NVVI Thesis Award 2013 goes to Willemijn Hobo

Strengthening the T-cell's morale and intelligence against tumours

omslagproefschriftwillemijnhobo-1_kl.jpgFor an allogeneic stem cell transplantation, the donor's cells are carefully matched for HLA-molecules to those of the patient. Despite this, genetic differences in various proteins can occur. “This can lead to donor's T-cell mediated recognition of remaining patient-specific cells in the blood as 'foreign'. Donor T-cells will attack of those patient blood cells”, says Willemijn Hobo. “This is what you want, because these include the tumour cells. But despite such tumour-specific T-cell responses, tumour cells are in many cases able to return nonetheless. These tumour cells are able to actively counteract T-cell effectiveness.”

Tumour cells can restrain the T-cell reaction and thus escape, in the same way as chronic viral infections such as HIV do. Hobo: “Firstly, we have shown that this is indeed what can happen. We took blocking antibodies to look if we could prevent interactions of the inhibitory proteins, PD-1 and BTLA, to block the tumour cell's restrain of T-cells. This proved to be possible. Although probably other inhibitory proteins on the tumour cells are also involved, PD-1 and BTLA are important ones. We suppose that we can influence the scale to the right side, so that T-cell restraint is turned into T-cell activation. From American clinical research we know that blocking PD-1 was an effective immunotherapy against solid tumours.”

However, antibody mediated blocking of PD-1 and BTLA in transplanted cancer patients might be dangerous, due to aggravating life-threatening graft-versus-host disease. Hobo: “Blockage of T-cell restraining proteins on tumour cells is one step. Yet, patients may have insufficient numbers of highly functional tumour-reactive T-cells to engage in a successful fight against tumour cells. We think, therefore, that interference with inhibitory signaling pathways should be combined with tumour specific T-cell activating vaccination using dendritic cells. These stimulate T-cells to actually kill tumour cells.”   

Currently used dendritic cell vaccines are effective in inducing T-cell immunity, but clinical effectiveness must be improved. “We therefore enhanced the stimulatory potential of the vaccine”, Hobo comments, “by applying small interfering RNA's to lower the protein expression of restraining proteins on the surface of dendritic cells. This was preclinical work, but I'm excited that we can continue this work in a patient study. I'm curious about the results.” Hobo herself will be involved in coordination of this patient study. 

Another part of her present work, enabled by winning a Bas Mulder Award in 2012 and also a continuation on her Ph.D. research, involves selective targeting of restraining proteins on the tumour by delivery of small interfering RNA’s into the tumour cells through nanoparticles. This has the advantage of lowering expression levels of inhibitory proteins on the tumour cells, while at the same time avoiding systemic toxicity (graft-versus-host-disease). In combination with vaccination strategies, this would lead to improved anti-tumour immunity.

Hobo believes that all steps together will lead to improved results in patients: more tumour-reactive T-cells, better T-cell activation and more effective tumour cell recognition. “First you have to prevent the T-cell restraining action by tumour cells and to boost tumour recognition by T-cells. When this has been accomplished, sufficient numbers of T-cells should be ready to effectively fight the tumour cells. I'm confident such a three-step approach could prove effective. But it will take some more years to have it all in place in the clinic.”

Text: Leendert van der Ent, bureau Lorient


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