Developing Novel Immunotherapies by Profiling the Cancer Cell Surface

A major area of interest for our group is using enrichment-based strategies to identify protein targets specifically present on the surface of cancer cells.

For example, in recent work (M. Nix et al, Cancer Discovery (2021)) we have discovered cell surface targets specifically upregulated in the MLL-rearranged, poor-prognosis subtype of B-cell acute lymphoblastic leukeumia. We found that a B-cell restricted marker was not only upregulated in this genomic subtype but actually widely expressed across hematologic malignancies. We demonstrated a recently-described, fully in vitro nanobody yeast display library (McMahon et al, Nat Struct Mol Biol (2018)) could develop robust binders to this target with high activity in a CAR-T cell format. In vitro and in vivo testing revealed equivalence to an FDA-approved scFv binder targeting CD19 in multiple B-cell malignancy models.

We have now obtained significant external support for these efforts and our "nanoCARs" targeting CD72 are moving toward clinical trials at UCSF, planned in 2024.

Other work in the group focuses on developing new technologies to profile the tumor cell surface with high sensitivity for application to primary tumor specimens, new technologies combining chemical biology and mass spectrometry to define unique protein conformations at the cell surface, as well as using cell surface protein dynamics to propose rational combinations of small molecules and antigen-targeted immunotherapies (for example, Choudhry et al., Leukemia, 2020). We aim to use these strategies to develop entirely new classes of cancer diagnostics and immunotherapeutics.