Advances in Fundamental Research

Overcoming T Cell Exhaustion

We have made several basic research advancements that are poised to enhance safety and efficacy and expand the reach of CAR-T cell therapy. Our previous studies demonstrated that many CAR-T cells fail in patients due to the development of “T cell exhaustion”, a poorly understood phenomena associated with progressive immune dysfunction. To address this problem we worked with Howard Chang, MD, PhD, using a technique his laboratory developed called ATAC-Seq. We were able to pinpoint areas of the genome where regulatory circuits are most dysregulated during CAR-T cell exhaustion and discovered that exhausted T-cells manifest an imbalance in the activity of AP-1 transcription factors, a major class of genes that regulate proteins in cells. 

Armed with this understanding, we modified CAR-T cells to restore the balance by overexpressing c-Jun, an AP-1 family member that increases expression of proteins associated with T cell activation. C-Jun overexpressing CAR-T cells are “exhaustion-resistant” and demonstrate greatly enhanced potency in numerous cancer models. We published these results, “C-Jun Overexpression in CART T Cell Induces Exhaustion Resistance” in Nature, 2019. Plans are underway to bring this discovery to the clinic by testing overexpression of c-JUN in several CAR-T cell platforms, in patients with leukemia and solid tumors.

New Cell Therapy Option for Brain Tumors

We have made important strides toward determining how to use cell therapy for brain tumors, including a group of devastating pediatric brain tumors known as atypical teratoid/rhabdoid (ATRT) tumors. Working in collaboration with the laboratory of Michelle Monje MD, PhD, as well as collaborators from UCSF, British Columbia, Heidelberg Germany, and Paris France, we led an effort that discovered that the B7-H3 protein is abundant on ATRT tumors but not present on healthy brain cells. We engineered CAR-T cells to target B7-H3 and they potently killed ATRT cells. 

We further discovered that administering the CAR-T cells into the cerebrospinal fluid that bathes the brain was a superior delivery method compared to delivering them into the bloodstream. Compared to blood delivery, brain delivery required fewer CAR-T cells to cure the tumor and had less toxicity, and they persisted in the brain after the cancer was gone. Moreover, some of these cells migrated out of the brain and stayed in other parts of the body where they protected animals against a new challenge with the cancer. This work, “Delivery of CAR T cells Directly Into the Central Nervous System Enhances Cure Rates of Brain Tumors in Preclinical Models” was published in Nature Medicine, 2020 and lays the foundation for clinical trials using brain delivery of CAR-T cells for pediatric brain tumors as well as for adults with the brain tumor glioblastoma. We plan to launch these groundbreaking trials in 2021.

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