The purpose of this study is to assess the safety and efficacy of infusing immune cells from
a donor as treatment for patients with acute myeloid leukemia that is resistant to
chemotherapy or who have experienced relapse. Unlike standard bone marrow or stem cell
transplantation which uses donors who are well 'matched' to the patient, this study uses
donors whose immune cells are not compatible with the patient. With standard stem cell or
bone marrow transplantation, the well-matched immune cells will attack the leukemia but they
also attack the patient's organs (a situation called graft-versus-host disease, which can
persist in the long term). Our hypothesis is that the mismatched donor cells will fight the
leukemia but will then be eliminated from the patient's body, so long-term side effects like
graft-versus-host disease should not occur.
The ATAC cell therapy product contains unselected, non-mobilized peripheral blood mononuclear
cells from related donors who are mismatched to the recipients at 3 or more (out of 6) HLA
loci. Cohorts of 3 patients will be treated at each of four pre-specified dose levels (T
cells per kg recipient weight). One ATAC infusion is administered 24-48 hours following
re-induction chemotherapy (for relapsed or primary refractory AML patients not in remission).
In situations where ATAC infusion is not available immediately following re-induction
chemotherapy and patients nonetheless achieve complete remission, one ATAC infusion is given
24-48 hours after consolidation chemotherapy.
Recipient Inclusion Criteria:
- Age ≥ 18 years (no upper age limit, but physician discretion is advised)
- AML that is refractory to 2 courses of induction therapy (that together constitute the
'first-line' therapy) or that has relapsed after a period of morphologic complete
remission or morphologic remission with incomplete blood count recovery (CRi)
- Candidacy for intense induction chemotherapy (ECOG 0-2, adequate renal, liver and
cardiac function, absence of uncontrolled infections)
- Availability of parents, siblings or children who are HLA haploidentical (and not
homozygous for the shared haplotype), who are deemed suitable donors after medical
evaluation, and who complete peripheral blood mononuclear cell collection
- No history of autologous or allogeneic stem cell transplant, purine analog
chemotherapy or cyclophosphamide, or total body irradiation
- Ability to comprehend the investigational nature of the study and provide informed
consent
Recipient Exclusion Criteria:
- Acute promyelocytic leukemia (including those with non-classical rearrangements of
RARα)
- History of severe myelodysplastic syndrome clearly preceding the diagnosis of AML
(i.e., red cell transfusion dependence or erythropoietin dependence over a 4-month
period, or in the absence of a clear cause, any of the following: hemoglobin
consistently below 9 g/dL or platelets below 50 x 10^9/L or ANC below 1000/uL on 2 or
more occasions 2 weeks apart, or use of G-CSF to maintain the ANC threshold in the
absence of infection, in the 3 months preceding the diagnosis of AML). Exception: If
ATAC therapy is being considered as a bridge to stem cell transplantation in patients
with an available standard transplant donor (familial, unrelated, or cord blood), this
exclusion criterion does not apply.
- Grade 2-3/3 fibrosis in the diagnostic bone marrow biopsy
- DLCO < 40% predicted
- Left ventricular ejection fraction < 40% (evaluated by ECHO or MUGA)
- AST/SGOT > 2.5 x ULN
- Bilirubin > 1.5 x ULN
- Creatinine > 1.5 x ULN
- Creatinine clearance < 50 mL/min
- HIV positive
- Major anticipated illness or organ failure incompatible with survival from
chemotherapy
- Concurrent second primary cancer or a prior malignancy that required cytotoxic
treatment within the past 12 months, other than cervical carcinoma in-situ or prostate
cancer in-situ
- Severe psychiatric illness or mental deficiency sufficiently severe as to make
compliance with the treatment unlikely and informed consent impossible
- Any congenital or acquired immunodeficiency that would possibly permit permanent
engraftment of donor cells
- Receiving systemic steroid therapy or systemic immunosuppression such as cyclosporine
or TNF-inhibitors
- Prior or concurrent receipt of any marketed or investigational agent deemed on an ad
hoc basis to cause immunomodulation, pose a threat of permanent engraftment or
increase the risk of GVHD.
Donor inclusion criteria:
- Mismatched family donor (incompatibility at 3 loci HLA-A, B and DR of the unshared
haplotype, or higher-order incompatibility)
- Age ≥ 16 and ≤ 80 years
- Fit to undergo apheresis (normal blood counts, normotensive and no history of stroke).
- Donor has been tested negative for HIV-1, HIV-2, hepatitis B virus (HBV, surface and
core antigen), hepatitis C virus, human T-lymphotropic virus types I/II, and Treponema
pallidum (syphilis).
- ECOG performance status of 2 or less.
- Adequate veins for leukapheresis or agree to placement of a temporary central venous
catheter.
- Donor must provide written informed consent.
- Where multiple equally-suitable donors are available, sex mismatched donors will be
preferred.
Donor exclusion criteria:
- Medically uncontrolled coronary heart disease
- Myocardial infarction within the last 3 months
- History of seizure
- History of stroke
- History of malignancy (except basal cell or squamous carcinoma of the skin, or
positive PAP smear and subsequent negative follow-up)
- Presence of a transmissible disease (such as HIV seropositivity)
- Presence of a major illness or a suspected systemic dysfunction
- Presence of an an active inflammatory or autoimmune disorder
- Female donors who are pregnant or nursing
