autologous blood and marrow transplantation - Blog Science ...

Champlin, Khouri, and Giralt 699
is the kinetics of growth of the leukemia; rapid regrowth may outpace the
development of an effective immune antileukemic response.
A major challenge is to separate the beneficial GVL effect from the adverse
manifestations of GVHD. A number of approaches have been studied as indicated.
There is a dose-response effect with higher rates of GVHD as well as antileukemia
responses with increasing doses of T cells. 50
MacKinnon et al. performed a study
administering graded doses of T cells to patients with CML relapsing into chronic
phase after an allogeneic transplant from an HLA-identical sibling. Antileukemic
responses and GVHD did not occur at doses of 10 5
to 5X10 6
T cells per kg. Of 21
patients receiving 10 7
T cells per kg, eight achieved CR and only one developed
acute GVHD. At higher doses, there were additional responses but a much
increased risk of GVHD. Thus, it may be possible to induce antileukemic responses
at a T cell dose below the threshold necessary to produce GVHD. This general
approach has been confirmed by others. 20
' 51
An alternative strategy is to infuse T cell subpopulations that can mediate GVL
with a reduced potential for GVHD. Selective depletion of CD8-positive cells from
the allogeneic donor marrow transplants reduces the incidence of GVHD without
5 2 - 5 4
increasing the risk of relapse in CML. Donor lymphocyte infusions using CD8depleted
cells have also been effective to reinduce remission in patients with CML
5 5 5 6
with a low rate of GVHD.
GVHD is initiated by alloreactive T cells. A novel strategy to prevent GVHD is
to transduce donor T cells with a suicide gene, such as Herpes simplex virus
thymidine kinase (HSV-TK), which confers sensitivity to ganciclovir treatment.
The viral thymidine kinase phosphorylates ganciclovir into a monophosphate that
is subsequently converted by cellular kinases into the cytotoxic triphosphate form.
In preliminary studies, TK-transduced lymphocytes are capable of alloreactivity
resulting in GVL effects. If the patient develops GVHD, it can be abrogated by
ganciclovir treatment, lysing the transduced lymphocytes. This approach has been
successful in pilot studies using TK-transduced T cells for donor lymphocyte
infusions 57
or combining TK-transduced lymphocytes with T cell-depleted marrow
transplants. 5859
In each setting, acute GVHD could be successfully treated with
ganciclovir. Ganciclovir treatment may also abrogate GVL effects, and it is
uncertain if this strategy will improve leukemia-free survival.
INDUCTION OF GVL AS A PRIMARY TREATMENT MODALITY
USING NONABLATIVE PREPARATIVE REGIMENS
The high-dose chemotherapy and radiation typically used as the preparative
regimen for bone marrow transplantation produces considerable morbidity and
mortality and limits the use of this modality to a minority of patients who are young
and in good general medical condition.