Adoptive T cell transfer and vaccination as treatment for stage IV melanoma in patients

Location: Leids Universitair Medisch Centrum, clinical oncology, Leiden, Netherlands
Collaboration: Dr. Ir. E.M.E. Verdegaal en Prof. Dr. S.H. van der Burg

 

The activation and expansion of tumor reactive T cells outside a patients body and their subsequent re-infusion (adoptive cell transfer (ACT)) is at this moment the most effective approach to induce objective anti-tumor responses in end-stage metastasized melanoma patients. We have developed a clinically successful strategy in which the patient’s own melanoma cells - cultured from surgically removed tumor tissue – are used to stimulate and expand the tumor-specific T cells present in their peripheral blood lymphocytes. These T cells are adoptively transferred in combination with low dose Interferon-alpha to sustain T cell activation in vivo. The treatment is safe, has a low toxicity profile and results in durable clinical benefit in halve of the patients treated thus far. Clinical effectiveness of adoptively transferred T cells can be further improved by vaccination.

Because our analyses revealed that T cells administered to responder patients uniquely recognize ‘private antigens’ expressed only by their own tumor cells and not by HLA-matched tumor cells from other patients, we decided to vaccinate patients with their own tumor cells that have been irradiated to prevent their outgrowth. Furthermore, we add the TLR3 agonist Hiltonol to the vaccine as this has a high potency to stimulate the appropriate immune response. We anticipate that the patient’s tumor cells will display a good capacity to boost the response of the adoptively transferred tumor-specific T cells since they were also successful in stimulating these T cells in vitro. Importantly, in contrast to generic vaccines they will be able to directly stimulate all the relevant T cells including those that recognize parts (epitopes) only expressed by the patient’s own tumor. We hypothesize that increasing the in vivo effectiveness of transferred T cells by this tailor-made vaccination will result in an increased number of patients that will obtain clinical benefit after treatment.