autologous blood and marrow transplantation - Blog Science ...

216 Chapter 5: Myeloma
patients with relapsed MM after allografting has provided unequivocal evidence of
2 9 , 3 0
GVM. The largest single-center experience showed that eight of 13 patients
treated with DLI for relapsed MM after allografting responded, including four CR
and four PR. 31
In these cases, GVHD was observed after DLI; however, infusion
of thymidine kinase gene-transduced DLI followed by treatment of the recipient
with ganciclovir has been proposed as one potential strategy to treat DLI-
3 2
associated GVHD.
The observations that total T cell and CD8 +
numbers correlate with GVHD
post-CD6-depleted BMT, 33
coupled with the demonstration by Champlin and
colleagues that CD8 +
T cell depletion of donor BM or DLI can avoid GVHD, 34
suggested to us that CD4 +
enrichment of DLI could perhaps preserve GVM while
avoiding GVHD. Our early experience suggests that CD4 +
DLI, both in the context
of treating relapsed MM after allografting and when given at 6-9 months after
allografting to treat MRD, can be associated with GVM in the absence of clinical
GVHD in some patients. 21
Moreover, we are evaluating T cell repertoire, assessed
by V(3 T cell receptor gene (TCR) rearrangement, to identify clonal T cells
associated with clinical GVM and to delineate potential target antigens on tumor
cells. To date, we have completed molecular analysis of the TCR repertoire in four
patients with relapsed MM who received CD4 +
DLI, three of whom responded but
also developed GVHD (Orsini et al., manuscript submitted). PCR amplification of
24 VP subfamilies determined the relative utilization each VB gene subfamily, and
analysis of complementarity-determining regions 3 (CDR3) for each TCR VB gene
subfamily identified clonal and oligoclonal T cells. Interestingly, distinct clonal T
cell populations were evident at the time of GVM vs. GVHD in these three patients.
In a single patient, we have identified two distinct GVM clones, both of which are
CD8 +
cytolytic T cells and one of which targets the idiotypic protein. The target
antigen of the other GVM clone remains under active investigation. The results of
these studies will lay the groundwork for ex vivo expansion of antigen-specific T
cells targeting MM cells to be used in trials of adoptive immunotherapy to treat
MRD posttransplant.
We are also attempting to improve the outcome of autografting in MM by
increasing the efficacy of PBSC purging and, importantly, by developing methods
for enhancing autologous anti-MM immunity to treat MRD posttransplant. In terms
of autograft purging, mAb-based techniques deplete only 2-3 logs of tumor
cells. 22-25
CD34 selection of autologous PBPCs can achieve up to 5 logs' depletion
of tumor cells, 26
and in a larger randomized multicenter trial has recently been
shown to deplete 3.1 logs of MM cells. 28
The clinical significance of this degree of
depletion of tumor cells remains to be determined. Moreover, although depletion of
up to 5 logs of MM cells can be achieved using these approaches, 2635
residual
tumor cells are detectable in the autograft, as well as in the patient, after
transplant. 27
To improve depletion of MM cells from autografts, we have recently