Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

The existence of a graft-versus-myeloma (GvM) and GvL effect has been shown directly
by remissions occurring after DLI; a GvM effect is obtained in 20±40 % of patients
after cumulative doses of T cells higher than those currently needed in CML
[18, 19].
15.5
Complications of DLI: GvHD and Marrow Aplasia
About 50±60% of patients treated with DLI develop GvHD. The rates of acute GvHD
reported in EBMT registry are 18% for grade I, 24% for grade II and 13% for grade
III-IV.
15.6
Strategies to reduce GvHD while preserving GvT
15.6 Strategies to reduce GvHD while preserving GvT
In recent years, different strategies have been investigated in order to prevent GvHD
without losing the GvL effect. Mackinnon et al. focused on the infusion of small
doses of cells, increasing the amount in a stepwise fashion until the disease responds
or GvHD develops [12]. In a series of 22 patients with CML, the incidence of
GvHD was correlated with the total dose of T cells administered: only one of the
eight patients who achieved remission at a T cell dose of 1 × 10 7 /kg developed
GvHD, whereas this complication developed in eight of the 11 responders who
achieved a T cell dose of 5 × 10 7 /kg or higher. Unfortunately, the GvL reactions may
require several weeks or even months for the elimination of the leukemic clone; given
the slow rate of response in some patients, it is impossible to know when to discontinue
the increasing cell doses of DLI unless GvHD occurs. The escalating doses
regimen (EDR) has been extensively tested in CML patients by Dazzi et al.; EDR has
been shown to give an equal GvL rate with a significant reduction in GvHD [20]. Another
approach to decrease the risk of GvHD is the depletion of CD8 + T cells from
the inoculum [21]. The transfer of specific effector cells rather than a heterogeneous
lymphocyte population should significantly reduce the risk of GvHD; in vitro cultured
leukemia-reactive CTL lines have been successfully used to treat a patient with
accelerated phase CML, without inducing GvHD [22].
However, the therapeutic usage of a heterogeneous T cell population with a wide
range of antigen specificity carries some advantages over the usage of specific CTLs
[23]. First, such a population can provide a more complete immunologic reconstitution
to immunocompromised transplanted patients. Moreover, since the antigen
specificity of the GvL effector cells is not completely clear, the usage of the entire T
cell repertoire is up to now considered the best option to obtain a GvL effect. In this
complex context, we investigated the genetic manipulation of donor lymphocytes
with a suicide gene which could enable their selective elimination in the case of severe
GvHD.
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