Tumor-Specific Immunotherapy for a Rare Pediatric Liver Cancer


ASPIRE Award (2020-Present)

Paul Thomas, PhD, St. Jude Children’s Research Hospital

Fibrolamellar carcinoma (FLC) is a rare and lethal liver cancer that has no effective systemic therapy. It occurs primarily in young patients, and nearly all of the tumors are driven by the oncogenic fusion protein DNAJ-PKAc. The fusion of any two cellular proteins should create a unique and novel antigen at the fusion point. The Thomas lab hypothesizes that engineered antigen receptors directed at this fusion neoantigen could form the basis for an effective adoptive cell therapy in FLC. The group has preliminary data suggesting that patients can mount a T-cell response against the fusion antigen in FLC. The goal of the project is to identify endogenous T-cell receptors (TCRs) targeting the fusion antigen that could be used for adoptive T-cell therapy. One potential obstacle is that a TCR must be matched to an appropriate human leukocyte antigen (HLA) molecule in each patient for the therapy to be effective. A suite of different fusion-specific TCRs will need to be identified to cover the diverse array of HLA molecules found in patients. Using patient-derived FLC samples of multiple HLA types, researchers in the Thomas lab aim to identify and clone TCRs capable of mediating a therapeutic response. Candidate TCRs will be taken forward for functional testing in vitro to ascertain their impact on HLA restriction in models of different HLA types. This research is a critical first step in developing a cellular immunotherapy that relies on native, patient-derived TCRs, which could one day change the landscape of immunotherapy for FLC and other solid tumors.

PUBLISHED RESEARCH

Garfinkle E, Zamora A, Crawford J, Thomas PG, Gruber T. A novel humanized murine model to identify neoantigen-specific T cells in pediatric acute megakaryoblastic leukemia. Journal for ImmunoTherapy of Cancer. 2020.

Chaib M, Sipe LM, Yarbro JR, Bohm MS, Counts BR, Tanveer U, Pingili AK, Daria D, Marion TN, Carson JA, Thomas PG, Makowski L. PKC agonism restricts innate immune suppression, promotes antigen cross-presentation and synergizes with agonistic CD40 antibody therapy to activate CD8+ T cells in breast cancer. Cancer Lett. 2022.

Talleur A, Qudiemat A, Métais JY, Langfitt D, Mamcarz E, Crawford JC, Huang S, Cheng C, Hurley C, Madden R, Sharma A, Suliman AY, Srinivasan A, Velasquez MP, Obeng EA, Willis CM, Akel S, Karol SE, Inaba H, Bragg A, Zheng W, Zhou S, Schell S, Tuggle-Brown M, Cullins D, Patil SL, Li Y, Thomas PG, Zebley C, Youngblood BA, Pui CH, Lockey T, Geiger TL, Meagher MM, Triplett BM, Gottschalk S. Preferential expansion of CD8+ CD19-CAR T cells postinfusion and the role of disease burden on outcome in pediatric B-ALL. Blood Adv. 2022.

Zhang T, Yin C, Fedorov A, Qiao L, Bao H, Beknazarov N, Wang S, Gautam A, Williams RM, Crawford JC, Peri S, Studitsky V, Beg AA, Thomas PG, Walkley C, Xu Y, Poptsova M, Herbert A, Balachandran S. ADAR1 masks the cancer immunotherapeutic promise of ZBP1-driven necroptosis. Nature. 2022.

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