This U54 “Immuno-engineering to improve Immunotherapy (i3) Center” was developed in
response to RFA-CA-19-013. The purpose of this U54 is to employ immune-engineering
principles to design more durable, accessible, and less toxic immunoprevention and
immunotherapy strategies. A national priority set by the cancer Moonshot initiative is to support
studies incorporating next-generation genetic engineering, engineered biomaterials,
nanotechnology, computational and mathematical modelling, or systems biology approaches in
design, implementation and evaluation of next generation immunotherapies focused on
overcoming immunosuppressive barriers, targeting tumor cells for killing, and generating long
lasting anti-cancer immunological memory. The focus of our U54 entitled “Engineering the Next
Generation of T cells” is on developing next-generation gene-editing or modification of immune
cells to improve persistence in vivo, control and manipulate the immune system to reduce offtarget
toxicities and enhance anti-tumor effectiveness of adoptive cell therapy. Our central
hypothesis is that next generation engineering can improve the safety and efficacy of CAR T cells
while decreasing the cost of goods.
There are three scientific projects in our U54 Center. The shared goal of these projects is to
enable this powerful therapy to reach a broader spectrum of patients with blood cancer and solid
cancers. In Project 1, we are using CRISPR/Cas9 to edit the epigenome of T cells and to make
cells resistant to cytokine release syndrome (CRS), while employing engineering technologies to
automate CAR T cell culture. The goal of Project 2 is to generate universal CAR T cells (UCART)
using advanced genetic editing technologies and then to compare UCAR to autologous CAR T in
a unique model of canine cancer. In Project 3 we will use advanced protein engineering, cell
engineering and oncolytic vectors to test synthetic cytokine and cytokine receptor systems in
mouse and human T cells, with the long-term goal of eliminating or reducing the need for
lymphodepleting conditioning chemotherapy prior to adoptive cell transfer. Our approach is
multidisciplinary and multi- institutional. We have brought together a cadre of exceptional
investigators from multiple disciplines who have collaborated and published together for many
years. State of the art genetic editing with CRISPR/Cas9 and cell culture technologies at the
University of Pennsylvania are synergistically coupled with world-class protein engineering and
structural biology at Stanford University. Each project is led by recognized authorities in the field.
The Administrative Core for this U54 is designed to manage and coordinate all i3 Center Research
Project activities and serve as the liaison between the i3 Center and the IOTN Data Management
and Resource-sharing Center (U24) and other Cancer Moonshot consortia, including the Pediatric
Immunotherapy Discovery and Development Network (PI-DDN). In addition, the Administrative
Core will coordinate collaborative research activities between the i3 Center Research Project
PD(s)/PI(s) and IOTN (or other) investigators. The potential for paradigm-shifting impact this U54
is to transform the lessons of first-generation CAR T for leukemia and lymphoma into meaningful
efficacy against all malignancies.