Research
We're enabling improved outcomes with cancer immunotherapy
By studying immunotherapies in patients and in model systems, we are using what we learn to improve outcomes through iteration.
Triggering endogenous immunity to cancer
Our lab focuses upon defining the mechanisms that underlie responses, immune toxicities and resistance to cancer immunotherapy. We study approaches to prime and potentiate endogenous immune responses in tumor-bearing individuals. Our initial work was on autologous dendritic cell vaccines targeting shared tumor associated antigens, both in preclinical models and also in patients. This helped to lay the groundwork for the FDA-approved cancer vaccine sipuleucel-T. We have continued to study how approaches for endogenous vaccination with cancer therapies can serve to prime anti-tumor immune responses. We are also studying the impact of targeting immune checkpoints and conventional cancer therapies. We use mouse models to dissect specific immune effectors (including T cells and B cells) in mediating responses to different immunotherapies. Using this approach, we have identified novel mechanisms of resistance to immunotherapy, which we have shown to be at work in cancer patients.
With this information, we can develop treatment regimens to improve treatment response in patients.We also examine these immune mechanisms and potential biomarkers in patients receiving immunotherapies. We are tracking antigen specific immune responses through the use of MHC-peptide tetramers and high-throughput sequencing of T cell antigen receptors (TCR-seq). We also utilize single cell techniques including high dimensional flow cytometry as well as next generation sequencing (single-cell RNA-seq) to determine the effects of immunotherapy on the functional states of immune cells. Future work will focus on identifying novel determinants of response as well as novel targets for future therapies.
Discovering mechanisms of response and resistance to cancer immunotherapy
We are leveraging novel approaches to dissect how immunotherapies work in patients and pre-clinical models at single cell resolution. These include h flow cytometry (e.g. CyTOF), multi-omic single cell sequencing, and high-dimensional spatial studies. By using these unbiased techniques that enable profiling of all cells within a tumor, we can uncover previously unappreciated immune effectors that mediate tumor rejection. One emerging population are cytotoxic CD4 T cells that are present in multiple cancers. We have also been able to elucidate mechanisms that suppress these cells. These findings can enable biomarkers and therapeutic targets for future studies.
Improving cellular therapies through dissection of immune responses in treated patients
Cellular therapies (e.g. CAR T cells, tumor infiltrating lymphocytes) are approved treatments for multiple hematologic and solid malignancies. Using multi-omic single cell techniques, we dissecting determinants of response with these treatments. We are able to discriminate immune cell states that are associated tumor responses. We are using these discoveries to enable improved cell therapies in the future.
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