Pilot Study of Radiation-Enhanced Allogeneic Cell Therapy for Progressive Hematologic Malignancy After Allogeneic Hematopoietic Stem Cell Transplantation

Background: * Allogeneic hematopoietic stem cell transplantation (allotransplant) has been used to treat many kinds of cancer that develop in cells from the blood or immune system. After allotransplant, donor cells take over production of the recipient s blood and immune cells, and donor immune cells can directly attack and control tumor. However, for cancers that do not respond to allotransplant, there are no proven cures. * A single treatment with radiation can improve the potency of immune-cell therapies. This is probably because the tumor tissue is damaged in a way that new tumor proteins are exposed, attracting immune cells to the tumor. By giving only a single dose of radiation, the immune cells that are attracted to the tumor are allowed to survive and function in their usual way, traveling throughout the body and educating other immune cells to recognize tumor, and to activate and expand in order to kill the tumor cells. Some research has shown that radiation may have a widespread effect on stimulating the immune system, educating immune cells to recognize and control tumors that have not been radiated. Objectives: \- To determine whether a single treatment of radiation will help donor immune cells control cancer after allotransplant without causing excessive side effects. Eligibility: * Recipients: Individuals 18 years of age and older who have blood cancers that have not responded to allotransplant. * Donors: Healthy individuals 18 years of age and older who were previous allotransplant donors for one of the study recipients. Design: * Donors will provide additional blood immune cells, called lymphocytes, through apheresis. Apheresis involves drawing blood, separating out the lymphocytes, and returning the rest of the blood to the donor. * Recipients will receive a single dose of radiation to the greatest amount of tumor that can be irradiated safely. Researchers will intentionally leave some tumor that will not be radiated in order to evaluate whether there is a widespread response to the treatment. * There are two treatment arms on the study. * Arm 1: Study participants who have donor lymphocytes available and who have not had major complications from the allotransplant will be given a dose of donor cells after they receive radiation, to provide an additional boost to the donor immune response. * Arm 2: Study participants who cannot receive donor lymphocytes because their donor is not available, they received an allotransplant from a partially matched relative, or they have had significant complications from the allotransplant - will receive radiation without additional donor lymphocytes. * All recipients will be followed closely for side effects and for tumor response to radiation with or without donor lymphocytes. Additional tests will be performed, including tumor biopsies, bone marrow samples, and blood draws, in order to study the immune effects of radiation and donor lymphocytes. * A separate, control group of allotransplant recipients will not receive radiation. This group will include participants whose transplant doctors plan to use donor lymphocyte therapy alone to control cancer progression. This group will donate blood immune cells through blood draws and apheresis. These cells will be examined to study the immune effects of receiving donor lymphocytes without radiation.

Background: * The prognosis for patients with cancer who have relapsed or progressive disease after allogeneic hematopoietic stem cell transplantation (allotransplant) is poor. Effective therapies for patients who fail withdrawal of immune suppression and administration of donor lymphocyte infusions (DLI) have not been identified. * Increasing the efficacy of allotransplant without increasing toxicity is a major goal of transplantation research. A major research effort within the Experimental Transplantation and Immunobiology Branch (ETIB) is to identify ways to build on the allogeneic platform to treat relapse after allotransplant. * We hypothesize that a single fraction of radiation to tumor prior to administration of donor lymphocytes will increase the potency of systemic graft-versus-tumor (GVT) effects without increasing graft-versus-host disease (GVHD). Objectives: \- To determine the safety, in relation to GVHD and allograft function, and efficacy, in terms of systemic tumor response, of administering single-fraction, targeted radiotherapy with or without DLI to patients with persistent tumor after allotransplant. Eligibility: * Adults with hematologic malignancies that progress or recur after allotransplant, successful donor T cell engraftment, and trial of withdrawal of immune suppression. * Disease that is amenable to radiation as well as additional measurable disease outside the radiation field. * Subjects with treatment-refractory acute or chronic GVHD will not be eligible. Design: * Subjects will receive radiation in a single, 8-Gy fraction to sites of disease. At least one site of measurable disease will remain untreated with radiation for evaluation of systemic response. * There will be two arms. Arm A will include subjects with available donor lymphocytes and who have not had GVHD requiring systemic treatment; they shall receive a DLI the day after completion of radiation. Arm B will include those who have previously required systemic therapy for GVHD, are at high risk of significant GVHD, and/or who do not have available donor lymphocytes; they shall receive radiation without DLI. * Additional disease that is outside the field of radiation will be monitored for systemic effects of the therapy. * Subjects will be monitored on an outpatient basis for the development or exacerbation of GVHD, excessive hematologic toxicity or other toxicity from radiation, and for tumor responses for at least 60 days. * Enrollment: * Treatment Subjects: The protocol will treat 21 subjects per arm (total 42). There are stopping rules after 8 and 15 patients per arm for excessive GVHD or radiation toxicity. * DLI Control Subjects; 15 control subjects who receive DLI for persistent disease as part of their care on another National Institutes of Health (NIH) protocol, will be included to compare the immunologic effects of radiation followed by DLI (Arm A) with DLI alone. * Donor Subjects: Related donors of Arm A Treatment Subjects and DLI Control Subjects will be enrolled for collection of clinical DLI product, a portion of which will be used for research (up to 36 Donor Subjects).