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Multiplex immunohistochemistry of human melanoma metastasis showing CXCL13+ CD4+ T cells localizing within lymphoid structures containing CD79A+ B cells.

Cancer Cell paper, 2022

The Veatch lab studies T cells targeting tumor antigens in solid tumors with the goal of developing novel cellular therapies for treating cancer. 

CD4 T cells as tools to modify the tumor microenvironment

One research focus in the lab is understanding the functions of CD4 T cells in immune responses to solid tumors and developing strategies to target solid tumors with engineered CD4 T cells.  We have found that conventional CD4 T cells infiltrating human melanoma tumors include both tumor antigen specific cells and non-specific “bystanders” and that the tumor antigen specific cells have a unique transcriptional signature.  The presence of cells with this signature across patients of multiple cancer types is correlated with improved prognosis and an activated tumor microenvironment as measured by the number and activation of CD8 T cells, the activation of macrophages, and the number and maturation of B cells.  This has led to the hypothesis that CD4+ T cells targeting tumor antigens could be used to activate the tumor immune microenvironment and potentially benefit patients with solid tumors. We use mouse models to understand the functional effects of CD4 T cells on the tumor microenvironment, and to engineer cells that have enhanced functional therapeutic properties.  We also conduct clinical trials of adoptive T cell transfer of CD4+ T cells in cancer patients, including an upcoming trial of T cell receptor transgenic CD4+ T cells targeting the recurrent BRAF V600E mutation in melanoma, and use these trials to ask what effects CD4 T cells can have on the tumor microenvironment.  We plan to expand this approach to multiple antigen targets across multiple tumor types.

A novel cellular vaccine to enhance tumor specific T cell responses

A second focus of the lab is the development of a new platforms for therapeutic cancer vaccination.  During the development of therapies using genetically engineered T cells, it was unexpectedly discovered that foreign antigens introduced into a patient’s T cells would induce potent T cell responses against those antigens when the T cells were reinfused into patients, even if those patients had severe immunocompromise.  While this is undesirable in most T cell therapy applications, it suggested that T cells modified with cancer antigens could function as a vaccine to induce T cell responses directed at the patient’s cancer. Using a mouse model, we determined that T-vaccine functions through delivery of antigens to dendritic cells in the recipient, and that the immunogenicity could be greatly increased by incorporating additional inflammatory signals into the T-vaccine cells to activate host immune cells.  We are currently developing this approach for a first in human trial of this vaccine platform in patients with non-small cell lung cancer.

Featured Publications

Veatch, J. R., Lee, S. M., Shasha, C., Singhi, N., Szeto, J. L., Moshiri, A. S., ... & Riddell, S. R. (2022). Neoantigen-specific CD4+ T cells in human melanoma have diverse differentiation states and correlate with CD8+ T cell, macrophage, and B cell function. Cancer cell40(4), 393-409.

Veatch, J. R., Singhi, N., Srivastava, S., Szeto, J. L., Jesernig, B., Stull, S. M., ... & Riddell, S. R. (2021). A therapeutic cancer vaccine delivers antigens and adjuvants to lymphoid tissues using genetically modified T cells. The Journal of Clinical Investigation131(16).

Veatch, J. R., Lee, S. M., Fitzgibbon, M., Chow, I. T., Jesernig, B., Schmitt, T., ... & Riddell, S. R. (2018). Tumor-infiltrating BRAF V600E-specific CD4+ T cells correlated with complete clinical response in melanoma. The Journal of clinical investigation128(4), 1563-1568.