Credentials: MD, PhD
Position title: Professor
1111 Highland Ave.
Madison, WI 53705
- McNeel Lab
MD, University of Chicago, Pritzker School of Medicine (1994)
PhD, University of Chicago, Department of Biochemistry and Molecular Biology (1992)
Dr. Douglas McNeel, MD PhD is a genitourinary medical oncologist with a translational laboratory research focus on prostate cancer immunology. Since 1997 he and his laboratory have studied vaccines for prostate cancer, specifically identifying antigens to target in vaccines, evaluating DNA vaccines in murine models to elicit tumor-reactive CD8+ T cells, and translating these studies to human clinical trials.
Overall my clinical, laboratory and translational research program has been focused on immune-based treatments for prostate cancer, and anti-tumor vaccines in particular. We began studies 20 years ago evaluating different proteins produced by prostate tissue that might best serve as targets for vaccines, and different methods to target these proteins (“antigens”) able to elicit immune responses able to lyse prostate cancer cells. Over the last ten years my lab has focused efforts on three specific target antigens, and on DNA vaccines as a simple approach to elicit anti-tumor immune responses to these target antigens. This research is translational in nature, taking results from preclinical immunology studies to clinical trials, and then using this information to guide the laboratory research direction. These research efforts have been continuously extramurally funded by multiple grants from the National Institutes of Health, the DOD Prostate Cancer Research Program, and the Prostate Cancer Foundation.
Over the last 5 years, our research has specifically sought to understand the mechanism of action of anti-tumor DNA vaccines, using this information to increase their immunogenicity, and apply these findings to clinical testing as treatment for prostate cancer. To date we have conducted two clinical trials evaluating the safety and immunogenicity of a DNA vaccine encoding the prostate-specific antigen, prostatic acid phosphatase (PAP), in patients with biochemically recurrent prostate cancer. We are currently completing accrual to a multi-center phase I clinical trial evaluating a second DNA vaccine, encoding the ligand-binding domain of the androgen receptor, in patients with newly metastatic prostate cancer. In the first two trials, we found that this method of immunization can elicit T-cell immunity to the PAP target antigen, and patients who develop persistent Th1-biased immunity appear to have a delay in disease progression. Based on these observations, we have recently completed accrual to a multi-center, randomized, placebo-controlled clinical trial to determine whether immunization results in a delay in the time to metastasis in patients with biochemically recurrent prostate cancer.
In preclinical models, over the last 5 years our lab has been evaluating different antigens as targets for vaccines, and means to improve the immunogenicity of DNA vaccines by making changes to the DNA vector sequence to increase the persistence of transgene expression and/or encode epitopes with greater MHC class I affinity. We have found that efforts to increase the binding of encoded epitopes for MHC class I resulted in a higher frequency of elicited CD8+ T cells, and cells with an activated Th1 phenotype. However these cells expressed higher PD-1, and as a result of IFNg released by these CD8+ T cells, resulted in increased PD-L1 on tumor cells. Together this resulted in an inferior anti-tumor response, an effect which could be abrogated in the presence of PD-1 or PD-L1 blockade. Contrarily, in studies using altered DNA sequences that led to persistent antigen expression following local delivery of DNA vaccines, we found that immunization led to increased numbers of antigen-specific CD8+ T cells that expressed higher LAG-3. Similarly, this approach elicited an inferior anti-tumor response which could be abrogated in the presence of LAG-3 blockade. We have similarly found that patients with prostate cancer, previously treated with a DNA vaccine who developed an antigen-specific IFNg-secreting T cells, also developed an increase in PD-L1 expression on circulating tumor cells, and that PD-1 blockade of immune cells from these immunized patients in vitro resulted in greater antigen-specific Th1 cytokine expression. Together these results have demonstrated that blockade of specific T cell checkpoint molecules at the time of T-cell activation can lead to superior anti-tumor immunity using vaccines in murine models. We are currently testing this in clinical trials, as well as in laboratory models to identify appropriate sequence of treatments and checkpoint molecules to target in combination with tumor vaccines.
In other preclinical studies, we have been seeking to improve the immunogenicity of DNA vaccines by studying the expression of DNA-encoded antigens in, and presentation by, professional antigen-presenting cells. We have identified that both B cells and myeloid cells (monocytes, macrophages, dendritic cells) take up DNA passively, however B cells serve as primary antigen-presenting cells for DNA. Passive uptake of DNA by myeloid cells led primarily to degradation and no induction of immunity to the encoded antigen. This finding serves as a new direction for our lab in which we aim to specifically target different professional antigen-presenting cells, B cells in particular, to understand and optimize preferred means for DNA immunization.