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Monoclonal
Antibodies May Reduce Relapse of Acute Leukemia Following
Allogeneic Stem Cell Transplantation
by
Robert Krance,
M.D.
Conventional allogeneic stem cell transplantation (SCT)
has relied on high and often toxic doses of drugs and/or
radiation to produce sufficient host stem cell and immune system
ablation to permit donor stem cell engraftment. The intensity of
the therapy was also considered essential to eradication of
residual leukemia. Using this approach, allogeneic stem cell
transplantation (alloSCT) has been able to salvage many patients
with relapsed/resistant leukemia. Nevertheless relapse stands as
the foremost cause for treatment failure following stem cell
transplantation. Clinical trials aimed at improving outcome by
decreasing the relapse rate have examined the impact of more
intensive pre-transplant conditioning, but such efforts have led
to an unacceptable increase in toxicity. Clearly needed are
treatments, which bring additional anti-leukemia activity but do
not add to the toxicity surrounding transplant conditioning.
To that end, antibodies targeted to specific antigens
may be a means to achieve these goals. One particularly
attractive target antigen is CD45, the common leukocyte antigen,
expressed by almost all nucleated white blood cells, including T
cells, B cells, natural killer (NK) cells, and granulocytes.
Moreover, virtually all hematologic malignancies also express
high levels of the antigen, potentially allowing intensification
of pretransplantation antileukemic therapy without an associated
increase in nonspecific toxicity.
CD45 monoclonal antibodies (CD45 MAbs) conjugated to a
radionuclide already have been used in both animal models of
leukemia and in human disease. Although this approach has proved
promising and appears to improve disease-free survival following
SCT, the delivery of a substantial dose of radiation to some
tissues has caused hypothyroidism and interstitial pneumonia in
a significant proportion of patients. Unconjugated anti-CD45
antibodies capable of recruiting host lytic effector mechanisms
may be an alternative to the hazards of radioisotope use,
specifically sparing normal tissue from radiation. These
unconjugated antibodies may induce target cell destruction
through any combination of antibody-dependent cellular
cytotoxicity, complement-mediated lysis, and opsonization and
phagocytosis. In murine transplant models, administration of
lytic CD45 MAbs has produced marked leucodepletion followed by
recovery of hematopoiesis; however T-cell, NK cell, and B-cell
numbers remain profoundly reduced. For mice, combining CD45 MAbs
with sublethal doses of irradiation promotes successful stem
cell engraftment of fully H2 allogeneic stem cells.
These promising animal data led us to investigate the
effects of lytic CD45 MAb given to patients who were to undergo
an allogeneic SCT for advanced hematologic malignancy.1
The antibody preparation used in this study combined two
unconjugated rat antihuman CD45 MAbs. Each antibody binds to a
distinct and noncompeting epitope of CD45, and each epitope is
present on all CD45 isoforms. Together these two antibodies
exhibit a synergistic ability to lyse human hematopoietic and
lymphoid cells by complement-mediated and cell-dependent
mechanisms. The objectives of our phase I study were to
determine the safety of these highly lytic MAbs in vivo, and to
discover whether, in tolerated doses, they produced the
myeloreduction observed in mice.
We treated 14 children with advanced and/or high risk
leukemia or myelodysplastic disease using fully ablative
transplant conditioning.2 CD45 MAbs were administered
over four days prior to the chemotherapy and total-body
irradiation followed by stem cell transplantation from either
related or unrelated donors. Mild systemic hypersensitivity
reactions were the principal toxicity accompanying the
administration of the CD45 MAb combination. Dose limiting
toxicity was due to bronchospasm. Twelve of the 14 patients
engrafted between day 11 and day 27 (median, day 20), whereas
two failed to engraft. Seven patients remain alive and disease
free, while seven patients have died, including three of
recurrent or persistent disease. Although treatment outcome was
not an endpoint, event-free survival appears comparable to that
achieved among patients undergoing transplantation for less
advanced disease.
At therapeutic concentrations, CD45 MAbs fixed human
complement and decreased neutrophil and lymphocyte counts. Based
upon marrow studies and colony assays, CD45 MAbs exhibited
little effect on immature hematopoietic precursors. This is not
surprising, as the CD45 expression is lower on these cells. We
also examined the activity of CD45 MAbs against T- and NK cell
populations because these components of the immune system are
critical in mediating graft rejection. Our results indicate that
the in vivo myeloreductive and lymphoreductive properties of
lytic CD45 MAb in humans closely parallel the nonmyeloablative
activity seen in a murine model and, therefore, may be of
similar value to facilitate stem cell engraftment.
Based upon this phase I study, we have begun to explore
how lytic CD45 MAb may be incorporated into human SCT. As these
antibodies do not produce prolonged myeloablation, their primary
contribution may be as an adjunct to conditioning for
nonmyeloablative transplantation. Because CD45 MAbs cytoreduce
all lymphoid subsets, including T and NK cells, the perturbation
of the immune system they produce may be more extensive than
that achieved with other MAbs active against fewer cellular
compartments. This latter activity may be most beneficial in
promoting donor immunosuppression permissive of allogeneic
engraftments.
To examine this potential role, we have undertaken a
pilot study using CD45 MAbs as a component of nonmyeloablative
conditioning.3;4 This trial is open to patients with
hematologic malignancy who because of age or prior comorbidity
are not suitable candidates for fully ablative transplantation.
To date 24 patients, including six children have been enrolled.
All but one patient has engrafted and as in the prior study
treatment with CD45 MAbs was well tolerated. Outcomes
appear to be at least equivalent to other studies using nonmyeloablative conditioning.
A second potential application for CD45 MAbs is to
enhance the antileukemic activity of SCT because these
antibodies have been shown to bind leukemic blasts. In the
original phase I study, three patients had measurable numbers of
blasts in the marrow before MAb infusion. In two patients, there
was a reduction in the proportion of leukemic cells post
treatment. If this secondary effect is confirmed in a larger
series, CD45 MAb also may be a useful addition to the treatment
of malignant disease. When administered as part of a more
conventional myeloablative conditioning regimen, CD34 MAbs did
not appear to add to the toxicity of the procedure. To examine
this potential application, we have recently opened a trial in
which patients with advanced leukemia will received CD45 MAbs
and undergo fully ablative conditioning.
Finally, the role of stem cell transplantation for
nonmalignant disease remains problematic. While patients with
inherited diseases, for example sickle cell anemia, clearly have
benefited from transplantation, there are major concerns
regarding both immediate and delayed risk following allogeneic
transplantation. Because, CD45 MAbs are permissive of
engraftment in the nonmyeloablative setting, there may be value
in exploring the use of these MAbs in HLA mismatched
transplantation, particularly for patients with nonmalignant
disease, where exposure to chemotherapeutic agents and to
radiation is least desirable.
Robert Krance, M.D. is a hematologist/oncologist with Texas
Children's Cancer Center and director of the
Pediatric Stem Cell Transplant Program. Dr. Krance's research focuses on the development of
transplantation using alternative donors and less than fully HLA
matched related donors. In collaboration with other
investigators in the
Cell and Gene Therapy Program, new
cell-based approaches are being conducted hopefully to diminish
the impact of viral infection post transplantation.
References
1. Brenner MK,
Wulf GG, Rill DR et al. Complement-fixing CD45 monoclonal
antibodies to facilitate stem cell transplantation in mouse and
man. Ann.N.Y.Acad.Sci. 2003;996:80-88.
2. Krance RA,
Kuehnle I, Rill DR et al. Hematopoietic and immunomodulatory
effects of lytic CD45 monoclonal antibodies in patients with
hematologic malignancy. Biol.Blood Marrow Transplant.
2003;9:273-281.
3. Popat U, Heslop
HE, Durett A et al. Outcome of reduced-intensity allogeneic
hematopoietic stem cell transplantation (RISCT) using
antilymphocyte antibodies in patients with high-risk acute
myeloid leukemia (AML). Bone Marrow Transplant. 2006;37:547-552.
4. Popat
U, Carrum G, May R et al. CD52 and CD45 monoclonal antibodies
for reduced intensity hemopoietic stem cell transplantation from
HLA matched and one antigen mismatched unrelated donors. Bone
Marrow Transplant. 2005;35:1127-1132.
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