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

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).

- INCLUSION CRITERIA:

Treatment Subjects:

- Patients must have received allotransplant (related or unrelated donor) for
hematologic malignancies and have disease progression with a component of solid-phase
disease. Eligible diagnoses will include any acute or chronic leukemia with a
solid-phase component, Hodgkin's lymphoma, any non-Hodgkin's lymphoma, including
mantle cell lymphoma, multiple myeloma. Pathology slides from patients pretransplant
diagnoses will be reviewed by National Cancer Institute (NCI)/Center for Cancer
Research (CCR) Department of Pathology.

- Patients must have at least two distinct sites of disease:

- At least one site must be in solid phase and amenable to irradiation, determined by
Radiation Oncology evaluation.

- In addition to the target(s) of irradiation, there must be disease that is discrete
from local effects of the radiation that can be evaluated for systemic response to
therapy.

- Patients must have disease that has failed to respond after a minimum of four weeks
to:

- Evidence of complete donor-T cell engraftment (greater than 90% chimerism) of the
circulating T cells

- A trial of tapering immunosuppressive therapy, including trials that are discontinued
due to development or flare of graft versus host disease (GVHD)

- Patients must be 18 - 75 years of age.

- Eastern Cooperative Oncology Group (ECOG) less than or equal to 3 (Karnofsky greater
than or equal to 50%).

- Life expectancy greater than or equal to 1 month.

Arm A

- Patients with minimal to no clinical evidence of acute GVHD (Grade 0-I) or mild-
chronic GVHD (GVHD Score of no more than 1 in no more than two organ systems) while
off of systemic immunosuppressive therapy.

- Available source of clinical donor lymphocyte cell product, including stem
cell-mobilized product.

- Patients whose related allotransplant donor is available, eligible and enrolled on
this or another National Institutes of Health (NIH)/Clinical Center (CC) protocol that
permits collection of a clinical donor lymphocyte cell product, and donors are
first-degree relatives with genotypic identity at 5-6/6 human leukocyte antigen (HLA)
loci (HLA- A, B, and DR. Haploidentical (less than 5/6 genotypic identity)
allotransplant recipients will not be eligible, due to risk of severe GVHD with donor
lymphocyte infusion (DLI).

- Patients whose related or unrelated allotransplant donors are unavailable or
ineligible, but who have cryopreserved donor lymphocyte cell products available for
use on this trial.

Arm B

- Patients with history of GVHD. Specifically:

- Patients who have a past history of resolved grade III acute GVHD or
moderate/severe chronic GVHD and who are no longer requiring systemic therapy to
treat GVHD.

- Patients who require continued prophylaxis with steroid-sparing agents, e.g.,
cyclosporine. Due to concerns that sirolimus (rapamycin) could interfere with the
potential efficacy of radiation-enhanced allogeneic cell therapy, patients on
sirolimus as part of GVHD control must be switched to another agent two weeks
prior to enrollment.

- Patients with GVHD controlled with local therapy, e.g., topical steroids,
budesonide.

- Patients with controlled acute GVHD (Grade I-III) or chronic-moderate/severe GVHD
on a stable (at least four weeks) or tapering dose of systemic immunosuppression
will be eligible for enrollment.

- Patients who do not have donor lymphocytes available for use on this trial, including
recipients of unrelated donor allografts.

- Patients whose allotransplant was from a haploidentical (less than 5/6 genotypic
identity) related donor.

- Provision for a Durable Power of Attorney.

- Ability to give informed consent.

Donor Subjects:

- Donors are the same individual whose cells were used as the source for the enrolling
Arm A Treatment Subject or DLI Control Subjects original allotransplant.

- Age 18 - 90.

- Adequate venous access for peripheral apheresis, or consent to use a temporary central
venous catheter for apheresis.

- Donors must be human immunodeficiency virus (HIV) negative, hepatitis B surface
antigen negative, and hepatitis C antibody negative.

DLI Control Subjects:

The DLI Control Subjects will serve as a comparison for Arm A, and eligibility criteria are
intended to enroll subjects who are similar with respect to allotransplant characteristics.

- Patients must be 18-75 years of age.

- Patients who have received an allotransplant to treat malignancy and who are going to
receive an unmanipulated or stem-cell mobilized DLI to treat persistent tumor as part
of their treatment program on another National Institutes of Health (NIH)/Clinical
Center (CC) protocol.

- Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to
3 (Karnofsky performance status of greater than or equal to 50%).

- Life expectancy greater than or equal to 1 month.

- Patients with minimal to no clinical evidence of acute GVHD (Grade 0-I) or mild-
chronic GVHD while off of systemic immunosuppressive therapy.

- Available source of clinical donor lymphocyte cell product, including a stem
cell-mobilized product.

- Patients whose related allotransplant donor is available, eligible and enrolled
on this or another NIH/CC protocol that permits collection of a clinical donor
lymphocyte cell product, and donors are first-degree relatives with genotypic
identity at 5-6/6 human leukocyte antigen (HLA) loci (HLA- A, B, and DR.
Haploidentical (less than 5/6 genotypic identity) allotransplant recipients will
not be eligible, for consistency with Arm A Subjects.

- Patients whose related or unrelated allotransplant donors are unavailable or
ineligible, but who have cryopreserved donor lymphocyte cell products available
for clinical use on this trial.

- Patients must have disease that has failed to respond after a minimum of four weeks
to:

- Evidence of complete donor-T cell engraftment (greater than 90% chimerism) of the
circulating T cells.

- A trial of tapering immunosuppressive therapy, including trials that are discontinued
due to development or flare of GVHD.

- Adequate venous access for peripheral apheresis, or consent to use a temporary central
venous catheter for apheresis or consent to a large-volume (70cc) blood draw.

- Permission from their treating transplant physician or designee to participate on
study.

- Ability to give informed consent.

EXCLUSION CRITERIA:

Treatment Subjects:

- Tumor-directed therapy within two weeks of DLI.

- Patients with rapid disease progression or aggressive tumor histology which, in the
opinion of the principal investigator (PI), is likely to require urgent therapy within
60 days in order to preserve organ function or quality of life, and there is an
available standard therapy to which the patient has a reasonable chance of responding.

- Progressive disease that, in the opinion of the PI, requires urgent standard therapy,
e.g., threatened organ function, acceptable quality of life, etc.

- Uncontrolled GVHD, i.e., either acute GVHD Grade III or chronic-moderate/severe GVHD
that has not responded to the current dose of systemic therapy or any history of
steroid-refractory acute GVHD, Grade IV acute GVHD, or chronic-severe GVHD.

- Active infection that is not responding to antimicrobial therapy.

- Active psychiatric disorder which may compromise compliance with transplant protocol,
or which does not allow for appropriate informed consent (as determined by Principal
Investigator and/or her designee).

- Pregnant or lactating. Subjects of childbearing potential must use an effective method
of contraception. The effects of the immunosuppressive medications that could be
required to treat GHVD are likely to be harmful to a fetus. The effects upon breast
milk are also unknown and may be harmful to an infant.

- Absolute neutrophil count of less than 500 cells/microL. At the PIs discretion,
patients with marrow replacement by tumor as the probable etiology of an absolute
neutrophil count of less than 500 cells/microL may be eligible for enrollment.

- In order to prevent delay of potentially stabilizing palliative therapy, the following
conditions will exclude eligibility: untreated active leptomeningeal involvement with
malignancy, untreated brain metastasis, and other organ-threatening diseases in which
palliative treatment options with reasonable probability of efficacy (15% or higher)
are available. Patients with these conditions for whom available palliative options
have been tried or deemed unacceptable but who otherwise meet eligibility criteria
may, at the discretion of the PI, be considered for enrollment.

Donor Subjects:

- History of a psychiatric disorder that the PI determines might compromise compliance
with transplant protocol, or that does not allow for appropriate informed consent.

- Hypertension that is not controlled by medication, history of stroke, or severe heart
disease (donors with symptomatic angina will be excluded). Donors with a history of
coronary artery bypass grafting or angioplasty who are symptom free will receive a
cardiology evaluation and be considered on a case-by-case basis.

- History of prior malignancy. However, cancer survivors who have undergone potentially
curative therapy and have had no evidence of that disease for at least 5 years may be
considered for lymphocyte donation on a case-by-case basis.

- Anemia (hemoglobin (Hb) less than 11 gm/dl) or thrombocytopenia (platelets less than
100,000 per ml). However, potential donors with Hb levels less than 11 gm/dl that is
due to iron deficiency will be eligible as long as the donor is initiated on iron
replacement therapy and the case is individually approved by NIH Department of
Transfusion Medicine (DTM).

- Pregnancy. Donor Subjects of childbearing potential must use an effective method of
contraception until after completion of apheresis. The effects of apheresis are
unknown to be safe to a fetus.

DLI Control Subjects:

- Tumor-directed therapy within two weeks of DLI.

- Uncontrolled GVHD

- Pregnant or lactating. Subjects of childbearing potential must use an effective method
of contraception until after completion of apheresis. The effects of apheresis are
unknown to be safe to a fetus.

- History of a psychiatric disorder that the PI determines might compromise compliance
with protocol, or that does not allow for appropriate informed consent.

- Hypertension that is not controlled by medication, history of stroke, or severe heart
disease (subjects with symptomatic angina will be excluded).