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Selective inhibitors of cyclooxygenase-2 (COX-2) enzyme activity have shown chemopreventive activity in carcinogen-induced and transgenic rodent tumor models and clinically for colon cancer. However, the mechanism(s) by which COX-2 inhibitors reduce carcinogenesis remains controversial. We report herein that administration of the selective COX-2 inhibitor, celecoxib, significantly reduces the number of Gr1(+)CD11b(+) immature myeloid suppressor cells (IMSCs) during chemoprevention of 1,2-dimethylhydrazine diHCl-(1,2-DMH-) induction of large intestinal tumors in Swiss mice. Celecoxib administration also increased splenic lymphatic number and tumor infiltration by lymphocytes. The 1,2-DMH induction of large intestinal tumors was associated with a four-fold increase in IMSCs, and a decrease in splenic T cell number and function. Concordant with the changes in the IMSC frequency, messenger ribonucleic acid (mRNA) levels of inducible nitric oxide synthase (NOS-2) and arginase (Arg) were increased in the spleen of the tumor-bearing mice and normalized by celecoxib administration. In addition to delaying tumor induction, reducing tumor number, and increasing lymphocyte infiltration of tumors, celecoxib therapy reversed CD4(+) T cell loss, decreased IMSC numbers and increased mRNA levels of NOS-2 and Arg in the spleen. In summary, our results suggest that celecoxib chemoprevention of autochthonous intestinal tumors can regulate IMSCs and CD4(+) T cell numbers.

NST provides graft-versus-leukemia (GVL) activity with reduced regimen related toxicity. We used a conditioning regimen consisting of Pentostatin 4 mg/m2 daily × 3 days and 200 cGy TBI 24 hrs prior to stem cell infusion in patients (pts) with high-risk/relapsed/refractory hematologic malignancies. The importance of the timing of stem cell infusion relative to Pentostatin administration was examined in a comparison of two sequential protocols. In cohort 1 (n=39) Pentostatin was given on days -21, -20, and -19. In cohort 2 (n=39) Pentostatin was given on days -10, -9, and -8. The median age of the day -21 cohort was 52 years (range 22–70) and the day -10 cohort was 59.5 years (range 36–70). The median number of prior therapies in the day -21 cohort was 4 (range 0–8), including prior autologous SCT in 22 pts, while in the day -10 cohort, the median number of prior therapies was 6 (range 0–18), including prior autologous SCT in 9 pts. Post-grafting immunosuppression was cyclosporine (CsA)/mycophenolate mofetil (MMF). In both protocols, CsA 2.0 mg/kg IV q12 hrs was administered on days -1, 0, and +1, and then converted to oral 5 mg/kg PO BID with a taper beginning on day +70. In the second protocol, pts with unrelated donor transplants tapered CsA starting at day +100. MMF at 15 mg/kg PO BID was administered on days 0–27 for related donor transplants in both protocols and in the second protocol this was extended until day +40 for the unrelated donor transplants. In the day -21 protocol, SCTs were obtained from matched related (n=14) or unrelated (n=25) donors. The cumulative incidence of all grades of acute GVHD at day 100 was 40% and was more common in unrelated donor (60%) vs. related donors (15%) transplants. In the day -10 protocol, SCT was performed with products from matched related (n=15) or unrelated (n=21) donors. The cumulative incidence of grade II–IV acute GVHD was approximately 35% (30% in related versus 40% in unrelated donors). In both protocols, the median chimerism values for CD3+ cells and white blood cells at day 28 were >80% and 90% donor cells, respectively. T, B and natural killer (NK) lymphocyte frequency and numbers were identical at protocol entry. One day following TBI conditioning, there was a 57% depression in CD3+ cells in the day -21 protocol that was retained on day 28 post transplant (55%). In the day -10 protocol, there was a significant depression (47%) in the frequency of CD3+ cells one day following TBI, which was depressed further (68%) on day 28 post transplant. The dendritic cells (DCs), both CD123+ and CD11c+, were not suppressed by the conditioning regimen. Separation of pts on day 28 into cohorts with an absolute number of CD3+ cells >0.25×106/ml revealed that those pts with a higher CD3+ cell count had a median OS time of 36.7 weeks, which was significantly longer than pts whose absolute number of CD3+ cells

NST is increasingly being used to introduce a graft-versus-malignancy (GVM) effect with reduced regimen related toxicity. The first NST protocol, which accrued patients (pts) between 9/01 and 7/04, 39 pts with high risk/relapsed/refractory hematopoietic malignancies who were not candidates for full intensity allogeneic SCT underwent NST using Pentostatin/TBI. Their median age was 52 years (range 22–70). The median number of prior therapies was 4 (range 0–8) including prior autologous SCT in 22 pts. Conditioning consisted of Pentostatin 4 mg/m2 daily on day -21, -20, and -19, followed by 200 cGy TBI on day -1. The second protocol, between 10/04 and 6/06, 24 pts received the same conditioning regime on days -10, -9, and -8, and TBI on day -1. The median age of these pts was 59.5 years (range 36–70) and the median number of prior therapies was 2 (range 0–6). Post-grafting immunosuppression was cyclosporine (CsA)/mycophenolate mofetil (MMF). In the both protocols CsA 2.0 mg/kg IV q12 hrs was administered on days -1, 0, and +1 and then converted to oral 5 mg/kg PO BID with a taper beginning on day +70. In the second protocol pts with unrelated donor transplants remain on CsA until day + 100. MMF at 15 mg/kg PO BID was administered on days 0–27 for related donor transplants in both protocols and in the second protocol this was extended until day +40 for the unrelated donor transplants. Results: In the day -21 protocol SCTs were from matched related (n=14) or unrelated (n=25) donors. The cumulative incidence of all grades of acute graft-versus-host disease (GVHD) at day 100 was 40% and was more common in unrelated donor transplants (60% vs. 15%). In the day -10 protocol, SCT was performed with products from matched related (n=8) or unrelated (n=16) donors. The cumulative incidence of grade II–IV acute GVHD was approximately XX% (XX% in related versus XX% in unrelated donors). In both protocols, the median chimerism values for CD3+ cells and WBC at day 28 were >80% and 90% donor cells, respectively and T, B and NK lymphocyte frequency and numbers were identical at protocol entry. One day following TBI conditioning there was a 32% depression in CD3+ cells in the day -21 protocol that was partially recovered on days 28 and 70 post transplant (27% and 16% respectively). In the day -10 protocol there was a 45% depression in the frequency of CD3+ cells (p Conclusions: There appears to be a trend for a lower incidence of acute GVHD in the day -10 protocol, which can be associated with a reduction in the frequency of circulating T cells. This significantly greater reduction in T cell frequency, observed one day following TBI and 28 days post transplant, is directly associated with the timing of transplant relative to pentostatin conditioning as the post-grafting immunosuppression was similar between the two protocols at these time points.