Synopsis of research lines:
The Heemskerk group has a long standing interest in using a “bedside to bench and back” approach to increased knowledge on antigen specific immunity after allogeneic stem cell transplantation and improving adoptive immunotherapy strategies for patients with hematological malignancies and solid tumors. In 2013 we started the first clinical TCR gene therapy study in the Netherlands for the treatment of high risk leukemia. In collaboration with Bellicum Pharmaceuticals we will initiate this year a clinical study in which patients suffering from acute myeloid leukemia will be treated with PRAME-TCR engineered T cells. Several CAR and TCR gene therapy studies have demonstrated that engineering of T-lymphocytes with high affinity antigen receptors can overcome immune tolerance, and that these re-engineered T-cells demonstrate potent anti-tumor reactivity in cancer patients. The major hurdle however for TCR gene therapy is the limited number of potent tumor specific TCRs. To identify more clinically relevant TCRs for the treatment of both hematological as well as solid tumors, we have developed a high-throughput strategy in which we use the immunogenicity of allogeneic HLA molecules to selectively induce antitumor reactivity. This research builds on the fundamental insights gained on T cell immune responses towards non-self HLA molecules after allogeneic stem cell transplantation. From the HLA-mismatched T cell repertoire of healthy individuals we have now identified several TCRs with potent anti-tumor reactivity. Recently, we have identified a high affinity TCR directed against intracellular transcription factor BOB1. T cells expressing the BOB1-specific TCR efficiently lysed malignant B cells ranging from acute lymphoblastic leukemia to mantle cell lymphoma and multiple myeloma. Potent antitumor reactivity was also demonstrated in a preclinical xenograft mouse model of established multiple myeloma, indicating that BOB1-specific TCRs can broaden immunotherapy to diseases such as multiple myeloma for which existing immunotherapeutic interventions are scarce.