This phase I trial studies the side effects and best dose of CD4+ and CD8+ HA-1 T cell
receptor (TCR) T cells in treating patients with acute leukemia that has come back or does
not respond to treatment following donor stem cell transplant. T cell receptor is a special
protein on T cells that helps them recognize proteins on other cells including leukemia. HA-1
is a protein that is present on the surface of some peoples' blood cells, including leukemia.
HA-1 T cell immunotherapy enables genes to be added to the donor cells to make them recognize
HA-1 markers on leukemia cells.
PRIMARY OBJECTIVES:
I. To evaluate the feasibility and safety of HA-1 T TCR T cell immunotherapy in approximately
12 children and adolescents and 12 adults with recurrent acute leukemia after allogeneic
hematopoietic stem cell transplantation (HCT).
SECONDARY OBJECTIVES:
I. To determine the in vivo persistence of transferred HA-1 TCR T cells in peripheral blood.
II. To determine the ability of HA-1 TCR T cells to migrate to bone marrow.
III. To evaluate the function of HA-1 TCR T cells before and, if possible, after adoptive T
cell transfer.
IV. To observe whether infusion of HA-1 TCR T cells is followed by a reduction of leukemia
burden.
V. To observe whether infusion of HA-1 TCR T cells is followed by a reduction of recipient
hematopoietic chimerism.
VI. To observe whether infusion of HA-1 TCR T cells is followed by the appearance or
recurrence of signs or symptoms of graft-versus-host disease (GVHD).
OUTLINE: This is a dose-escalation study of CD4+ and CD8+ HA-1 TCR T cell.
Patients receive fludarabine phosphate for 1-3 doses 7-14 days prior to HA-1 TCR T cell
administration. Patients then receive CD4+ and CD8+ HA-1 TCR T cells intravenously (IV) over
1 hour.
After completion of study treatment, patients are followed up closely for 12 weeks and then
every 6 months for 5 years, and then annually for up to 10 years.
Inclusion Criteria:
- Initially only patients who are >= 16 years old will receive HA-1 TCR T cell infusions
on the protocol; younger patients may be screened, enrolled in the protocol and
monitored for relapse but will not be eligible for infusion until at least one patient
>= 16 years old has been treated and discussed with the Food and Drug Administration
(FDA)
- Patients must express HLA-A*0201
- Patients must have the HA-1(H) genotype (RS_1801284: A/G, A/A)
- Patients must have an adult donor for HCT who is adequately HLA matched by
institutional standards (includes HLA-matched related or unrelated donors, and
HLA-mismatched family donors, including haploidentical donors) and is either:
- HLA-A*0201 positive and HA-1(H) negative (RS_1801284: G/G) or
- HLA-A*0201 negative
- Patients who are currently undergoing or who previously underwent allogeneic HCT for
- Acute myeloid leukemia (AML) of any subtype and any of the following:
- With relapse or refractory disease (>= 5% marrow blasts by morphology, or
circulating blasts, chloroma or granulocytic sarcoma) at the time of the
pre-HCT work-up
- With minimal/measurable residual disease (MRD: defined as detectable disease
by morphology, flow cytometry, molecular or cytogenetic testing but < 5%
marrow blasts by morphology, no circulating blasts) at the time of the
pre-HCT work-up
- With marrow aplasia or marked hypoplasia (bone marrow cellularity =< 10%)
following chemotherapy for prior refractory AML at the time of the pre-HCT
work-up
- With relapse or refractory disease (>= 5% marrow blasts by morphology, or
circulating blasts) at any time after HCT
- With MRD at any time after HCT
- Acute lymphoid leukemia (ALL) of any subtype and any of the following:
- With relapse or refractory disease (>= 5% marrow blasts, or circulating
blasts) at the time of the pre-HCT work-up
- With MRD at the time of the pre-HCT work-up
- With marrow aplasia or marked hypoplasia (bone marrow cellularity =< 10%)
following chemotherapy for prior refractory ALL at the time of the pre-HCT
work-up
- With relapse or refractory disease (>= 5% marrow blasts, or circulating
blasts) at any time after HCT
- With MRD at any time after HCT
- Biphenotypic/undifferentiated/any other type of acute leukemia and any of the
following:
- With relapse or refractory disease (defined as detectable disease by
morphology, flow cytometry, molecular or cytogenetic testing but < 5% marrow
blasts by morphology, no circulating blasts) at the time of the pre-HCT
work-up
- With MRD at the time of the pre-HCT work-up
- With marrow aplasia or marked hypoplasia (bone marrow cellularity =< 10%)
following chemotherapy for prior refractory acute leukemia at the time of
the pre-HCT work-up
- With relapse or refractory disease (>= 5% marrow blasts, or circulating
blasts) at any time after HCT
- With MRD at any time after HCT
- Chronic myeloid leukemia with a history of blast crisis and
- With relapse or refractory disease (>= 5% marrow blasts, or circulating
blasts) at any time after HCT
- With persistent rising minimal residual disease (defined as detectable
disease by morphology, flow cytometry, molecular or cytogenetic testing but
< 5% marrow blasts by morphology, no circulating blasts on >= 2 of two
consecutive tests), refractory or ineligible for treatment with tyrosine
kinase inhibitors at any time after HCT
- Patients must be able to understand and be willing to give informed consent; parent or
legal representative will be asked to consent for patients younger than 18 years old
- Patients must agree to participate in long-term follow-up for up to 15 years if they
are enrolled in the study and receive T cell infusion
- Patients who have relapsed or have MRD after HCT may receive other agents for
treatment of disease and remain eligible for the protocol
- A specific performance status score is not required for enrolling on the protocol; a
delay in infusion of the HA-1 TCR T cells may be required for patients with low
performance status
DONOR SELECTION INCLUSION
- Donor age >= 18 years
- Donors must be able to give informed consent
- Patients must have an adult donor for HCT who is adequately HLA matched by
institutional standards (includes HLA-matched related or unrelated donors, and
HLA-mismatched family donors, including haploidentical donors) and is either:
- HLA-A*0201 positive and HA-1(H) negative (RS_1801284: G/G) or
- HLA-A*0201 negative
Exclusion Criteria:
- Central nervous system (CNS) leukemia (including leukemia detectable in the
cerebrospinal fluid and/or solid chloromas) refractory to intrathecal chemotherapy
and/or craniospinal radiation within 15 days prior to enrollment
- Human immunodeficiency virus (HIV) seropositive on test obtained within 30 days prior
to enrollment
- Medical or psychological conditions present within 30 days prior to enrollment that
would make the patient unsuitable candidate for cell therapy at the discretion of the
principal investigator (PI)
- Pregnancy or breast-feeding within 30 days prior to enrollment
- Fertile patients unwilling to use contraception during and for 12 months after
treatment
- Patients with a life expectancy < 3 months of enrollment from coexisting disease other
than leukemia
- Patients who develop grade IV acute GVHD or severe chronic GVHD prior to enrollment on
the protocol
- The presence of organ toxicities will not necessarily exclude patients from enrolling
on the protocol at the discretion of the PI; however, a delay in the infusion of HA-1
TCR T cells may be required
DONOR SELECTION EXCLUSION
- Donors who are HIV-1, HIV-2, human T-lymphotropic virus (HTLV)-1, HTLV-2 seropositive
or with active hepatitis B or hepatitis C virus infection
- Unrelated donor residing outside of the United States of America (USA)
