Targeting tumors using T-cell receptor gene transfer: a balance between efficacy and safety

Doctoral Thesis

The use of T-cell receptor (TCR) gene transfer for the treatment of both hematological and solid tumors is increasing. Using TCR gene transfer T cells can be redirected to target tumor or lineage-specific antigens. Especially for poor immunogenic tumors this offers the potential to circumvent limitations of the endogenous T-cell repertoire. Still, the broad use of TCR-based therapy is hampered by a limited number of targeted antigens and HLA class I binding restrictions of TCRs. Furthermore, several of the pioneering T-cell based therapies have demonstrated that the balance between therapeutic efficacy and safety remains a challenge as T-cell mediated toxicities have occurred. In this thesis we identified novel targets, peptides and TCRs in order to treat a broader patient population, among others ovarian and prostate cancer patients. We stringently selected appropriate tumor- and lineage-specific targets using a differential gene expression analysis, and identified naturally...Show moreThe use of T-cell receptor (TCR) gene transfer for the treatment of both hematological and solid tumors is increasing. Using TCR gene transfer T cells can be redirected to target tumor or lineage-specific antigens. Especially for poor immunogenic tumors this offers the potential to circumvent limitations of the endogenous T-cell repertoire. Still, the broad use of TCR-based therapy is hampered by a limited number of targeted antigens and HLA class I binding restrictions of TCRs. Furthermore, several of the pioneering T-cell based therapies have demonstrated that the balance between therapeutic efficacy and safety remains a challenge as T-cell mediated toxicities have occurred. In this thesis we identified novel targets, peptides and TCRs in order to treat a broader patient population, among others ovarian and prostate cancer patients. We stringently selected appropriate tumor- and lineage-specific targets using a differential gene expression analysis, and identified naturally expressed peptides from the HLA class I associated ligandome. We isolated peptide-specific T cells, sequenced their TCRs and carefully selected the most promising TCRs. Overall, we selected ten TCRs that demonstrated an effective and safe reactivity pattern based on the performed T-cell reactivity screenings. These TCRs demonstrated reactivity against broad panels of patient-derived tumor samples and/or tumor cell lines, without reactivity against a broad variety of healthy cell subsets or other antigen negative cells. Furthermore, in this thesis we set up human induced pluripotent stem cell (hiPSC)-derived models to additionally examine toxicity risks of T cells against vital organs or specialized cell subsets. We demonstrated added value of these models in determining toxicity risks in the preclinical pipeline of TCRs.
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Tumor immunotherapy

T-cell receptor (TCR)

Allogeneic HLA

Tumor-associated antigens (TAA)

Lineage-specific antigens

Acute myeloid leukemia (AML)

Ovarian cancer

Prostate cancer

Preclinical screening models

Human induced pluripotent stem cells (hiPSC)