T cell-based therapies have emerged recently as important therapies for cancer. Resistance to the activity of these cells, relapse, toxicities and deaths are still important hurdles to their success and strongly call for mechanisms to potentiate efficacy, while at the same time, to better control the safety of cell therapies. The goal of this project is to create a new generation of synthetic, tumor-specific T cells (based on CAR and TCRm technology) that will selectively home to cancer cells in vivo and then synthesize and release anti-neoplastic drugs at the cancer cell surface or into the tumor microenvironment. The selective and local elaboration of potent anti-neoplastic drugs at the tumor site, or on the cancer cells, should simultaneously: 1) reduce toxicity relative to conventional cancer drug therapy; 2) overcome immune mediated resistance to conventional CAR T cell therapy from regulatory cells and cytokines in the tumor microenvironment (because the cytotoxic drugs made will not be affected;) 3) overcome antigen loss variant mechanisms of resistance (because the drugs will kill cancer cells without antigen on the cell surface;) 4) reduce toxicity relative to conventional CAR T cells because the prodrug infusions can be pharmacologically regulated, scheduled, or stopped. In addition, the enzyme expression can be made conditional. The components of the proposed strategy are: 1) prodrug/drug pair in which the prodrug is not toxic to normal cells or tissues and the resulting drug potently kills cancer cells. Several types of prodrug systems will be developed for various functions and properties (Aim 1). 2) A CAR T cell directed to a tumor specific antigen via a lineage specific scFv (such as CD19 or MUC16) or a more specific TCRm-based scFv (such as to WT1 or PRAME,) 3) An enzyme genetically engineered into the CAR T cell capable of converting the prodrug into the active drug locally. We term these cells ?Synthetic Enzyme Armed KillER? cells or SEAKER cells. These cells will be designed and tested in vitro (Aim 2) and in animal models (Aim 3.) This work will be carried out through a multi-PI, multidisciplinary collaboration between the labs of David A. Scheinberg (PI), Derek S. Tan (Co-PI), and Renier Brentjens (Co-Investigator), comprising extensive expertise in synthetic and medicinal chemistry, biochemistry, pharmacology, cell biology, and cancer immunology, that builds on prior work from the leaders over 15 years.

Public Health Relevance

Cellular therapies are emerging as effective therapies for cancer but are still toxic and not tumor specific. Nearly all tumor-specific targets and proteins that cause cancer are intracellular proteins. Therefore, we propose to create new cellular immunotherapies that recognize these antigen targets from intracellular, tumor specific and oncogenic proteins and make them more potent and less toxic by allowing them to secrete cancer killing drugs.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA023766-39A1
Application #
9704827
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
39
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Staffas, Anna; Burgos da Silva, Marina; Slingerland, Ann E et al. (2018) Nutritional Support from the Intestinal Microbiota Improves Hematopoietic Reconstitution after Bone Marrow Transplantation in Mice. Cell Host Microbe 23:447-457.e4
Velardi, Enrico; Tsai, Jennifer J; Radtke, Stefan et al. (2018) Suppression of luteinizing hormone enhances HSC recovery after hematopoietic injury. Nat Med 24:239-246
Moskowitz, Craig H (2018) Should all patients with HL who relapse after ASCT be considered for allogeneic SCT? A consult, yes; a transplant, not necessarily. Blood Adv 2:821-824
Kim, Seong Jin; Huang, Yao-Ting; Foldi, Julia et al. (2018) Cytomegalovirus resistance in CD34+ -selected hematopoietic cell transplant recipients. Transpl Infect Dis 20:e12881
Maslak, Peter G; Dao, Tao; Bernal, Yvette et al. (2018) Phase 2 trial of a multivalent WT1 peptide vaccine (galinpepimut-S) in acute myeloid leukemia. Blood Adv 2:224-234
DeFilipp, Zachariah; Peled, Jonathan U; Li, Shuli et al. (2018) Third-party fecal microbiota transplantation following allo-HCT reconstitutes microbiome diversity. Blood Adv 2:745-753
Haak, Bastiaan W; Littmann, Eric R; Chaubard, Jean-Luc et al. (2018) Impact of gut colonization with butyrate-producing microbiota on respiratory viral infection following allo-HCT. Blood 131:2978-2986
Boudreau, Jeanette E; Hsu, Katharine C (2018) Natural Killer Cell Education and the Response to Infection and Cancer Therapy: Stay Tuned. Trends Immunol 39:222-239
Lin, Richard J; Ho, Caleb; Hilden, Patrick D et al. (2018) Allogeneic haematopoietic cell transplantation impacts on outcomes of mantle cell lymphoma with TP53 alterations. Br J Haematol :
Malard, Florent; Labopin, Myriam; Cho, Christina et al. (2018) Ex vivo and in vivo T cell-depleted allogeneic stem cell transplantation in patients with acute myeloid leukemia in first complete remission resulted in similar overall survival: on behalf of the ALWP of the EBMT and the MSKCC. J Hematol Oncol 11:127

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