PROJECT SUMMARY/ABSTRACT
Few children with recurrent neuroblastoma survive. New therapies, particularly immunotherapies, are badly
needed. Some promising results have recently been presented from neuroblastoma trials with a CAR T
therapy demonstrating that redirected T cell therapeutics have a promising role to play in the future. We
propose to redirect T cells to kill neuroblastoma cells using a multispecific T cell engager (MTE) that binds
ROR1, PD-L1, and CD3. ROR1 is targeted because it is expressed in most neuroblastoma patients’ tumors
and has been shown to be necessary for tumor initiation, migration, and other aggressive cancer features in
multiple types of cancer. PD-L1 is targeted because cells surrounding ROR1-positive cells that are being killed
by the MTE will upregulate PD-L1 in response to the interferon gamma that is released by the engaged T cells.
While PD-L1 upregulation is normally a defense mechanism against immune surveillance, our molecule
converts it into a cancer vulnerability because the more cancer cells upregulate PD-L1, the better T cells will be
able to engage and kill them due to the PD-L1 and CD3 binding motifs on the MTE. Concerns about on-target,
off-cancer toxicity due to PD-L1 expression on normal human tissues are mitigated by a recent human clinical
trial results showing that Davoceticept, an MTE that targets PD-L1, achieved good cancer control at doses that
were well tolerated in the clinical trial. We propose the following: Aim 1: Determine the extent to which patient-
derived neuroblastomas are vulnerable to R2P3 plus activated T cells. Aim 2: Determine R2P3 efficacy in
pediatric tumors that are heterogeneous for ROR1 expression. The innovation stems from co-targeting ROR1
and PD-L1, which addresses two common mechanisms of resistance to redirected T cell therapies, namely
target heterogeneity and upregulation of PD-L1. Further innovation relates to the MTE itself, which contains
single domain binders of ROR1, PD-L1, and CD3, which intends to overcome the manufacturing challenges
associated with heavy-light chain pairing. The significance of our proposal is that the molecule we have
designed could rapidly advance to human clinical trials for children with neuroblastoma and other pediatric
solid tumors (e.g., Ewing sarcoma, rhabdomyosarcoma, osteosarcoma) if the results from these studies
support further clinical development. Over a half century of failed clinical trials in recurrent neuroblastoma
patients has taught us that bold, creative, and thoughtful new approaches must be advanced.
