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Clinical Trials of Immunotherapies for Childhood Cancer

Crystal Mackall

1 Collaborator(s)

Funding source

National Cancer Institute (NIH)
In FY14 we published a manuscript demonstrating expansion of myeloid derived suppressor cells in patients with pediatric solid tumors. This is the first description of circulating MDSC in pediatric cancer patients. Furthermore, the MDSC were unique in that they possessed features of previously described monocytic and neutrophilic MDSC and also expressed cell surface markers associated with fibrocytes. Fibrocytes have been well described in chronic inflammatory conditions but have not previously been described in humans with cancer. Further studies demonstrated these cells to be angiogenic and 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. 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. In FY14, we completed enrollment on a clinical trial of anti-CD19 chimeric antigen receptor based therapy for children and young adults with relapsed/refractory B cell malignancies. Twenty-one patients were enrolled and this trial observed a very high response rate in this patient population. The major toxicities were related to cytokine release syndrome and were reversible with immunosuppression. We observed that efficacy is correlated with several biomarkers including expansion of the CD19-CAR expressing T cells. This work has been submitted for publication and will lead to a follow-up trial incorporated stratified chemotherapy induction based upon disease burden in an attempt to increase the response rate and diminish the rate of Grade 4 cytokine release syndrome. Through this experience we have also focused on improving the grading system and treatment algorithm for cytokine release syndrome. We developed a consensus manuscript with collaborators for four institutions to accomplish this and published this manuscript in BLOOD in 2014. In FY14, we completed enrollment of the first cohort of patients to receive 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 GVHD that was unexpected given that the grafts were T cell depleted and NK cells have not previously been implicated in causing GVHD. These results have been submitted for publication and the clinical trial has subsequently been modified to incorporate GVHD prophylaxis. In FY14 we completed enrollment to the only Phase I study of anti-CTLA4 in pediatrics, which represents the only study of checkpoint inhibition in children with cancer. 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 FY14, 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. At the current time, follow-up studies are on hold pending access to recombinant human interleukin-7, which is a critical element in the immunorestorative regimen. In FY14, we continued enrollment 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. Thus far the treatment has been well tolerated with a very high response rate: four of five patients treated have had an objective response which persist for several months. Enrollment on this study is ongoing. In FY14 we continued enrollment on a trial using autologous activated NK cells for the treatment of solid tumors. We identified the maximally feasible dose of activated NK cells and observed interesting clinical results including a high response rate in patients with refractory solid tumors and significant inflammation at the sites of tumor and sites of previously irradiated disease. We could observe no clear evidence for NK cell persistence or expansion although these cells are not genetically marked and thus this is hindered by technical limitations. However, in an attempt to improve expansion and persistence we have begun administering recombinant human interleukin-15 following infusion of activated NK cells. The first patient received a dose of 0.25 mcg/kg/d x 10d as a continuous IV infusion. On Day 11 he developed severe, localized capillary leak syndrome involving the lungs and pericardium. He was treated with supportive care and corticosteroids with ultimately resolution of symptoms. We plan to enroll a second patient at this dose level and assess toxicity. This represents the first use of recombinant human interleukin-15 in children.

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