WT1 is a protein that is highly expressed in a wide variety of cancer types. Collaborating with Fred Hutch colleagues in Dr. Phil Greenberg’s group, Dr. Chapuis participated in the identification and generation of a native, high-affinity WT1-specific TCR (TCRC4) and optimized the Good Manufacturing Process (GMP) methods for transfer (by lentiviral transduction) into T cells for clinical use.
The T cell subtype that is most involved in attacking abnormal cells is known as a CD8+ ‘killer’ T cell. Dr. Chapuis wrote and successfully obtained necessary regulatory approvals, and the team is now evaluating the safety and efficacy of transplant donor-derived CD8+ T cells carrying the HLA-A*0201-restricted WT1-specific TCRC4. Dr. Chapuis is the Co-Principal Investigator of this Phase I/II clinical trial for patients with relapsed AML, MDS or CM after donor stem cell transplant. Preliminary results suggest the therapy is safe and can block relapse for up to 2 years. Now ongoing is a Phase I/II study of patient-derived TCRC4-transduced CD8+ T cells for recently diagnosed AML patients who have not undergone stem cell transplantation.
Dr. Chapuis and colleagues established a platform for developing gene-modified adoptive T cell therapies targeting an array of tumor antigens in solid and liquid tumors. They are using high-throughput strategies to identify and generate native high-affinity TCRs from multiple donors to target ‘cancer-testis antigens’ that are expressed on various cancers but not on normal tissues (except for male germ cells in adults).
In particular, the MAGE-A1antigen is frequently expressed in triple-negative breast cancer and in other poor prognosis tumor types, including squamous non-small cell lung carcinoma and advanced-stage melanomas, so the MAGE-targeting therapy they are developing may be broadly useful.
The Chapuis team is developing strategies to modulate infused T cell products and the resident tumor microenvironment to enhance clinical efficacy. As transferred T cell persistence is critical to clinical success, new strategies aim to increase the tumor-binding strength (affinity/avidity) of tumor-specific TCRs and to use T cell subset(s) with long-lived therapeutic potential. Based on promising laboratory results, Chapuis and colleagues designed a clinical trial for patients with late-stage lung cancer or mesothelioma. They are testing whether naïve and central memory CD8+ T cell subsets do persist longer, localize better to tumor tissue, retain function and are more effective at eliminating detectable tumor, as previous findings suggest.
State-of-the-art tests (HTTCS and pMHC multimer binding assays) are being used to characterize the diversity of T cells (identify individual clonotypes) within therapeutic T cell products, track them post-infusion, and then deduce the frequencies and characteristics of the specific T cells ultimately responsible for effecting tumor regression. The lab is also working to engineer TCRs that confer function to both CD8+ and CD4+ T cells, as opposed to more typical CD8+ only protocols, to further enhance anti-cancer immune activity.