Early Lymphocyte Recovery in Ewing Sarcoma

Pediatric Blood & Cancer

Bielack

Görlick

et al. 2016

BackgroundRobatumumab (19D12; MK‐7454 otherwise known as SCH717454) is a fully human antibody that binds to and inhibits insulin‐like growth factor receptor‐1 (IGF‐1R). This multiinstitutional study (P04720) determined the safety and clinical efficacy of robatumumab in three separate patient groups with resectable osteosarcoma metastases (Group 1), unresectable osteosarcoma metastases (Group 2), and Ewing sarcoma metastases (Group 3).ProcedureRobatumumab infusions were administered every 2 weeks and were well tolerated with minimal toxicity. Centrally reviewed response data were available for 144 patients.ResultsLow disease burden was important for osteosarcoma response: three of 31 patients had complete response or partial response (PR) by Response Evaluation Criteria in Solid Tumors (RECIST) in resectable patients (Group 1) versus zero of 29 in unresectable patients (Group 2); median overall survival was 20 months in Group 1 versus 8.2 months in Group 2. In centrally reviewed patients with Ewing sarcoma with PET‐CT data (N = 84/115), there were six PR, 23 stable disease, and 55 progression of disease by RECIST at 2 months. Patients with Ewing sarcoma had a median overall survival of 6.9 months. However, responding patients with Ewing sarcoma were allowed to continue on treatment after study closure. A minority of patients with metastatic Ewing sarcoma showed clinical responses and have remained healthy after receiving 25–115 doses of robatumumab with remissions of >4 years duration (N = 6).ConclusionsThese findings show that although the IGF‐1R remains an attractive treatment target, additional research is needed to identify responders and/or means to achieve durable remissions in order to successfully exploit IGF‐1R signal blockade in Ewing sarcoma (clinicaltrials.gov: NCT00617890).

Section: Introductionmentioning

confidence: 73%

A phase II study of clinical activity of SCH 717454 (robatumumab) in patients with relapsed osteosarcoma and Ewing sarcoma

Pediatric Blood & Cancer

Bielack

Görlick

et al. 2016

Clinical Cancer Research

“…We and others have shown that many standard cytotoxic regimens for cancer induce profound prolonged alterations in T-cell number, function and repertoire diversity (15,16). Numerous correlative studies link lymphocyte depletion with adverse outcomes in cancer, (18)(19)(20)(21)(22)(23)(25)(26)(27)(28) and animal models demonstrate diminished sarcoma metastases following immune reconstitution (31). These facts raise the dual possibilities that tumor recurrence may be enhanced by cancer therapy-induced immune depletion and that immunotherapies administered to lympho-depleted hosts might prove effective at eradicating less immune sculpted residual cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…Standard cytotoxic regimens administered for pediatric sarcomas incorporate highdose alkylators and induce profound, prolonged lymphocyte depletion (15)(16)(17). Several studies demonstrate correlations between lymphopenia and diminished survival in cancer (18)(19)(20)(21)(22)(23)(24)(25)(26), including ES (27,28), but it remains unclear whether lymphopenia plays a causal role in this observation. Numerous animal studies demonstrate that naturally acquired immune responses contribute to control of cancer (29,30), and in a murine model of osteosarcoma, lymphopenia enhanced metastatic recurrence, whereas immune reconstitution diminished metastatic recurrence (31).…”

Section: Introductionmentioning

confidence: 99%

Adjuvant Immunotherapy to Improve Outcome in High-Risk Pediatric Sarcomas

Merchant

Bernstein

Amoako

et al. 2016

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 AE 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 ¼ 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. Ó2016 AACR.

“…In ES, the recovery of lymphocytes after initial chemotherapy was shown to be an independent and significant predictor [4,20] . ImmTher is an investigational agent related to an immune activating peptidoglycan; it is now in a clinical trial as a post chemotherapy immunologic adjuvant after completion of chemotherapy ( [21] ; ClinicalTrials.gov identifier NCT00038142).…”

Section: Front-line Therapy For Es and Os With Investigational Agentsmentioning

confidence: 96%

Novel bone cancer drugs: investigational agents and control paradigms for primary bone sarcomas (Ewing's sarcoma and osteosarcoma)

Kopp

Expert Opinion on Investigational Drugs

et al. 2008

Background : New investigational agents and chemotherapy regimens including cyclophosphamide + topotecan, temozolomide + irinotecan, and anti-IGF-1R antibodies in Ewing's sarcoma (ES) and liposomal muramyltripeptide phosphatidylethanolamine (L-MTP-PE), aerosol therapy, and bone-specific agents in osteosarcoma (OS) may improve survival and/or quality of life on 'continuation' therapy. Objective : Review of investigational approaches and control paradigms for recurrent or metastatic primary bone tumors. Methods : Analyze temozolomide + irinotecan data and review in the context of other newer approaches including antiangiogenesis, anti-IGF-1R antibodies and bisphosphonates for ES. Review some current stateof-the-art approaches for OS including L-MTP-PE, anti-IGF-1R inhibition, aerosol therapies and bone specific agents. Results/conclusion : L-MTP-PE with chemotherapy in OS has been shown to improve survival; compassionate access is available for recurrence and/or metastases. Aerosol therapy (granulocyte-macrophage colony stimulating factor, cisplatin, gemcitabine) for lung metastases is a promising approach to reduce systemic toxicity. The bone-specific agents including denosumab (anti-receptor activator of NF-κ B ligand antibody) and bisphosphonates may have benefit against giant cell tumor, ES and OS. Anti-IGF-1R antibody SCH717454 has preclinical activity in OS but best effectiveness will most likely be in combination with chemotherapy earlier in therapy. Both temozolomide + irinotecan and cyclophosphamide + topotecan combinations are very active in ES and are likely to be tested with anti-IGF-1R antibodies against ES.