Lymphoma Clinical Trial
Official title:
A Phase I Study of NK Cell Infusion Following Allogeneic Peripheral Blood Stem Cell Transplantation From Related or Matched Unrelated Donors in Pediatric Patients With Hematologic Malignancies
Background:
- Bone marrow stem cells, which are found in the bone marrow and blood stream, can be
collected and transplanted to treat a variety of types of cancer in a process known as
hematopoietic stem cell transplantation (HSCT). When stem cells are taken from one
person, most commonly a sibling or a family member, and then given to another person,
this is referred to as allogeneic HSCT. Allogeneic HSCT has proven to be an especially
effective treatment for patients with some types of cancers of the blood (leukemia) and
certain solid tumors. The transplanted stem cells travel to the patient's bone marrow
and begin producing normal blood cells, and also attack patients cancer cells.
- Because allogenic HSCT does not always prevent the cancer from returning, researchers
are interested in determining whether another type of immune cell taken from the stem
cell donors white blood cells, called a "natural killer" (NK) cell, can be given in
addition to the HSCT to help fight the tumor. In the laboratory, NK cells have been
shown to kill tumor cells, but it is not yet know if this will occur when given to
patients after HSCT.
Objectives:
- To determine the safety, effectiveness, and immune system response of giving NK white
blood cells to individuals who have received allogeneic HSCT.
- To identify possible side effects from the treatment.
Eligibility:
- Donors: Stem cell donors whose blood matches one of the recipients on six out of six
human leukocyte antigen (HLA) (blood immune marker) types. The donor may not be the
identical twin of a recipient.
- Recipients: Individuals between 4 and 35 years of age who have been diagnosed with
pediatric solid tumors that have not responded to standard treatment, or individuals
between 4 and 18 years of age who have been diagnosed with leukemia that has not
responded to standard treatment.
- Other eligibility requirements which include a physical exam and blood laboratory
evaluation are included to make sure it is safe for both the donor to donate and the
recipient to undergo the transplant procedure.
Design:
- Donors and recipients will be screened with a full medical history and physical
examination, and will provide blood and urine samples; recipients will have tumor
imaging studies and other tests as required by the researchers.
- Donors:
- Participants will receive filgrastim injections (to stimulate the bone marrow) for 1
week to make stem cells travel from bone marrow to blood.
- Participants will provide stem cells and NK cells through apheresis.
- Recipients:
- Participants will have three cycles of chemotherapy to treat the underlying cancer and
weaken the immune system so that it will accept the donor cells.
- Participants will then receive preparative chemotherapy for the transplant and two days
after the last dose of chemotherapy, participants will have allogenic HSCT using the
donated stem cells.
- Participants will receive an infusion of NK cells on days 7 and 35 after the HSCT. -
Participants will remain in the hospital for monitoring after the HSCT and NK cell
treatments, and will be followed closely as outpatients for the first 6 months after the
transplant and then less frequently for at least 5 years.
Background
- Despite progress in pediatric oncology, some patient subsets with hematologic
malignancies and pediatric solid tumors continue to experience extremely poor overall
survival. Allogeneic Hematopoietic Stem Cell Transplant (HSCT) is effective in some
high-risk hematologic malignancies.
- Allogeneic HSCT can be performed safely in these patient populations, but disease
recurrence is common and new approaches to enhance the antitumor effect of this therapy
are needed. Natural killer (NK) mediated killing appears to confer improved outcomes
after HSCT for patients with acute myelogenous leukemia (AML) and acute lymphoblastic
leukemia (ALL), and NK cell infusions have induced complete remissions in patients with
AML.
- Preclinical data demonstrates that activated NK cells readily kill pediatric solid
tumors and leukemias, that large numbers of activated NK cells can be generated ex vivo
using artificial antigen-presenting cells (APCs) and that the post-transplant period may
be favorable for expansion and survival of adoptively transferred NK cells.
Objectives
- To assess the feasibility and toxicity of infusing escalating doses of donor-derived
activated NK cell donor lymphocyte infusions (NK-DLI) on Days 7 plus or minus 2 days and
49 plus or minus 7 days following human leukocyte antigen (HLA)-matched T cell depleted
(TCD) peripheral blood stem cell transplant (PBSCT) in patients with metastatic or
recurrent pediatric solid tumors and high risk leukemias who have unrelated donors or
related donors;
- To determine if patients treated in this manner experience rapid, sustained donor
engraftment and acceptable rates of acute graft versus host disease (aGVHD) (less than
25% incidence of grade III or grade IV).
Eligibility
-Patients 4-35 years with hematologic malignancies (e.g., ALL, AML, Chronic Myelogenous
Leukemia (CML), Hodgkins Lymphoma (HD), Non-Hodgkins Lymphoma (NHL), with a 5/6 or 6/6
HLA-matched related or 9/10 or 10/10 HLA matched unrelated donor.
Design
- Pre-transplant disease specific immune depleting chemotherapy and the preparative
regimen will be the same as that used previously on 02-C-0259 and 01-C-0125, for those
patients undergoing reduced intensity transplant.
- For patients with ALL or AML, a myeloablative regimen based on current Children's
Oncology Group (COG) standard-of- care preparative regimen will also be included.
- Donors will undergo 1-3 apheresis sessions for filgrastim mobilized peripheral blood
stem cells (PBSC). This product will be T cell and NK cell depleted prior to
cryopreservation. NK cells selected from the product will be used for ex vivo activation
and expansion using KT64.4-BBL artificial antigen presenting cells.
- A phase 1 cell dose escalation of donor derived NK-DLI will be performed using 3 dose
levels (1 x 10(5), 1 x 10(6) and 1 x 10(7) NK cells/kg) infused on days 21 more or less
3 post-PBSCT and a second infusion on day 49 more or less 7 post-PBSCT.
- Three patients will be enrolled at each dose level, with the cohort expanded to 6 if
dose-limiting toxicity occurs. An expanded group of 12 patients will be treated at the
highest dose level tolerated.
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