Adjuvant Immunotherapy to Improve Outcome in High-Risk Pediatric Sarcomas

Abstract

Purpose: Patients with metastatic or relapsed pediatric sarcomas receive cytotoxic regimens that induce high remission rates associated with profound lymphocyte depletion, but ultimately few survive long term. We administered adjuvant immunotherapy to patients with metastatic and recurrent pediatric sarcomas in an effort to improve outcomes.

Experimental design: Mononuclear cells were collected via apheresis, and tumor lysate was acquired via percutaneous biopsy at enrollment. Participants received standard antineoplastic therapy, followed by autologous lymphocytes, tumor lysate/keyhole limpet hemocyanin-pulsed dendritic cell vaccinations ± recombinant human IL7. Primary outcomes were toxicity and vaccine responses. Secondary outcomes were immune reconstitution, event-free survival, and overall survival (OS).

Results: Forty-three patients enrolled and 29 received immunotherapy. The regimen was well tolerated. Intent-to-treat analysis demonstrated 5-year OS of 51% with significant differences based upon histologic group (63% vs. 0% for Ewing/rhabdomyosarcoma vs. other sarcomas) and response to standard therapy (74% no residual disease vs. 0% residual disease). Five-year intent-to-treat OS of patients with newly diagnosed metastatic Ewing/rhabdomyosarcoma was 77%, higher than previously reported in this population and higher than observed in a similar group treated with an earlier adjuvant immunotherapy regimen (25% 5-year OS). T-cell responses to autologous tumor lysate were identified in 62% of immunotherapy recipients, and survival was higher in those patients (73% 5-year OS with vs. 37% without immune response, P = 0.017). Immune reconstitution, measured by CD4 count recovery, was significantly enhanced in subjects treated with recombinant human IL7.

Conclusions: Adjuvant immunotherapy may improve survival in patients with metastatic pediatric sarcoma. Clin Cancer Res; 22(13); 3182-91. ©2016 AACR.

Figure 1.

Consort diagram illustrating enrollment of subjects on this second-generation consolidation immunotherapy trial (NCT00923351), and composition and timing of immunotherapy administered.

Figure 2.

A, survival was significantly higher for participants with ES/RMS compared with those with other sarcomas (desmoplastic small round cell tumor, synovial sarcoma, and undifferentiated sarcoma). Intent-to-treat analysis of all patients enrolled is shown. B–D, measuring OS from date of completion of standard therapy, OS was higher for participants without evidence of residual disease following standard therapy compared with those with evidence of residual disease (B) and for immunotherapy recipients compared with those who did not receive immunotherapy (C). Among immunotherapy recipients, OS did not differ between participants with metastatic versus recurrent disease (D). E, OS for intent-to-treat population of patients with newly diagnosed, metastatic ES/RMS enrolled on this second-generation trial (NCT00923351) is significantly higher than for those enrolled on the first-generation trial (NCT00001566). F, immunotherapy recipients who received at least three vaccines were evaluated for immune response to autologous tumor lysate (n = 26) at weeks 6, 14, and 20 after initiation of immunotherapy. Beginning at completion of immunotherapy, OS was higher for participants with a positive immune response at any time point compared with those without a positive response.

Figure 3.

Patient #2 presented at 24 years of age with disseminated ES involving kidney, bone, bone marrow, and lungs. She received standard cytotoxic therapy followed by immunotherapy on cohort 1. The image demonstrates FDG-PET scans taken at presentation and 4.5 years following presentation. She remains free of disease with no evidence of recurrence.

Figure 4.

A–D, immune reconstitution of circulating lymphocyte subsets in immunotherapy recipients. Asterisks designate time points with significant differences between groups ± CYT107. E, shown is the percentage of circulating CD4⁺ T cells expressing FOXP3 as a marker of the regulatory subset in samples obtained at the designated time point from clinical trials NCT00001566 (open shapes) and NCT00923351 (closed shapes). Lymphopenia induced by cytotoxic chemotherapy is associated with increased frequencies of CD4⁺ FOXP3⁺ cells. CYT107 recipients experienced reductions in the frequency of FOXP3⁺ cells at weeks 6, 14, and 20 compared with that measured following chemotherapy in clinical trial NCT00923351. Similar reductions were not observed in subjects who did not receive cytokine therapy (combined data from clinical trials NCT00001566 and NCT00923351 and in subjects treated with rhIL2 in clinical trial NCT00001566. *, P < 0.05; **, P < 0.01.