T-CELLS AND TRANSPLANTATION THERAPIES

Bone marrow transplantation (BMT) has allowed the treatment of cancer
patients with more intensive protocols of chemo/radiotherapy, thereby
decreasing the incidence of relapse. The use of peripheral blood derived
mononuclear cells in place of bone marrow has gained acceptance in those
patients for whom BMT is not an option. In a retrospective analysis at the
University of Nebraska Medical Center patients with intermediate grade
non-Hodgkin's lymphoma (NHL) receiving high dose therapy with autologous
BMT (AuBMT) (n=105) had a three-year event free survival (EFS) of 24%.
This compares to a three-year EFS of 38% for patients with intrinsic bone
marrow abnormalities who underwent high dose therapy with peripheral blood
stem cell transplant (PBSCT) (n=53). We hypothesize that patients
receiving a PBSCT would have an improved response rate, and T cell
activity due to the infusion of greater numbers of mature T cells relative
to BMT. Although the hematopoietic reconstitution of these patients has
been described, little data has been obtained on their immune
reconstitution. Thus, it is the overall intent of this proposal to examine
the reconstitution of the immune system after PBSCT and compare the
reconstitution observed after PBSCT to that observed after AuBMT and
determine if this has a role in the therapeutic response of the PBSCT
patients. The overall pattern of immune reconstitution in patients
receiving PBSCT will be compared to that in patients receiving AuBMT to
determine whether significant differences exist between these two groups
of patients in either the extent, pattern, timing or longevity of this
reconstitution and to correlate T cell reconstitution with clinical
disease progression or lack thereof. Based on preliminary results in both
preclinical and clinical studies, the hypothesis to be tested in this
application is that PBSCT has significantly greater potential (compared to
AuBMT) to reconstitute lymphocyte populations both phenotypically and
functionally (especially T lymphocytes) after marrow ablative therapy with
improved therapeutic activity. This hypothesis will be tested by examining
the phenotypic, functional and molecular characteristics of peripheral
blood lymphocytes in patients undergoing each therapy. Further, in
conjunction with the clinical portion of this interactive RO1, we will
correlate the various surrogates of immune function with EFS, time to
disease progression, sites of relapse and survival to provide some insight
into the therapeutic impact of functional T cells.