Ep. 4: “Therapeutic T Cell Engineering” Featuring Drs. Carl June and Philipp Rommel
May 11, 2021
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Dr. Carl June and Dr. Philipp Rommel discuss ex vivo T cell engineering for cancer and HIV therapies. They cover topics like m6A RNA modification in immune responses and synthetic Notch CAR T cells targeting solid tumors. The podcast also explores challenges in translating T cell therapy breakthroughs and immunotherapy strategies for cancer interception.
Combining synthetic notch receptors with CAR T cells enhances specificity for solid tumor targeting.
Innovative CAR T cell therapies show promise in treating challenging cancers like pancreatic cancer and glioblastomas.
Deep dives
Targeting Macrophage Activation with M6A Modification
The podcast explores a study that delves into the role of M6A RNA modification in macrophage activation. By focusing on the gene METTL3, critical for macrophage activation, researchers found that its deficiency led to impaired mRNA modification and signaling cascade dysregulation, impacting pathways like NF-CAP-B TLR signaling. Through mechanistic insights, they demonstrated how knocking out METTL3 affected RNA degradation, leading to elevated levels of specific proteins and reduced TLR activation.
Enhancing T Cell Recognition in Solid Tumors with Synthetic Notch CAR Circuits
Researchers discuss enhancing CAR T cell therapies for solid tumors using synthetic notch CAR circuits. By combining synthetic notch receptors with CARs targeting tumor-associated antigens, they aim to improve specificity and target tumor cells more effectively in complex environments. The inducible system ensures that CAR expression is triggered only in the presence of specific antigens, promoting persistent anti-tumor activity in mouse models for mesothelioma and ovarian cancer.
Addressing Clinical Challenges in Pancreatic Cancer Treatment
The conversation highlights the medical need for innovative therapies in pancreatic cancer, emphasizing the urgency to improve outcomes in challenging diseases like pancreatic cancer and glioblastomas. With existing therapies proving insufficient, researchers are focusing on developing advanced cellular therapies, utilizing pancreatic cancer as a translational proving ground due to its accessible nature for research and existing mouse models that closely mimic human disease. The goal is to push the boundaries of therapy options for these high-mortality cancers.
CAR T Cell Efficacy in Tumor Cells
CAR T cells have shown effectiveness in killing chemotherapy refractory tumor cells in pancreatic cancer and leukemia. Studies indicate that in a controlled environment without tumor microenvironment barriers, CAR T cells demonstrate similar effectiveness in targeting and killing different types of cancer cells, potentially offering a promising treatment approach.
Challenges in Engineering Complex CAR T Cells
Developing more complex genetic circuits for CAR T cells presents challenges due to size limitations of lentiviruses used to insert genetic components. Optimizing protocols from cloning to lentivirus production is essential to improve CAR T cell production yields. Overcoming size limitations and enhancing the efficiency of lentivirus-based methods are crucial steps in translating advanced CAR T cell designs into viable clinical treatments.
Dr. Carl June is the Richard W. Vague Professor in Immunology at the University of Pennsylvania, Director of the Center for Cellular Immunotherapies at the Perelman School of Medicine, and Director of the Parker Institute for Cancer Immunotherapy. Dr. Philipp Rommel is a Postdoctoral Researcher in the June lab. Together, they are interested in lymphocyte biology, with a major translational focus on ex vivo T cell engineering for cancer and HIV cell-based therapies.
Natural Killer Receptors Fine-Tune T Cells – Researchers identified a role for natural killer cell receptor signaling in regulating self/non-self discrimination by HLA-E–restricted T cells.
Notch4 Signaling in Viral Infections – Notch4 expression on Treg cells suppressed the induction of amphiregulin and promoted severe lung inflammation in viral infections.
