ALBERT

Description: Disease relapse remains a principle cause of mortality following autologous hematopoietic transplant. Strategies to enhance immune function in the post-transplant setting are needed to eliminate residual disease. CD40 stimulation through the use of agonistic CD40 antibodies has been shown to promote anti-tumor activity both as a single agent and in combination with IL-2 administration with increases in dendritic cell numbers being observed. We hypothesized that CD40 stimulation in combination with myeloablative syngeneic hematopoietic cell transplantation can act together to promote anti-tumor responses. We developed a model in which anti-CD40 given with syngeneic BMT was assessed in advanced tumor-bearing mice. We have found that delaying administration of anti-CD40 for one week post-BMT could obviate the severe toxicity associated with immediate post-BMT administration. BALB/c were given a syngeneic renal cell carcinoma cell line (Renca) i.v. After 4 days, at which time lung metastases were established, the mice were treated with syngeneic BMT followed one week later with initiation of anti-CD40 treatment (100 μg/dose; daily, 4 days per week for 2 weeks). CD40 stimulation resulted in significant expansion of GR-1+/CD11b+ myeloid and CD11c+/I-A+ dendritic cells in the spleen, similar to the expansion of these populations observed in mice that received anti-CD40 and no BMT. However, while B220+ IgM+ B cells are significantly expanded following anti-CD40 administration in mice that do not receive a transplant, B cell recovery is reduced following transplant in mice that also received anti-CD40. T cell recovery post-transplant did not differ significantly in animals that received anti-CD40 or control antibody. Importantly, significant increases in survival of anti-CD40 treated, tumor-bearing recipients of syngeneic BMT were observed compared to either treatment alone (log-rank test p〈 0.001). This promotion of anti-tumor activity by CD40 stimulation was seen in mice that were profoundly T cell deficient due to the transplant. These data suggest that despite severe immune depletion that occurs after lethal TBI, immunomodulation by anti-CD40 can result in significant protection from the residual disease despite the severe lack of T cells at this time period.

Description: Memory T cells exhibit tremendous antigen specificity within the immune system and accumulate with age. Our studies reveal an antigen-independent expansion of memory, but not naive, CD8+ T cells after several immunotherapeutic regimens for cancer resulting in a distinctive phenotype. Signaling through T-cell receptors (TCRs) or CD3 in both mouse and human memory CD8+ T cells markedly up-regulated programmed death-1 (PD-1) and CD25 (IL-2 receptor α chain), and led to antigen-specific tumor cell killing. In contrast, exposure to cytokine alone in vitro or with immunotherapy in vivo did not up-regulate these markers but resulted in expanded memory CD8+ T cells expressing NKG2D, granzyme B, and possessing broadly lytic capabilities. Blockade of NKG2D in mice also resulted in significantly diminished antitumor effects after immunotherapy. Treatment of TCR-transgenic mice bearing nonantigen expressing tumors with immunotherapy still resulted in significant antitumor effects. Human melanoma tissue biopsies obtained from patients after topically applied immunodulatory treatment resulted in increased numbers of these CD8+ CD25− cells within the tumor site. These findings demonstrate that memory CD8+ T cells can express differential phenotypes indicative of adaptive or innate effectors based on the nature of the stimuli in a process conserved across species.