The objective of the Immunology Section of the Pediatric Oncology Branch is to develop effective immune based therapies for pediatric cancer based on biologic insight from basic investigations. We build upon expertise in the biology of T cell regeneration to develop new therapies to enhance immune responses following T cell depleting chemotherapy and to amplify immune responses in the absence of T cell depletion (TCD). Data from multiple models suggests that one critical feature limiting the effectiveness of immune based therapies for cancer today is a quantitative disconnect between the potency of the immune response generated and the tumor burden present. By developing therapies to amplify immunity immediately following cytotoxic therapy, overall effectiveness should improve, since the tumor burdens are low at that point. In addition, the development of clinical therapies which mimic the host’s natural mechanisms for amplifying immunity in TCD hosts could potentially also be used to amplify immune responses in T cell replete hosts.
Studies focus on two primary projects: I. The biology and therapy of T cell depletion II. Immunobiology and immunotherapy of pediatric tumors. Specific aims of Project I are to improve the understanding of the immunobiology of T cell depletion through basic studies in murine systems and to identify new approaches to enhance immunity in T cell depleted hosts. Accomplishing these aims is expected to result in new therapies for patients with pediatric tumors, and also to benefit adults with cancer, patients suffering from TCD following allogeneic BMT, and patients with TCD due to HIV infection. These studies have shown that thymic-dependent and thymic-independent pathways of T cell regeneration work together to restore host immune competence following T cell depletion. IL-7, a cytokine produced by non-lymphoid stromal cells, plays a crucial role in this process by allowing thymopoiesis to proceed and by inducing peripheral T cells to undergo homeostatic peripheral expansion. Our work has shown that IL7 therapy can potently modulate immune reconstitution by increasing the number of progeny derived from each of these pathways. Based upon this, we are engaged in plans for a clinical trial of rhIL-7 to assess the capacity for this agent to modulate T cell homeostasis.
Because clinical translation of our work on immune reconstitution and immunotherapy is currently focused on pediatric sarcomas, the laboratory has also developed new projects aimed at understanding the immunobiology of pediatric sarcomas. Specific aims of Project II are to identify and characterize any endogenous immune responses which might naturally exist in patients with pediatric sarcomas. In addition, we aim to identify and characterize the programmed cell death pathways (e.g. Fas based, TRAIL based) which exist in pediatric sarcomas in order to 1) identify any particular blocks in the susceptibility to immune mediated cell death which might need to be overcome in the setting of immune based therapy and 2) to identify therapies to induce tumor apoptosis which could ultimately be used in conjunction with immunotherapy to amplify immune based responses.
These studies have identified the existence of oligoclonal T cell populations circulating in patients with Ewings which display potent cytolytic activity. The cytolytic activity is non-MHC restricted due to the existence of NK receptors on these oligoclonal T cells. The cytolytic cells lack the CD28 costimulatory molecule and express 4-1BB which appears to be important for providing a costimulatory signal for survival and expansion of these populations in vivo.
Within the context of this project, we also study programmed cell death in pediatric sarcomas. These studies have shown that Ewing’s sarcoma is highly susceptible to TRAIL mediated cell death and that even chemoresistant Ewing’s sarcoma cell lines are universally susceptible to TRAIL. Ongoing trials are under way to investigate activity in vivo using a sarcoma xenograft model in immunodeficient mice.
Finally, we are conduct clinical trials which attempt to translate the principles gleaned from our studies of immune reconstitution to induce antitumor immune responses following intensive chemotherapy for pediatric sarcomas. Our current trial uses a combination of immune reconstitution/immunotherapy wherein patients with high-risk pediatric sarcomas undergo T cell harvest prior to standard, cytotoxic antineoplastic therapy. Following standard therapy, patients receive infusions of T cells, dendritic cell-based immunization, and an HIV protease inhibitor which is under study as an immunorestorative agent. This trial targets the breakpoint region of the t(11;22) and t(2;13) found in pediatric sarcomas. The purpose of this trial is to study whether these approaches can enhance immune reconstitution and induce antitumor immune effects in the setting of minimal residual neoplastic disease.
In summary, immune incompetence related to T cell depletion is a central problem limiting therapeutic progress both in HIV infection and in the setting of bone marrow transplantation. Furthermore, if T cell-based immune responses could be successfully induced toward a variety of tumors in the postchemotherapy setting, when the tumor burden is low, it is likely that significant therapeutic benefit would result. Hence, the development of successful approaches to enhance immune reconstitution in these clinical settings would be expected to substantially improve the outcome in HIV infection, bone marrow transplantation, and potentially for cancer patients whose tumors can be targeted immunologically.

Crystal L. Mackall, M.D., Immunology Section

Last Updated: July 26, 2006

NCI Home Page|| NIH Home Page

© 2002-2003, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute