Harvard Catalyst Profiles

National Taiwan University, Taipei, Taiwan	DVM
Ludwig Maximilian University of Munich, Munich, Germany	PhD		Pharmacy

Recent immune-oncology (I-O) clinical trials have shown dramatic, durable responses in melanoma, renal cell carcinoma, lymphoma, leukemia, uroepithelial and non-small cell lung cancer. The goal of immune therapy is to counteract tumor editing that selects for tumors resistant to immune surveillance and activate dysfunctional immune cells that have evolved to tolerate the tumor. The most successful current immune therapies use checkpoint inhibitors to restore functionality to exhausted tumor-infiltrating lymphocytes (TIL) or adoptively transferred, genetically engineered cytotoxic T cells expressing chimeric receptors (CAR T cells) that target tumor cells for elimination.

However, most cancers, even in responsive cancer types, do not respond to checkpoint inhibitors. Much of the ongoing work to improve response rates focuses on combinations of checkpoint inhibitors, with some, mostly incremental, successes, but with the risk of increased autoimmune toxicity, because checkpoint inhibitors remove the brakes on all T cells, not just anti-tumor T cells. Increasing the response rate for I-O therapies will require new strategies that directly address the main problem (lack of tumor recognition by T cells), potentially used in combination with conventional chemotherapy, new targeted therapies or checkpoint inhibitors.

We aim to develop a new platform that can both evaluate new I-O targets in solid tumors and be used as tumor-targeted I-O drugs. We will evaluate new strategies to make aggressive cancers visible to the immune system and counteract T cell exhaustion. To accomplish this goal, we will knockdown genes selectively in cancer cells, but not in normal tissue. Immune modulation of the cancer cell should be largely free of autoimmune side effects. We have adapted an effective method for in vivo tumor-targeted gene knockdown that uses RNA aptamers (which can be thought of as RNA “antibodies”) - structured RNAs that bind with high affinity to a cell receptor - to deliver covalently linked small interfering RNAs (siRNAs) into cells. Knockdown occurs selectively in receptor-bearing cells when aptamer-siRNA chimeras are internalized and cleaved intracellularly to liberate an active siRNA. EpCAM, the first described tumor antigen, is expressed at several logs higher levels in epithelial cancers (97% of breast cancers, 100% of lung, pancreas, colon, ovarian, prostate cancers) and their “cancer stem cells” than normal epithelia, making it an attractive target for selective tumor targeting. For tumor targeting, we use an EpCAM aptamer that binds with low nanomolar affinity to both mouse and human EpCAM.

Our main goal is to identify novel strategies/drug targets to induce or restore anti-tumor immunity in solid tumors. As a corollary, another goal is to develop a useful platform to knockdown genes in vivo (with minimal off-target effects) in epithelial tumor cells, including the small populations of aggressive cancer stem cells. This platform could be used to investigate the in vivo importance of individual tumor dependency or immune modulating genes or to define the role of specific gene products on tumor biology or anti-tumor immunity. By the end of this grant, we will have identified individual EpCAM-AsiCs that could also serve as candidate immune modulatory drugs for preclinical evaluation.

• large molecule formulations
• drug delivery
• RNAi therapeutics
• cancer immunotherapy
• imaging-based biodistribution study
• molecular & systemic pharmacokinetic study