Allogeneic bone marrow or blood stem cell transplantation after intensive treatment with irradiation and/or chemotherapy is widely used to treat leukemias and other cancers of the blood and lymph nodes. Such transplants can cure leukemia, lymphoma and multiple myeloma. Other cancers including renal cell carcinoma and malignant melanoma may also benefit from this treatment approach. Two mechanisms operate to eradicate cancer. The first is the effect of intensive treatment with irradiation and/or chemotherapy, which kills normal as well as cancer cells. The second is the so-called “graft-versus-leukemia” (GVL) effect. In the last decade we have begun to understand the mechanism of the GVL effect and to witness the powerful therapeutic potential of this effect. For example, patients who relapse with leukemia after a bone marrow transplant can be put back into remission and apparently cured by the transfusion of the T-lymphocyte immune cells from the original bone marrow or blood stem cell donor. We argued that there may be no need to give the high doses of irradiation and/or chemotherapy before infusion of allogeneic bone marrow or blood stem cells to cure patients of their cancer. Rather we would rely on the immune response of the grafted donor cells to eradicate cancer and only give enough treatment to assure acceptance and growth of the allogeneic bone marrow or blood stem cells.
We have evaluated a program of “minitransplants” in two groups of patients; (1) older patients (age 55 to 75) or younger debilitated patients with hematological malignancies (leukemias, multiple myeloma, myelodysplastic syndrome) who historically have had a high death rate from the high doses of irradiation and/or chemotherapy usually administered for transplantation; (2) patients with metastatic cancer ages 10-60 years (renal cell carcinoma, malignant melanoma and other cancers not responsive to chemotherapy). We are exploring the possibility of treating such diseases by a “graft versus-tumor” (GVT) effect comparable to the well-known GVL effect observed in hematological cancers following allogeneic bone marrow or blood stem cell transplantation. Patients are given two well-known immunosuppressive chemotherapy drugs, cyclophosphamide and fludarabine followed by infusion of allogeneic blood stem cells obtained from an HLA compatible donor (usually a brother or sister) after the infusion of Neupogen®. The use of these two drugs rather than more the usual more intensive regimens reduces deaths from treatment from around 25% to less than 10%.
Blood stem cells from the donor are collected by a process called apheresis which is very similar to the process in general use for platelet collection from normal donors. To prevent reactions of the transplant against the patient, graft-versus-host disease (GVHD), patients receive the immunosuppressive drug cyclosporine for the first month following the transplant. At that time, we measure the amount of engraftment of donor cells that has occurred. The aim is to achieve a complete take over of the immune system by donor cells. This maximizes the GVL or GVT effect. If the donor cells have already reached 100%, we continue the cyclosporine for a longer period because the risk of GVHD is greatest when there is full engraftment of donor cells. If, on the other hand, a percentage of 25% or more of the blood lymphocytes are still the patients’ we help the donor cells to fully engraft by stopping the immunosuppressive cyclosporine. In the event that the patient appears to be rejecting the transplant, or if we want to enhance an effect against the cancer, we give a transfusion of donor lymphocytes.
We have now performed more than fifty minitransplants. Half the group consisted of patients with metastatic renal cell cancer and malignant melanoma for which there is no effective therapy. The other half are patients with advanced hematological cancers (leukemia, myelodysplasia, lymphoma and multiple myeloma). Preliminary results indicate that the transplant is well-tolerated even in older or debilitated patients. Only one patient rejected the transplant and we are encouraged by the GVL and GVT effects observed so far. Eradication of all disease has been seen in patients with chronic myeloid and chronic lymphoid leukemia and in patients with renal cell cancer. We are continuing to study large numbers of patients on these protocols to define and perfect this treatment.
Understanding DNA Damage Response or DDR and Cancer Treatment
What is DNA Damage Response or DDR?
The minitransplant approach forms an important platform for further developments in immunotherapy using the healthy donor’s immune system to specifically attack cancer cells. There are two challenges – the first is to remove from the transplanted cells the lymphocytes responsible for the unwanted and harmful GVHD reaction, and the second is to amplify the GVT and GVL effect. To prevent GVHD, we are developing a technique to selectively remove T-cells responsible for GVHD while preserving cells reactive against cancer and infectious agents. To amplify the GVT and GVL effects, we are evaluating methods to expand T-cells in a culture system that respond specifically to antigens present on cancer cells. These cells can then be infused after minitransplantation.
In the US, more than a dozen transplant centers are currently investigating the minitransplant approach for the treatment of a variety of cancers and in older patients. All have somewhat different approaches but with the same general theme of less intensive chemotherapy before the transplant. In the next year or two, the results from our and other centers should allow us to determine the role of this type of treatment for patients with cancer.