Abstract
Refractory metastatic rhabdomyosarcoma is largely incurable. Here we analyze the response of a child with refractory bone marrow metastatic rhabdomyosarcoma to autologous HER2 CAR T cells. Three cycles of HER2 CAR T cells given after lymphodepleting chemotherapy induces remission which is consolidated with four more CAR T-cell infusions without lymphodepletion. Longitudinal immune-monitoring reveals remodeling of the T-cell receptor repertoire with immunodominant clones and serum autoantibodies reactive to oncogenic signaling pathway proteins. The disease relapses in the bone marrow at six months off-therapy. A second remission is achieved after one cycle of lymphodepletion and HER2 CAR T cells. Response consolidation with additional CAR T-cell infusions includes pembrolizumab to improve their efficacy. The patient described here is a participant in an ongoing phase I trial (NCT00902044; active, not recruiting), and is 20 months off T-cell infusions with no detectable disease at the time of this report.
Highlights
We describe the longitudinal analysis of immune-monitoring studies and show evidence of endogenous immune reactivity accompanying CAR T-cell therapy, which may have contributed to this favorable clinical outcome[11]
A 7-year-old boy presenting with severe pancytopenia was diagnosed with metastatic RMS after bilateral bone marrow aspiration and biopsy (BMAB) revealed infiltration with alveolar-pattern RMS cells, which were immunoreactive to desmin and myogenin (Fig. 1a)
The child completed intense systemic chemotherapy lasting for 13 months and radiation therapy to the primary site (4140 cGy in 23 fractions) according to the Children’s Oncology Group’s (COG) co-operative trial ARST0431 for upfront treatment of high-risk RMS (Supplementary Table 1), resulting in local control[12]
Summary
We analyze the response of a child with refractory bone marrow metastatic rhabdomyosarcoma to autologous HER2 CAR T cells. The patient described here is a participant in an ongoing phase I trial (NCT00902044; active, not recruiting), and is 20 months off T-cell infusions with no detectable disease at the time of this report. An ongoing phase I trial (NCT00902044; active, not recruiting) is designed to evaluate the safety of autologous HER2 CAR T cells after lymphodepletion in patients with advanced sarcoma and incorporates multiple CAR T-cell infusions to improve their persistence. We report on an exceptional tumor response observed in a child with refractory bone marrow-metastatic RMS enrolled on this phase I trial. We describe the longitudinal analysis of immune-monitoring studies and show evidence of endogenous immune reactivity accompanying CAR T-cell therapy, which may have contributed to this favorable clinical outcome[11]
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