Phase I Study of Adoptive Immunotherapy With CD8 Minor Histocompatibility (H) Antigen-Specific CTL Clones for Patients With Relapsed of AML or ALL After Allogeneic Hematopoietic Stem Cell Transplant
- Determine the toxic effects of adoptive immunotherapy comprising CD8-positive minor
histocompatability antigen-specific cytotoxic T-lymphocytes in patients with acute
myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndromes that
relapsed after allogeneic hematopoietic stem cell transplantation.
- Determine the persistence of adoptively transfused T cells in vivo and assess their
migration to the bone marrow in these patients.
- Determine the anti-leukemic activity of this therapy in these patients.
OUTLINE: This is a pilot, open-label, nonrandomized study.
- Leukapheresis: Patients undergo leukapheresis to obtain peripheral blood mononuclear
cells (PBMCs) before transplantation. Donors undergo leukapheresis to obtain PBMCs to
use as feeder cells for generating adoptive immunotherapy. Patient PBMCs are combined
with donor PBMCs and expanded in vitro to generate CD8-positive minor
histocompatability antigen-specific cytotoxic T-lymphocytes (CTLs) for adoptive
- Transplantation: Patients undergo allogeneic bone marrow or peripheral blood stem cell
transplantation. Patients with a morphologic or flow cytometric relapse on or after day
100 post-transplantation proceed to cytoreductive chemotherapy. Patients with a
molecular or cytogenetic relapse on or after day 100 post-transplantation proceed
directly to adoptive immunotherapy. Patients with relapsed disease before day 100
post-transplantation are eligible to receive adoptive immunotherapy at a later date
provided the patient continues to relapse and CTLs are available.
- Cytoreductive chemotherapy: The chemotherapy regimen for each patient is determined
after consideration of prior chemotherapy, type of leukemia, and other clinical
parameters. Two regimens to consider are:
- Mitoxantrone IV and etoposide IV on days -6 to -2
- High-dose cytarabine IV over 2 hours twice daily on days -6, -4, and -2 Patients
achieving a complete remission after completion of cytoreductive chemotherapy
proceed to adoptive immunotherapy.
- Adoptive immunotherapy: Within 2-3 days after completion of cytoreductive chemotherapy,
patients receive CTLs IV over 1-2 hours on days 0, 4, 11, 21, and 28 in the absence of
unacceptable toxicity. Patients with evidence of persistent disease on or after day 35
OR relapsed disease after an initial response to CTLs receive a sixth infusion of CTLs
followed, no more than 24 hours later, by interleukin-2 subcutaneously once daily for
up 14 total doses in the absence of unacceptable toxicity. Patients with subsequent
relapsed disease after day 48 may be eligible for retreatment.
After completion of study treatment, patients are followed with bone marrow aspiration every
3 months for 1 year.
PROJECTED ACCRUAL: A total of 25-30 patients (10-15 with acute myeloid leukemia or
myelodysplastic syndromes AND 10-15 with acute lymphoblastic leukemia) will be accrued for
this study within 3 years.
Masking: Open Label, Primary Purpose: Treatment
Edus H. Warren, MD, PhD
Fred Hutchinson Cancer Research Center
United States: Federal Government
|Fred Hutchinson Cancer Research Center||Seattle, Washington 98109|