In addition to their ongoing HIV/AIDS-related research activities, the Weinhold Laboratory is focused on utilizing a comprehensive repertoire of highly standardized and formerly validated assay platforms to profile the human immune system in order to identify immunologic signatures that predict disease outcomes. These ongoing studies span a broad range of highly relevant clinical arenas, including: 1) cancer (non-small cell lung cancer, head and neck cancer, glioblastoma neoforme, ovarian cancer, and prostate cancer), 2) autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosis, multiple sclerosis, and myasthenia gravis), 3) pulmonary disease (idiopathic pulmonary fibrosis), 4) solid organ transplantation (lung, kidney, liver, and heart), and 5) rare diseases (Pompe disease).
Two of the areas that have been especially active over the past few years include the comprehensive immunologic profiling of cancer patients receiving so-called ‘immune checkpoint blockade’ therapies and the search for immune signatures in lung transplant recipients that track with resistance to CMV infection. The laboratory is conducting immune monitoring studies associated with a Phase I trial of Ipilimumab (anti-CTLA-4) in a neoadjuvant setting for the treatment of non-small cell lung cancer (NSCLC). For this trial we are extensively utilized several polychromatic flow cytometry (PFC) platforms to follow activation, maturation, exhaustion, and proliferation patterns within CD4+ and CD8+ subsets of T-cells. We are also utilizing an intracellular cytokine staining (ICS) platform in efforts to detect anti-tumor associated antigen (TAA) responses by CD4+ and CD8+ T cells from peripheral blood mononuclear cells as well as lymphocytes infiltrating the patients’ tumor. These assays are designed to measure antigen-driven intracellular production of IFN-γ, TNF-α, and IL-2, as well as the degranulation marker CD107. This strategy enables us to not only document individual cytokine responses, but to also assess (through Boolean gating) changes in relative polyfunctionality of the responses. We are performing similar immune monitoring of a Phase II trial evaluating nivolumab (anti-PD-1) alone vs. combined nivolumamb + ipilimumab vs. avastin (bevacizamab) alone in patients with glioblastomas. In both studies, we are seeking to identify pharmacodynamics markers and immune correlates predictive of clinical responses. In recently completed studies in a cohort of lung transplant recipients, we identified specific polyfunctional signatures in CD4+ and CD8+ subsets against CMV pp65 and IE-1 antigens that tracked with resistance to CMV infection (manuscript in preparation). These findings now serve as the basis for a Phase I clinical trial to compare conventional 6-month chemoprophylaxis in lung transplant recipients versus a regimen dictated by the presence or absence of the predictive signatures. This trial is the principal component of a recently awarded Clinical Trials in Organ Transplantation or CTOT award made from the NIH to Duke (Scott Palmer, PI). Ongoing studies will test the hypothesis that these signatures that have been validated in lung transplant recipients will also predict resistance to CMV infection in the context of other solid organ transplants such as kidney, liver, and heart.
Future studies will also attempt to identify predictive signatures for resistance to BK polyomavirus, the cause of graft threatening nephritis in kidney transplant recipients and cystitis in bone marrow transplant recipients. Other human diseases that are presently being subjected to comprehensive immune profiling by the laboratory include idiopathic pulmonary fibrosis (IPF), myasthenia gravis, multiple sclerosis, systemic lupus erythematosus, acute coronary syndrome, and Pompe disease
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Yi, J.S., Russo, M.A., Weinhold, K.J., and Guptill, J.T. Adaptive immune response to therapy in HMGCR autoantibody myopathy. Muscle Nerve. 53(2): 313-317, Feb. 2016. PMID: 26492512
Snyder, L.D., Chan, C., Kwon, D., Yi J.S., Martissa, J.A., Copeland, C.A.F., Osborne, R.J., Sparks, S.D., Palmer, S.M., Weinhold, K.J. Polyfunctional T cell responses predict protection from cytomegalovirus after lung transplant. Am J Respir Crit Care Med. 193 (1): 78-85, Jan.1, 2016 [PMID 26372850]
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Staats, J.S., Enzor, J.H., Sanchez, A.M., Roundtree, W., Guar, A., Jaimes, M., Denny, T.N., and Weinhold, K.J. “Toward a comprehensive external quality assurance program for polychromatic flow cytometry.” J. Immunol. Methods. 409:44-53, 2014. [PMID 24968072]
Nair, S.K., Tomaras, G.D., Sales A.P., Boczkowski, D., Chan, C., Plonk, K., Dannull, J., Pruitt, S.K., and Weinhold, K.J. “High-throughput identification and dendritic cell-based functional validation of MHC class I-restricted Mycobacterium tuberculosis epitopes.” Scientific Reports. Apr. 23, 2014. [PMID 24755960]
Yi, J.S., Guidon, A., Sparks, S., Osborne, R., Juel, V.C., Massey, J.M., Sanders, D.B., Weinhold, K.J., and Guptill, J.T. “Characterization of CD4 and CD8 T cell responses in MuSK myasthenia gravis.” Journal of Autoimmunity. 2013 Dec27 doi:1016/j.jaunt2013. 12.005. [PMID: 24378287]