Landsteiner lecture by Harry Dolstra | Cancer immunotherapy with ex vivo-generated NK cells from hematopoietic progenitor cells

On 3 June 2024, Prof Harry Dolstra PhD (Cell Therapy Facility at Radboudumc, Nijmegen, The Netherlands) will give a Landsteiner Lecture at Sanquin Research, Amsterdam.

Title: Cancer immunotherapy with ex vivo-generated NK cells from hematopoietic progenitor cells'

Host: Carlijn Voermans

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Abstract
Adoptive transfer of allogeneic natural killer (NK) cells is a relatively non-toxic approach which is gaining interest to combat cancer. However, further enhancement of its therapeutic effect is needed to achieve more and longer-lasting clinical responses. We therefore established a GMP-compliant AHR-antagonist and cytokine-based culture system for the manufacturing of NK cell products from umbilical cord blood CD34+ hematopoietic progenitor cells (HPC) with high cell numbers, purity and functionality, and importantly absence of T cell contaminants. In preclinical and upscaling studies this HPC-NK-cell product exerts potent anti-tumor reactivity. Furthermore, our clinical studies showed that nonengineered HPC-NK cells can be safely administered to acute myeloid leukemia and ovarian cancer patients with transient anti-tumor reactivity. To further increase clinical efficacy, we engineer HPC-NK cells with chimeric antigen receptors (CARs) to maximize tumor-directed cytotoxicity, combined with transpresentation of IL15 tethered with IL15Rα (tIL15) to improve CAR-NK-cell expansion and activity. Furthermore, we are investigating the potential of CRISPR/Cas9 editing to prevent immune suppression in the tumor microenvironment. These developments will generate off-the-shelf allogeneic CAR/tIL15-modified and CRISPR-edited NK cells for cancer immunotherapy.

Biography
Harry Dolstra is Professor of Translational Immunohematology at the Radboud University in Nijmegen. He received his Master’s degree from the University of Utrecht in 1993 in Molecular-Cellular Biology. He then received his doctorate from the University of Nijmegen in 1999. The topic of his thesis was "Donor cytotoxic T cell responses against leukemia in allogeneic bone marrow recipients“. He completed his post-doctorate work at the Radboud University Medical Center and the CRC for Cancer studies in Birmingham, UK. In 2023 he became Professor and in 2017 Head of the Cell Therapy Facility at the Radboud University Medical Center, where he continues to date. His research in the field of "Translational Immunohematology" is centered on immunobiology of graft-versus-tumor responses after allogeneic hematopoietic stem cell transplantation, and the development of innovative complementary (cellular) immunotherapy against cancer.