In FY13, we continued enrollment of a trial of activated NK cells administered following allogeneic stem cell transplantation for high risk pediatric cancer. This built upon a previous published study of allogeneic stem cell transplantation for patients with high-risk pediatric sarcomas, that used a non-myeloablative allogeneic peripheral blood stem cell transplant for patients with matched sibling donors to treat patients with ultra-high risk pediatric solid tumors. Results showed a high rate of tumor recurrence and chronic GVHD. We subsequently developed an approach to generate large numbers of activated NK cells ex vivo. NK cells have previously been reported to be capable of mediating graft-versus-tumor effects after allogeneic stem cell transplantation without GVHD. This represents the first time such cells have been used in humans, pediatric or otherwise, and thus is highly novel. Thus far, we have treated 10 patients on this study and have observed a surprisingly high incidence of GVHD. These results suggest that activated NK cells, unlike NK cells which naturally reconstitute following allogeneic stem cell transplant, are capable of initiating or potentially augmenting low level alloreactivity. We have subsequently amended the trial to incorporate GVHD preventative therapy and are preparing the results for publication. In FY13 we continued enrollment to the only Phase I study of anti-CTLA4 in pediatrics, targeting patients with pediatric melanoma. We have seen disease stabilization on this study, but not objective antitumor responses. We also have demonstrated that children experience autoimmune toxicity with this agent, which is similar in nature and severity to that observed in adults. In FY13, we completed treatment of patients treated on our combined tumor vaccine, immune reconstitution trial (NCI 07-c-0206) and presented clinical results at the American Society of Clinical Oncology. The biologic endpoints on this study regarding immune reconstitution are discussed in Project I, but we also observed a 80% rate for patients with metastatic Ewing sarcoma enrolled after completion of frontline therapy. These results are intent-to-treat and are significantly better than observed on our previous study of immune reconstitution/dendritic cell vaccine at the National Cancer Institute. We plan enrollment of future cohorts to attempt to identify what components of this regimen are responsible for the favorable outcomes, to generate more experience with his regimen and to optimize this therapy for export to other institutions. We enrolled 2 patients on a trial using a genetically engineered T cell receptor targeting NY-ESO-1+ in HLA-A2+ patients with synovial sarcoma. This trial seeks to reproduce promising results seen in a trial administering similar T cells with high dose IL2 to patients with sarcoma and melanoma and represents a collaboration with Adaptimmune LLC. The second patient enrolled had a dramatic complete response that is sustained after this therapy. Continue protocol enrollment will occur during FY14. In FY13, we also initiated a clinical trial of anti-CD19 chimeric antigen receptor based therapy for patients with refractory B cell acute lymphoblastic leukemia. Thus far, 10 patients have been treated on this study and 8 patients have been followed long enough to evaluate for response. Using an intent-to-treat analysis, we observe a 62.5% complete response rate overall, with a 71% CR rate for patients with acute lymphoblastic leukemia. Toxicity has been cytokine release syndrome as previously reported which has been readily managed with supportive care. Early results of this study have been highlighted in a press release at the American Association for Cancer Research and was presented in an oral session at ASCO 2013. Enrollment is ongoing. In FY13 we also published a manuscript demonstrating expansion of myeloid derived suppressor cells in patients with pediatric solid tumors. This is the first description of circulating MDSC is this population. Notably, the MDSC were unique in that they possessed feature of previously described monocytic and neutrophilic MDSC and also expressed cell surface markers associated with fibrocytes. Further studies demonstrated these cells to be angiogenic and to be immunosuppressive. They also express IL7R and TSLPR and are expanded by TSLP, but not IL7. In conclusion, we identified a new cell, termed an immunosuppressive fibrocyte and suggested utilization of a new nomenclature: F1 vs F2 fibrocytes to describe immunostimulatory vs immunosuppressive fibrocytes respectively. Although fibrocytes have been described in chronic inflammatory states, they have not previously been described in human cancer. We postulate that this cell comprises yet another mechanism through which cancer evade immunity and mediate angiogenesis. This work was selected as the Plenary Paper in BLOOD in August 2013.
|Lee, Daniel W; Gardner, Rebecca; Porter, David L et al. (2014) Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124:188-95|
|Mackall, Crystal L; Merchant, Melinda S; Fry, Terry J (2014) Immune-based therapies for childhood cancer. Nat Rev Clin Oncol 11:693-703|
|Corrigan-Curay, Jacqueline; Kiem, Hans-Peter; Baltimore, David et al. (2014) T-cell immunotherapy: looking forward. Mol Ther 22:1564-74|
|Zhang, Hua; Maric, Irena; Diprima, Michael J et al. (2013) Fibrocytes represent a novel MDSC subset circulating in patients with metastatic cancer. Blood 122:1105-13|
|Tumaini, Barbara; Lee, Daniel W; Lin, Tasha et al. (2013) Simplified process for the production of anti-CD19-CAR-engineered TÂ cells. Cytotherapy 15:1406-15|
|Lee, Daniel W; Barrett, David M; Mackall, Crystal et al. (2012) The future is now: chimeric antigen receptors as new targeted therapies for childhood cancer. Clin Cancer Res 18:2780-90|
|Merchant, Melinda S; Geller, James I; Baird, Kristin et al. (2012) Phase I trial and pharmacokinetic study of lexatumumab in pediatric patients with solid tumors. J Clin Oncol 30:4141-7|