Anti-tumour effect in solid tumours, tolerance and immune reconstition after allogeneic haematopoietic stem cell transplantation

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Immunology, Microbiology, Pathology and Infectious Diseases

Sammanfattning: Both in haematological malignancies and in disseminated solid tumours, re-occurrence of the underlying disease is the main complication. Allogeneic haematopoietic stem cell transplantation (HSCT) increases the chance of cure compared to only chemotherapy in haematological malignancies, but adds the risk of immunological complications such as graft-versus-host disease (GVHD) and severe infections. Immunosuppressive treatment is needed to prevent rejection of the graft and GVHD. The reason for lower relapse incidence after allogeneic HSCT has been attributed to a graft-versus-leukaemia (GVL) effect, which has also been suggested to be present against solid tumours after HSCT. The possible occurrence of a graft-versus-tumour (GVT) effect in different solid tumours after allogeneic HSCT and the feasibility of a reduced intensity conditioning (RIC) were investigated. Patients with renal cell carcinoma (RCC, n=10), colon carcinoma (CC, n=6), breast cancer (n=1) or a Klatskin tumour of the liver (n=1) were treated with HSCT with a RIC consisting of Fludarabine and 2 Gray of total body irradiation (TBI). During the study, four patients died of transplantation-related complications between 45 and 160 days after HSCT and three patients died of tumour progression 92-323 days after HSCT. Almost total tumour regression was seen in the first patient with CC, but he died of pneumonia 4 months after HSCT. Partial responses in the lungs of one additional patient with CC and two patients with RCC, were seen. Among 624 patients receiving transplants between 1977-1997 at Huddinge Hospital, 254 patients surviving more than 12 months, were retrospectively analysed regarding clinical tolerance, that was defined as the absence of GVHD or rejection after withdrawal of immunosuppression. Patients who did not develop GVHD had discontinued immunosuppression according to the protocols. Children discontinued immunosuppression faster than adults and male recipients with immunised female donors discontinued immunosuppression later. Acute GVHD was associated with longer time to withdrawal of immunosuppression. In multivariate analysis, a high donor age, donation from an immunised female donor to a male recipient, and acute GVHD grades II-IV were associated with longer time to clinical tolerance. Immune recovery analysed by diversity of the T cell receptor (TcR) and the B cell immunoglobulin heavy chain (IgH) using spectratyping of the third complementarity determining region (CDR3) was analysed in 24 patients after RIC (n=13) and myeloablative (n=11) HSCT. Reconstitution of diversity of the CDR3 region was significantly delayed in the IgH while significantly faster in the TcR after RIC HSCT compared to myeloablative HSCT even though differences were small. Patients in the RIC group were significantly older (54 vs. 42, p<0.05) and had slightly more viral infections including asymptomatic CMV infection (p<0.05). RIC patients also had a tendency for more chronic GVHD (ns, p=0.12). Immune function in vitro was tested by lymphocyte stimulation at 3, 6, and 12 months after HSCT. Decreased responses to CMV and VZV antigens were seen in patients suffering from acute GVHD grade II, compared to the healthy donors. Patients in the RIC group had significantly lower responses to concanavalin (Con-A), phytohemagglutinin (PHA), and Staph. aureus protein A (SpA) during the first six months after RIC HSCT while patients in the myeloablative group only showed lower responses to Con-A at three months, compared to the healthy donors. In conclusion, RIC HSCT is feasible in haematological diseases and solid tumours. A GVT effect seems to exist in RCC and CC but has to be enhanced. Most patients receiving HLA-identical stem cells are tolerant within two years after HSCT. The B cell and T cell repertoires are skewed during the first year after allogeneic HSCT and immune reconstitution after HSCT with myeloablative and RIC conditioning seem to be comparable. Individual factors such as GVHD, age and infections are probably more important for immune reconstitution than type of conditioning.

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