Chimeric Antigen T Cell (CAR-T) therapies, which redirect a patient’s own T cells towards their cancer,
are very promising therapies for difficult to treat and refractory cancers. While CAR T cell therapies have been
very successful in treating refractory B cell cancers,1,2 they have encountered many challenges when directed
towards more complex solid and liquid tumors, such as multiple myeloma. CAR T cells face challenges such as
an immunosuppressive tumor microenvironment, in which inhibitory ligands are often expressed, nutrients and
oxygen are lacking, and cytokines or soluble factors are secreted to support malignant cell growth.3 This hostile
environment, as well as cell intrinsic defects, can lead to reduced CAR T cell proliferation, inhibition of function
and loss of CAR T cell persistence. Previously developed synthetic Notch (synNotch) receptors allow for control
and customization of therapeutic immune cells.4,5,6 SynNotch T cells can deliver user defined cell intrinsic or
extrinsic payloads, such as transcription factors, cytokines, or antibodies in an antigen specific, spatially
controlled manner. While these receptor circuits could be used to address the many challenges of complex
tumors, these receptors lack the ability to initiate cytotoxicity like CARs or TCRs. Therefore, successful and
persistent engineered T cells require both the ability to recognize, activate and kill tumor cells, as well as the
ability to produce payloads to counteract a wide range of challenges encountered in challenging tumor
microenvironments. Recently, I have engineered a novel “Hybrid SynNotch CAR” receptor, whose architecture
incorporates signaling domains (e.g. co-stimulation, CD3z, etc.) that can initiate activation of T cells concomitant
with custom transcriptional regulation typical of a SynNotch receptor. These Hybrid synNotch CAR receptors are
functional and represent a new class of synthetic receptors that activate short timescale signaling and long term
custom transcriptional responses in a single receptor architecture. This proposal seeks to expand upon these
initial proof-of-concept Hybrid SynNotch CAR receptors, understanding their full range of function and effect on
engineered T cells, and demonstrating their ability to address therapeutic challenges in multiple myeloma.
The University of California, San Francisco (UCSF) is a leading institution in immunology and is regarded
as one of the top doctoral programs in Biomedical Sciences graduate education. As a graduate student in the
Roybal lab, I receive regular guidance and mentorship from renowned investigators and have access to
resources provided by the Parker Institute for Cancer Immunotherapy, and the Chan Zuckerberg Biohub. This
training plan also includes commitment to professional development programs, such as the UCSF TRAIN UP
Mentorship program, and courses in manuscript and thesis writing. This proposal seeks to develop and apply a
novel synthetic receptor circuit, which simultaneously targets cancer cells and addresses diverse challenges in
tumors and tumor microenvironments. Completion of the proposed work will move the field of engineered cancer
immunotherapy forward and prepare me for a future career as an independent investigator.