Project Summary:
The rising incidence of cancer among Black Wisconsin natives is a pressing public health concern, with 1,686 new cases anticipated this year. Notably, approximately 44% of these cases will involve lung, kidney, bladder, or skin cancers, which are often optimally treated with immunotherapy. However, Black patients and patients with Medicaid and/or lower incomes are less likely to receive these critical therapies, leading to poorer outcomes. Perceived higher treatment toxicity and resistance have been implicated as potential treatment barriers in this underserved patient population.
The advent of immunotherapy has significantly improved progression-free survival (PFS), overall survival (OS), and quality of life (QOL) when compared to chemotherapy in patients diagnosed with lung, kidney, bladder, and skin cancers. For example, in patients with advanced non-small cell lung cancer (NSCLC), administration of Nivolumab or Atezolizumab has shown improved clinical outcomes compared to chemotherapy, with long-term survival being achieved in more than 15% of patients vs. 5% in the pre-immunotherapy chemotherapy only. Similarly, Pembrolizumab administered for two years showed better results in both treatment-naïve and pretreated NSCLC patients. Prior to the introduction of immunotherapies, less than 10% of patients with metastatic melanoma survived for more than five years. The introduction of immunotherapies, such as Ipilimumab (anti-CTLA-4), Pembrolizumab (anti-PD-1) and Nivolumab (anti-PD-L1) have significantly improved both disease-free and overall survival rates, resulting in a five-year survival rate of up to 44% and a decline in mortality rates of 6% to 7% per year.
Despite these promising clinical outcomes, many patients experience immunotherapy toxicity limiting receipt of therapy and treatment resistance leading to disease progression or relapse. In one meta-analysis, only 63% of patients were able to tolerate single agent PD-1/PD-L1 therapy due to grade-three or higher immune-related adverse events (ir-AEs). The response rate (median [interquartile range]) was 33% (17–50%) for all studies. Three-drug combinations had higher response rates than two-drug combinations 53% [33–63%] (N = 23 studies) vs. 23% [14–39%] (N = 60 studies) (p<0.0001). African Americans, along with patients with Medicaid and lower incomes, were less likely to receive and complete all intended cycles of immunotherapy leading to poorer outcomes. Some have attributed this discrepancy to disproportionately higher rates of irAEs and immunotherapy resistance, though there is conflicting data regarding this hypothesis.
The etiopathogenesis of immunotherapy toxicity and resistance remains poorly understood. As a result, it is currently not possible to identify which patients are likely to respond and which patients will develop resistance prior to treatment initiation, withholding the opportunity to personalize treatment. Therefore, uncovering the causes and the mechanism of resistance is imperative for planning new cancer treatment combinations and improving clinical outcomes. CTLA4 polymorphisms have been associated with the increased toxicity and poor response to immunotherapy. But the current scientific evidence remains limited in quality and quantity, as well as consistency. Further research is needed to clarify the involvement of CTLA-4 and to evaluate the role of other immune response genes in immunotherapy toxicity and resistance.
This project aims to investigate the pharmacogenomic factors driving immunotherapy toxicity and resistance, with a particular focus on identifying the underlying mechanisms that disproportionately affect Black patients. The researchers intend to identify genetic signatures to predict which patients will respond, and which patients will fail various immunotherapy therapies in order to guide better selection of new cancer treatment combinations for each patient.
The work funded by this proposal will be hypothesis generating, as it will yield deeper understanding of the mechanisms of disparities in surgical oncology care delivery and outcomes. These findings and hypotheses will be used as the preliminary data for NIH R01/R25 applications and other extramural grants. Data leveraged may help to guide the design of innovative clinical trials through an equity lens focused both on the pharmacogenomic basis of treatment response but also on structural barriers to achieving equitable cancer outcomes.