SCIENTIFIC ADVISORY BOARD MEMBER
David Knorr, M.D., Ph.D.
I am currently an Assistant Attending Physician at Memorial Sloan Kettering Cancer Center and Visiting Assistant Professor in the Laboratory of Molecular Genetics and Immunology (Ravetch) at Rockefeller University, where I am Director of Clinical Operations and Translational Immunology. My clinical and laboratory interests focus on the mechanisms of immunotherapy, including how they both enhance the immune system and, in some patients, lead to severe adverse events limiting their use. Using novel immunocompetent mouse models expressing human receptors for antibody therapeutics (hFcyR mice), we have demonstrated the ability to recapitulate toxicities seen in patients while using this information to develop better treatment approaches limiting such toxicities. Our studies have provided mechanistic insights into how antibodies targeting CD40 on antigen presenting cells promote antitumor immunity within tumors. My recent research efforts have identified a unique approach whereby intratumoral delivery of an Fc-enhanced CD40 agonist leads to potent T cell immunity. This work was recently advanced into a phase I clinical trial (NCT04059588) for which I am the Principal Investigator and is also in studies for bladder cancer (NCT05126472) and glioblastoma multiforme (NCT04547777). We have more recently characterized CD40 as an important target in models of the cancer immune microenvironment, specifically its differential role on dendritic cells leading to its antitumor functions. My overall goal is to better understand how the immune system is dysregulated in patients with cancer in order to leverage this information for improved therapeutics.
Contributions to Science
The contribution of NMDA receptor activation to neurodegeneration: The mechanisms driving neurodegeneration in multiple diseases, including Alzheimer’s disease and HIV dementia, remain poorly defined. My early career contributions were focused on understanding how signaling through the NMDA receptor leads to excitotoxicity in these conditions. We also investigated the role of membrane lipid metabolites for their contribution to this process. This undergraduate work was informative and inspired me towards a commitment to a career as a physician scientist.
Arek Szklarczyk, Osafame Ewaleifoh, Jean-Claude Beique, Yu Wang, David A. Knorr, Norman Haughey, Tanya Malpica, Mark P. Mattson, Rick Huganir, Katherine Conant. MMP-7 cleaves the NR1 NMDA receptor subunit and modifies NMDA receptor function. FASEB.(2009) 22(11): 3757-67. PMC2574025
David Wheeler, Edward Knapp, Veera V.R. Bandaru, Yue Wang, David A. Knorr, Christoph Poirier, Mark P. Mattson, Jonathan D. Geiger, Norman J. Haughey. Tumor necrosis factor-α-induced neutral sphingomyelinase-2 modulates synaptic plasticity by controlling the membrane insertion of NMDA receptors. Journal of Neurochemistry. (2009) 109(5):1237-49. PMC2688711
Development and function of natural killer cells derived from human pluripotent stem cells: Cellular therapies have been increasingly used in the treatment of cancer, and the available donor sources for these therapies has continued to expand. My graduate research contributions focused on the development of lymphocytes from novel sources including human induced pluripotent stem cells and human embryonic stem cells. Here, I developed methods to generate anti-tumor NK cells in a completely feeder free system at clinically relevant levels. More recently, iPS-derived NK cells have been translated into clinical practice with the first patient being dosed in February of 2019, serving as the first example of iPS-derived therapies being used in humans in the US.
David A. Knorr, Dan S. Kaufman. Pluripotent stem cell-derived natural killer cells for cancer therapy. Translational Research. (2010) Sep;156(3):147-54. PMID: 20801411 PMC2932648
David A. Knorr, Zhenya Ni, Melinda K. Hexum, Laura Bendzick, Laurence J. N. Cooper , Dean A. Lee,, and Dan S. Kaufman. Clinical Scale Derivation of Natural Killer Cells From Human Pluripotent Stem Cells For Cancer Therapy. Stem Cells Transl Med. (2013) Apr;2(4):274-83. PMC3659832
David A. Knorr, Allison M. Bock, Renier J. Brentjens., and Dan S. Kaufman. Engineered human embryonic stem cell-derived lymphocytes to study in vivo trafficking and immunotherapy. Stem Cells Dev. (2013) Jul 1;22(13):1861-9. PMC3685314
David A. Knorr, Veronica Bachanova, Michael R Verneris, Jeffrey S Miller. Clinical utility of natural killer cells in cancer therapy and transplantation. Semin Immunol. (2014) Apr;26(2):161-72. Review. PMID: 24618042. PMC3984606
The role of T follicular helper (TFH) cells in chronic graft-vs-host disease (cGVHD): TFH cells are a subset of CD4 T cells important in providing help to B cells responding to infection. More recently, mouse models have described a role for TFH cells in the pathogenesis of cGVHD. As an internal medicine resident (WCMC) I completed work I started as a 4th year medical student, in which I received a grant to study the role of TFH cells in patients with cGVHD. Here, we demonstrated that in contrast to the mouse models, patients with active cGVHD actually have loss of TFH cells in the peripheral blood. This finding has since been corroborated in larger cohorts and ongoing studies trying to target these populations for treatment of cGHVD are ongoing.
David A. Knorr, Jeffrey S. Miller, Bruce R. Blazar, Michael R Verneris. Loss of T follicular helper cells in the peripheral blood of patients with chronic graft-vs-host disease. Biology of Blood and Marrow Transplantation. 2016 May;22(5):825-33. PMID: 26806586. PMC5015683
Defining the mechanisms of antibody-based immunotherapies: As a fellow in Hematology-Oncology at MSKCC and postdoctoral fellow in the laboratory of Jeffrey Ravetch at Rockefeller University, I focused my studies in understanding the mechanisms of cancer immunotherapy. My specific interests are in understanding the mechanisms by which antibody-based therapies can be optimized for the treatment of patients with cancer. I am also interested in studying how the immune system is dysregulated in cancer and how we can build on these findings to better inform our therapeutic approaches.
David A. Knorr, Jedd Wolchok, Dmitriy Zamarin. Immunoregulatory antibody therapy. Pocket Oncology. Philadelphia, PA: Lippincott Williams and Wilkins, 2018.
David A. Knorr, Rony Dahan, Jeffrey V. Ravetch. Toxicity of an Fc engineered, agonistic anti-CD40 antibody is abrogated by intratumoral injection and results in systemic and durable anti-tumor immunity. Proc Natl Acad Sci USA. 2018 Oct 23;115(43):11048-11053. doi: 10.1073/pnas.1810566115 PMC6205479
David A. Knorr, Jeffrey V. Ravetch. Immunotherapy and hyperprogression: Unwanted outcomes, unclear mechanism. Clin Cancer Res. 2019 Feb 1;25(3):904-906. doi: 10.1158/1078-0432.CCR-18-3144. Epub 2018 Nov 5. PMID:30397179
Christopher Garris, Jeffrey Wong, Jeffrey V. Ravetch, David A. Knorr. Dendritic cell targeting with Fc-enhanced CD40 antibody agonists induces durable antitumor immunity in humanized mouse models of bladder cancer. Science Translational Medicine. 2021 May 19;13(594):eabd1346. doi: 10.1126/scitranslmed.abd1346. PMID: 34011627
For a full list of publications, please use the following link:
https://www.ncbi.nlm.nih.gov/sites/myncbi/1dSy7jQlv1Y5b/bibliography/40079469/public/?sort=date&direction=ascending.
Additional Information: Research Support and/or Scholastic Performance Oral Presentations
2010 Plenary Session, American Society of Clinical Investigation Annual Meeting, Chicago, IL
2010 Medical Scientist Training Program (MSTP) Annual MD/PhD Conference, Keystone, CO
2010 American Society of Hematology Annual Meeting, Orlando, FL
Additional Information: Research Support
Current Research Support
ACTIVE
1K08CA248966-01 09/01/20-08/30/25 9.0 Cal Mos
Fc-enhanced CD40 agonist antibodies for immune modulation of the tumor microenvironment
NCI $183,167 Annual DC
Role: PI
