Allogeneic immunotherapy for solid tumors (ST) : a feasibility trial
- JO Bay, M Michallet, JM Boiron
- Bone Marrow Transplant 2002;
Preliminary results of nonmyeloablative stem cell transplantation in solid tumors provide some clinical evidence that allogeneic donor lymphocytes mediate a graft-versustumor (GVT) effect, which may be used for the immunotherapy of advanced solid tumors. Although the target antigens for the GVT effect are not defined, some tumors like renal cell cancer, breast cancer or, more recently, colorectal adenocarcinoma appear to be more responsive to this form of adoptive immunotherapy. As hepatocytes are known to be major targets for graft-versus-host disease (GVHD), one could speculate that cells from a hepatocellular carcinoma may be sensitive to the GVT reaction. We herein report an explosive progression of a previously unknown hepatocellular carcinoma in a patient who received allogeneic hematopoietic stem cells after a preparative regimen of reduced intensity for a myelodysplastic syndrome. A 50-year-old male suffering from a refractory anemia was considered for a bone marrow transplant from his HLA-identical sister. Moderate biological hepatic disturbances had been noted for several years consisting of increased values of gamma-glutamyl transpeptidase (3–4 times normal value) and alkaline phosphatase (2–3 times normal value) with normal transaminases and bilirubin levels. Ferritin was increased to 865mg/l and hepatitis serology was negative. Abdominal ultrasound performed 3 months prior to the graft did not detect any hepatic lesion. The patient received a reduced intensity conditioning regimen including total body irradiation (a 6Gy total dose divided into three fractions), cyclophosphamide 60mg/kg and antithymocyte globulin 10mg/kg. Prophylaxis of acute GVHD consisted of the association of short-course methotrexate and cyclosporine. The early post-transplant course was uneventful. Successive studies of marrow or peripheral blood chimerism from day +30 post-transplant showed full donor origin. The patient developed a grade I acute GVHD that was spontaneously regressive. The previously known cholestasis syndrome progressively worsened during the second month after transplantation without any sign of GVHD or veno-occlusive disease. Ultrasound findings at the end of the second month consisted of a voluminous heterogeneous tumor in the segments VI and VIII of the liver. The suspected diagnosis of primary liver cancer was confirmed by a highly elevated level of serum alpha-fetoprotein (1841mg/l). Thoracic and abdominal computerized tomography and bone scintigraphy did not reveal any metastasis. Cyclosporine was progressively tapered from day +115 and the patient was given regional chemoembolization because of a nonresectable tumor. Unfortunately, the patient died of tumor progression 6 months after transplantation. Since biological hepatic problems had been noted prior to transplantation, a retrospective serum alpha-fetoprotein dosage (950 mg/l) on serum stored immediately before conditioning regimen confirmed that the liver cancer was emerging before the bone marrow graft. Cancer immunotherapy with allogeneic lymphocytes may represent a new therapeutic option for solid tumors resistant to conventional chemotherapy and radiotherapy. However, not all types of cancer may reach the same level of sensitivity to this approach. Scarce data concerning immunotherapy in primary liver cancer are found in the literature. Only one report describes a decrease in serum alpha-fetoprotein in a patient with a primary liver cancer who received a liver transplantation immediately followed by a combined autologous and incompatible allogeneic bone marrow transplantation from the same cadaveric donor. Nevertheless, the authors could not clearly demonstrate a graft-versus-liver cancer effect. In our patient, the tumor was probably limited prior to the graft and therefore more likely to be controlled by immunotherapy. However, it rapidly progressed after the transplantation despite the occurrence of a limited GVHD. Tumor outgrowth may certainly have been facilitated by the pretransplant use of antithymocyte globulin and the prolonged posttransplantation immunosuppression, which may have blocked any possible GVT effect. Moreover, DLI were not given because of a too rapid tumoral progression. As they are a well-established treatment for posttransplant relapse of haematological malignancies, we could suppose that they could have exerted a GVT effect if our patient might have lived long enough. Despite the fact that no definitive conclusion can be drawn from this individual case, our report raises the question of a GVT effect in a tumor arising from a target tissue for GVHD.