Antitumor effect in allogeneic hematopoietic stem cell transplantation in patients with solid cancer

Allogeneic hematopoietic stem cell transplantation (HSCT) has been presented as a promising immunotherapy not only against hematological malignancies but also against solid tumors. Different solid tumors such as renal cell, breast, colon, prostate and advanced primary liver cancer have been treated with HSCT at our center. Treatment with HSCT gives rise to an anti-tumor response so called graft-versus-tumor (GvT) effect that has been demonstrated as tumor regression of metastasis.

Before transplantation, patients receive non-myeloablative conditioning also known as low intensity conditioning (LIC) or reduced intensity conditioning (RIC) that eradicates the bone marrow to a lesser extent, allowing place for the new hematopoietic stem cells from the donor. The presence of remaining tumor cells or mixed chimerism threatens the patient with disease relapse after the LIC/RIC regimen. Therefore, the GvT effect after LIC/RIC regimen relies on donor lymphocyte infusions (DLI), i.e. adoptive immunotherapy that can contribute to full donor chimerism.

A common complication after HSCT is graft-versus-host disease (GvHD), i.e. the attack of the transplanted cells against the patient’s epithelial cells in the skin, bowel and liver. It seems that donor T lymphocytes mediate both GvHD and the GvT effect, since the risk for tumor recurrence is higher when donor T lymphocytes are depleted from the transplant. Therefore, a patient having mild acute or chronic GvHD, has a predictable high chance of the GvT effect.

In paper I, we studied inflammatory and anti-inflammatory cytokines in serum using ELISA in four patients with metastatic renal cell and two with colon cancer. We found dominating TNF-α and IFN-γ levels in serum, which correlated with tumor regression. In paper II, we retrospectively determined the risk factors for complications in 48 patients with solid tumors receiving LIC as compared to RIC regimen. We reported that engraftment and development of donor B cell chimerism occurred earlier in patients receiving LIC than in patients receiving RIC. The best GvT effect was demonstrated in patients with advanced primary liver cancer who had previously undergone liver transplantation. The most favorable GvT effect was found in patients who received DLI and developed chronic GvHD. A tendency for prolonged survival was found in patients receiving RIC compared to the LIC group.

In paper III, we measured cytokine secretion using ELISpot during DLI given to four patients with solid tumors and four with hematological malignancies. Increased expression of TNF-α, IFN-γ, IL-10 and IL-12 in mononuclear cells (MNC) was found in patients with favorable outcome of disease response after DLI. In paper IV, we detected and identified tumor-reactive T lymphocytes from an HLAidentical sibling against tumor cells from a patient with pancreatic cancer using flowcytometric assay of specific cell-mediated immune responses in activated whole blood (FASCIA). Using CDR3 size spectratyping tumor-reactive T lymphocytes could be distinguished from T lymphocytes activated against peripheral blood MNC from the patient.

In conclusion, these findings might give a better treatment aiming at a more effective GvT effect. Monitoring cytokines before DLI could predict those patients who will gain from immunotherapy. Combining FASCIA and CDR3 size spectratyping might be a way to identify, isolate, in vitro expand and infuse tumor-specific T lymphocytes from donors in order to intensify the GvT effect.

List of scientific papers

I. Inflammatory cytokines predominate in cases of tumor regression after hematopoietic stem cell transplantation for solid cancer Réka Conrad, Mats Remberger, Kerstin Cederlund, Patrik Hentschke, Berit Sundberg, Lisbeth Barkholt. Biology of Blood and Marrow Transplantation 2006. 12:346-354.
https://doi.org/10.1016/j.bbmt.2005.10.028

II. A comparison between low intensity and reduced intensity conditioning in allogeneic hematopoietic stem cell transplantation for solid tumors Réka Conrad, Mats Remberger, Kerstin Cederlund, Olle Ringdén, Lisbeth Barkholt. Haematologica 2008. 93(2):265-272.
https://doi.org/10.3324/haematol.11672

III. Cytokine expression in patients with solid tumors and hematological malignancies treated with donor lymphocyte infusions after allogeneic hematopoietic stem cell transplantation. Réka Conrad, Mats Remberger, Kerstin Cederlund, Lisbeth Barkholt. (Submitted to Immunotherapy).

IV. Novel methodology for detection of tumor-reactive cell-mediated immune response against pancreatic cancer cells in HLA-identical setting. Réka Conrad, Brigitta Omazic, Mats Alheim, Sam Ghazi, Mehmet Uzunel, Dan Hauzenberger, Lisbeth Barkholt. (Manuscript).