Reducing Cancer Health Disparities in Detroit - P20 SPORE
Overview
Racial disparities in cancer outcomes will likely widen without a comprehensive understanding of the biologic mechanisms driving treatment response in diverse populations and the applicability of clinically guidelines to all populations. The Karmanos Cancer Institute at Wayne State University Specialized Program of Research Excellence (SPORE) seeks to address racial disparities in metropolitan Detroit, a uniquely important underserved population where great cancer disparities exist. This SPORE will enable clinical, basic and population scientists to translate relevant, high-impact scientific discoveries in diverse patients to reduce racial disparities in cancer outcomes, with initial work focused on immune checkpoint inhibitor (ICI) treatment for lung cancer. This work will provide the basis for moving towards a more race-inclusive, equity-focused precision medicine approach to the use of ICIs and serve as a model for future research on other cancer sites and new agents. The application includes two scientific projects as follows:
Project 1. Characterizing race-specific immune profiles with respect to the tumor environment and host genetic background to determine their contribution to response to ICIs.
Project 2. Understanding racial differences in patients’ responses to ICI treatment.
These projects are supported by three shared resources: Core A. Biospecimen Core; Core B. Patient and Community Engagement Core; and Core C. Administrative Core. This SPORE also supports a Developmental Research Program to support innovative translational research.
Principal Investigator:
Project 1: Characterizing race-specific immune profiles with respect to the tumor environment and host genetic background to determine their contribution to response to ICIs
Project Co-Leaders:
The recent breakthroughs in immunotherapy, particularly immune checkpoint inhibitors (ICIs) that have received FDA approval, have been a major advancement for lung cancer treatment. Thus far, ICI clinical trials have had poor representation from African American patients (<4%); but in the limited data available, African Americans show poorer response to ICIs than whites. In these therapies, antibodies that mediate the blockade of PD-1, PD-L1, and CTLA-4 signaling are utilized to both reverse tumor-mediated immune suppression and boost anti-tumor immune activity, however, many patients fail to benefit. Our preliminary studies identified a subset of immune genes that associate with PD-L1 expression, where interferon (IFN) signaling is a common driver, in both animal models and in tumors from NSCLC patients, where expression of these PD-L1-associated genes differs by race. Additionally, relative to tumors from white patients, tumors from African Americans were more likely to express components of antibody heavy and light chains, despite similar expression of general B cell markers, which may indicate a functional difference in intratumoral B cells from these populations. The presence of B cell-rich tertiary lymphoid structures (TLS) have recently been identified in lung and other cancers as a potential biomarker for ICI response. Importantly, while a direct link between patient germline genetics and response to immunotherapy remains elusive, decades of autoimmunity and inflammation research have identified host genomic associations and racial disparities in the onset and/or severity of several immune-mediated diseases. Supported by our preliminary data, we hypothesize that genetically-driven immune profiles associate with response to immune-based therapies and uniquely define subsets of lung cancer patients by race, contributing to differential outcomes after ICI treatment. To characterize immune profiles, we will utilize data/samples from a previous study coupled with new case identification in a cohort of patients receiving treatment with ICIs to address the hypotheses that 1) there are distinct immune profiles associated with PD-L1 expression and tertiary lymphoid structures in NSCLCs; 2) these immune profiles vary by race and 3) are associated with response to ICIs.
Project 2: Understanding racial differences in patients’ responses to ICI treatment
Project Co-Leaders:
One of the most significant advancements in lung cancer treatment has been the introduction of immune checkpoint inhibitors (ICIs), which either as single agents or in combination with platinum-based chemotherapy, are now front-line therapy for most patients with metastatic non-small cell lung cancer (NSCLC). While treatment response rates can be remarkable, side effects, especially immune-related adverse events (irAEs), are of major concern. When uncontrolled, side effects can result in unscheduled care, increased out-of-pocket costs for patients, and treatment delays or discontinuation. African Americans continue to have worse outcomes after a lung cancer diagnosis than whites, and there are known differences between African Americans and whites with respect to many aspects of cancer treatment, including time to initiation and dose of chemotherapy, symptom burden, and even treatment of side effects. However, little is known about potential differences by race with respect to response to ICI treatment largely due to a lack of inclusion of African American patients in the clinical trials leading to FDA approvals. Thus, there is a critical need to explore whether African American and white patients are differentially impacted by side effects related to ICI treatment. While ICIs holds promise for improved outcomes, little is known about whether potential predictors of patient-reported side effects and quality of life and irAEs vary by race. This study will directly evaluate multi-level predictors of response to ICI treatment in African American and white patients. Understanding the sociodemographic, individual, and disease-specific determinants of these outcomes in lung cancer patients provides the basis for moving towards a more equity-focused approach to the use of ICIs. By identifying drivers of potential disparities, we can better identify patients at high risk for side effects and irAEs, develop interventions to reduce risk factors, thereby improving patient quality of life and reducing racial disparities in outcomes.
Biospecimen Core
Core Director:
The Biospecimen Core will provide the following services to the components of the SPORE as follows; (1) To collect, process and bank cancer tissue and associated biological samples with ongoing quality control to ensure timely distribution of appropriately diagnosed, high-quality samples to investigators and collaborators on all SPORE projects for molecular and genomic analysis, for culture and for xenograft assays, and for ancestry informative markers to further define patient race; (2) Perform high quality immunohistochemical staining and provide pathological interpretation of stained tissue sections to investigators and collaborators on all SPORE projects; (3) Generate tissue microarrays using samples from African American cancer patients for use in future projects and made available to the broader research community to support expanded efforts in the reduction of cancer health disparities; (4) To maintain and update a central Detroit SPORE database of biospecimens from cancer patients collected at KCI that is annotated with demographic, clinical, and pathologic data, and provide access to data and specimens; and (5) To actively participate in the design of pathology/ancillary studies of SPORE projects, the Developmental Research Program projects, and projects for consideration for a full P50 SPORE application, including providing input on suitability for samples for studies proposed, histologic characterization, immunohistochemical analyses, and microscopic scoring, and construction of study specific tissue microarrays.
The goal of this SPORE Core is to ensure that high-quality biospecimens, collected while ensuring compliance with federal and institutional guidelines, are delivered in a timely manner to SPORE investigators and to provide pathologic and molecular analytic expertise to support the innovative and translational cancer health disparities research projects in this application.
Patient and Community Engagement Core
Core Director:
The Patient and Community Education Core (PCEC) will offer services to support high levels of engagement among African American study participants as well as the broader African American community in metropolitan Detroit. Specifically, the PCEC will; (1) Coordinate a council of local community stakeholders (of cancer survivors, caregivers, and advocates) — the P20 Cancer Action Council (CAC) — that will collaborate with the Patient and Community Engagement Core (PCEC) team on the development and execution of PCEC services; (2) Implement strategies to increase genomic literacy and awareness of immunotherapy among African American patients and community members; (3) Provide ongoing feedback to all projects on strategies to optimize recruitment and retention of African American participants; and (4) Support dissemination of research project progress and findings to study participants and community members.
The PCEC is distinct from the other proposed cores in its focus on the ways in which community stakeholder involvement can improve patient/participant experience, and this core will ensure that community members are well-informed regarding the scientific and equity-based rationale for the proposed studies as well as developmental projects.
Administrative Core
Core Directors:
The Administrative Core provides a common management structure for the SPORE. Specifically, the Core will; (1) provide leadership and oversight of all SPORE activities involving Research Projects, the Biospecimen Core, Patient and Community Engagement Core and the Developmental Research Program as well as a seamless integration with the Cancer Center overall; (2) facilitate communications between SPORE participants, the National Cancer Institute, and the general public, and fostering intra-SPORE and inter-SPORE interactions; (3) oversee fiscal and resource management for each component of the SPORE; (4) ensure compliance with all NIH and institutional grant regulations; (5) develop measures to evaluate the progress and effectiveness of each component of the SPORE as well as the overall effectiveness of the SPORE in cancer health disparities; (6) solicit guidance and objective feedback from the Internal and External Advisory Boards, P20 Cancer Action Council, and coordinating those meetings, including the Annual SPORE Research Retreat; and (7) provide central guidance in transitioning the P20 planning grant to a full P50 SPORE application.
Developmental Research Program
Program Directors:
The Developmental Research Program (DRP) provides a unique opportunity for soliciting new research ideas and encourages development of cancer health disparities projects with high translational potential. These projects provide investigators with the resources to conduct high-impact translational research consistent with the SPORE’s objectives. The DRP will encourage participation from a broad range of investigators at Karmanos Cancer Institute and Wayne State University by providing support for pilot projects with the potential to develop into impactful translational projects.
This content originally appeared on The National Cancer Institute website.