current paradigm is that distributed disease requires distributed therapy. Conventionally, this is a prescription for injectable chemotherapies, but the dose-limiting toxicities in off-target sites of these powerful drugs contribute to the resistance associated with eventual progression and poor clinical outcomes. What if a local therapy could be used to generate a systemic response? What if an extraordinarily strong treatment, accessible primarily to the tissue of a detectable metastasis, could enable the eradication of distant tumors? Such an approach would revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival and eliminate the mortality associated with metastatic breast cancer. We propose a novel approach to the sustained, controlled, local delivery of strong therapies in metastases that are large enough to identify and treat. Importantly, these therapies are immunomodulators that are hypothesized to generate immune functions that result in systemic, adaptive immunity against the local metastasis – and the other, unknown, distributed metastases of similar composition. These immunomodulators have known therapeutic benefit, but are too powerful to administer systemically, even with advanced formulations such as targeted nanoparticles. Instead, we will use a novel gel that can be injected in, or adjacent to, an appropriate metastasis. In this way, the powerful immunomodulatory functions will be limited to the area in and near the metastasis, avoiding the dose-limiting toxicities of systemic therapies. The cytokines that carry out the immunomodulation in and near the gel are not suitable for systemic injection; our approach cannot be used as a conventional therapeutic – it requires the controlled release from a biocompatible gel near the metastasis. A systemic therapy, however, is, of course, necessary to address the other sites of distributed disease. In this case, that systemic therapy is the adaptive immunity that is generated locally and then operational anywhere immune cells can access. This approach breaks the paradigm of conventional chemotherapies for distributed disease and represents a high-impact opportunity to revolutionize treatment of metastatic breast cancer. So, why will this work when systemically administered immunotherapies have failed to demonstrate broad and significant benefits in metastatic breast cancer? Our approach has two components, one of which is an existing, Food and Drug Administration-approved immunotherapy. We propose here a new local therapy that reverses the immunosuppressive tumor microenvironment. The treated breast cancer metastasis is then "primed" for a strong response to conventional immunotherapies such as anti-PD1 (and others). The proposed, localized initial therapy enables efficacy of the immunotherapy that generates the adaptive immunity responsible for eradication of breast cancer metastases. The previously demonstrated biocompatibility and immune cell modulation of the proposed injectable cryogel and our own work on the polarization of tumor-associated macrophages in breast cancers support the feasibility of this application. We have compelling preliminary data on some, but not all, of the components of the proposed study, consistent with the Level 1 mechanism, which seeks high-impact ideas justified through evidence that may not include extensive previous studies. This novel approach is supported by two principal investigators with complementary expertise in biomedical engineering material science and clinical immunology, but in a new partnership. T
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910089
Entities
People
- Todd D. Giorgio
Organizations
- United States Army
- Vanderbilt University