Effects on tumor immunity, liver, gut, lung and survival after cutaneous graft-versus-host disease regulated by photochemotherapy

The present thesis describes the effect and timing of photochemotherapy in relation to the onset and severity of cutaneous graft-versus-host (GvHD) in relation to the survival and cure of patients. Leukemia is the most common childhood malignancy and an entity of cancer that is increasing in elderly. Allogeneic stem cell transplantation following myeloablative treatment (conditioning) and using methotrexate-based prophylaxis still remains the best choice to cure of high-risk acute and relapsed chronic myeloid leukemia. To improve the long-term disease free survival, we have to redirect the adoptive immunity from GvHD towards graft-versus-leukemia (GvL).

The aim of the present thesis was to test the theory postulating that effects of photochemotherapy are confined to the skin. The theory was tested by whether photochemotherapy had effects on GvHD in liver and gastrointestinal tract (GI), and if it affects the anti-tumor immunity post transplantation. The complete response in GI and liver in addition to the pulmonary mortality after photochemotherapy, which intercalate with DNA, were compared in two groups of patients. One group had received myeloablative ionizing irradiation, which leaves long-lasting DNA-breaks and the second group who received myeloablative chemotherapy including busulfan, which alkylates DNA. The effect on anti-tumor immunity was determined by the effect on the cumulative GvL with regard to whether photochemotherapy was given direct after the onset of cutaneous acute-GvHD or after a week.

The main theoretical background to the present studies was the effect of photochemotherapy on cell mediated immunity evident by an inhibition of the delayed type hypersensitivity of the skin and the ability to induce circulating immunomodulatory regulatory-T cells in human. Four different patient populations were investigated; patients with cutaneous acute-GvHD; patients with cutaneous- and visceral acute-GvHD; patients with acute leukemia; and patients with chronic myeloid leukemia. Complete response, tumor immunity (GvL) and survival were considered as outcomes. Established risk factors including transplantation across the female-male barrier were assessed.

The key result was the possible synergistic-effect between ionizing irradiation and photochemotherapy, which may cure GI GvHD. Furthermore, our results indicated that cutaneous acute-GvHD may enhance the anti-tumor immunity, but also the pulmonary mortality. However, cutaneous complete response to photochemotherapy may decrease the pulmonary mortality after TBI. The studies of patients with acute-leukemia and chronic-myeloid-leukemia implied that after transplantation, the adoptive tumor immunity was modulated by the timing of photochemotherapy with regards to the onset of cutaneous acute-GvHD.

In conclusion, photochemotherapy has effects on disease in internal organs. The overall results suggest that the optimal time to start the photochemotherapy in patients with hematological malignancy is at least after the first week of cutaneous acute-GvHD.

List of scientific papers

I. Photochemotherapy of cutaneous graft-versus-host disease may reduce concomitant visceral disease. Feldreich N., Ringdén O., Emtestam L., Omazic B. Dermatology. 2016, Vol. 232 pp. 453-463.
https://doi.org/10.1159/000447058

II. Photochemotherapy and graft-verus-leukemia reaction in acute-leukemia: Tumor immunity and survival are dependent on timing of photochemotherapy of the skin. Feldreich N., Ringdén O., Emtestam L. Dermatology. 2017, Vol. 233 pp. 314-324.
https://doi.org/10.1159/000484138

III. Severity of graft-versus-host disease confined to the skin predicts pulmonary mortality after irradiation, photochemotherapy possibly alleviates lung injury. Feldreich N., Ringdén O., Hassan M., Emtestam L. [Manuscript]

IV. Timing of photochemotherapy may preserve graft-versus-leukemia associated with cutaneous GvHD after transplantation for chronic myeloid leukemia. Feldreich N., Ringdén O., Hassan M., Emtestam L. [Manuscript]