Grade 3, 4 Toxicities Possibly Related and Grade 2 Toxicities Likely Related to Regimen

Absolute numbers of CD3+ and CD4+ HLA-DR+ activated T cells increase at day 21 and day 42 following ipilimumab infusion.

OS and EFS for all patients enrolled and PFS according to histologic group

DC phenotypes reveal consistent pattern of activation.

T Cell doses administered in autologous lymphocyte infusions.

Abstract Purpose: Ipilimumab is a first-in-class immune checkpoint inhibitor approved for treatment of metastatic melanoma but not studied in children until this phase I protocol. Experimental Design: This study examined safety, pharmacokinetics, and immunogenicity, and immune correlates of ipilimumab administered to subjects ≤21 years old with recurrent or progressive solid tumors. Dose escalation cohorts received 1, 3, 5, or 10 mg/m2 intravenously every 3 weeks in a 3 + 3 design. Response was assessed after 6 weeks and 12 weeks, and then every 3 months. Treatment was continued until disease progression or unacceptable toxicity. Results: Thirty-three patients received 72 doses of ipilimumab. Patients enrolled had melanoma (n = 12), sarcoma (n = 17), or other refractory solid tumors (n = 4). Immune-related adverse events included pancreatitis, pneumonitis, colitis, endocrinopathies, and transaminitis with dose-limiting toxicities observed at 5 and 10 mg/kg dose levels. Pharmacokinetics revealed a half-life of 8 to 15 days. At day 21, subjects had increased levels of cycling T cells, but no change in regulatory T-cell populations. Six subjects had confirmed stable disease for 4 to 10 cycles (melanoma, osteosarcoma, clear cell sarcoma, and synovial sarcoma). Conclusions: Ipilimumab was safely administered to pediatric patients using management algorithms for immune-related toxicities. The spectrum of immune-related adverse events is similar to those described in adults; however, many of the pediatric toxicities were evident after a single dose. Although no objective tumor regressions were observed with ipilimumab as a single agent, subjects with immune-related toxicities had an increased overall survival compared with those who showed no evidence of breaking tolerance. Clin Cancer Res; 22(6); 1364–70. ©2015 AACR.

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.

Meeting abstracts Relapsed or metastatic synovial sarcoma remains a significant unmet medical need. NY-ESO-1 is an attractive target for sarcoma, since it is expressed in approximately 70% of synovial sarcomas but not on vital tissues. We generated NY-ESOc259, a human-derived affinity-enhanced T-

Abstract NY-ESO-1 is expressed in ∼70% of synovial sarcomas and not expressed in vital tissues. We report interim results of NCT01343043 evaluating safety and activity of autologous T cells engineered to express an HLA-A2+ restricted, affinity-enhanced T cell receptor (TCR) targeting NY-ESO-1. HLA-A2+ patients with unresectable, metastatic, or recurrent synovial sarcoma were eligible if tumors expressed NY-ESO-1 by IHC. Lymphocytes were activated using anti-CD3/28 microbeads, genetically modified with a lentivector, then cryopreserved. Subjects received fludarabine 30mg/m2/d (D-6 to -2) and cyclophosphamide 1800mg/m2/d (D-3,-2), and infusion of engineered T cells. Systemic IL-2 was not administered. Nine subjects have received NY-ESO-1 cell infusions. Median transduced T cell dose was 3.4 × 109 cells (range 0.4-14.4), 60×106 cells/kg (range 5.7-165.5), and median transduction efficiency was 45.8%. Toxicity likely attributable to the T cells included fever, and grade 1-2 cytokine release syndrome. No autoimmune toxicity has been observed. Circulating engineered NY-ESO-1 cells were detected in all patients, peaking 3-21 days post-infusion. Persistence has been evaluated beyond 3 months in 4 subjects, all of whom had detectable NY-ESO-1 cells at 4 mos, 6 mos+, 12 mos+ and 12 mos+. We identified persisting NY-ESO-1 T cells using dextamer and/or anti-vβ13.1 mAbs, and observed that a high fraction of CD4+ and CD8+ NY-ESO-1 TCR expressing T cells were CD45RA+CCR7+CD95+, consistent with a stem cell memory phenotype. Persisting cells also demonstrate a polyfunctional (IFN-γ and TNF-α) and cytotoxic (CD107a and granzyme B) signature without overexpression of exhaustion markers (PD-1, LAG-3, and TIM-3). Of 8 patients whose follow-up is sufficient to assess response, 4 experienced objective responses (1CR x 9 mos, 1PR x 9 mos, 2PR x 6 mos). Tumor shrinkage could not be attributed to chemotherapy alone as progressive decreases in tumor size were observed over several months following completion of the lymphodepleting regimen. All PR patients (2 upon signs of progression and 1 still responding to therapy) ultimately underwent resection for residual disease and two remain without evidence of disease. Adoptive immunotherapy with NY-ESO-1 engineered T cells shows promising results in synovial sarcoma with acceptable toxicity. High dose IL-2 is not required for therapeutic benefit with this regimen. Citation Format: Melinda S. Merchant, Sandra P. D'Angelo, Hua Zhang, Donna Bernstein, Gwen Binder-Scholl, Tom Holdich, Luca Melchiori, Dan Williams, Marylene Fortin, Yoav Peretz, Jason Howe, Michael Mehler, Bruce A. Hug, Matthew Wright, Stephen Grupp, Paul A. Meyers, William Tap, Bent Jakobsen, Crystal L. Mackall. Genetically engineered NY-ESO-1-specific T cells in HLA-A2+ patients with synovial sarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4707. doi:10.1158/1538-7445.AM2015-4707

e21026 Background: Tumor biopsies are increasingly utilized in the research setting to identify patients eligible for trial, to validate molecularly targeted therapies, or to confirm target inhibition by investigational agents. As a result, there has been growing interest in the use of biopsies for research endpoints in pediatric studies of targeted therapies. However, little has been published on the feasibility, risk, or outcome of tumor biopsies, particularly in the pediatric population. Here we report safety and feasibility of percutaneous biopsies undertaken in a recent immunotherapy protocol for pediatric and young adult patients with sarcomas. Methods: Patients with pediatric sarcomas were enrolled on an IRB approved protocol and underwent protocol-directed, image-guided biopsy in order to obtain tumor lysate for use as a component in a dendritic cell vaccine. The biopsy safety and efficacy data were obtained on chart review at the completion of accrual of all patients. Results: Nineteen pediatric patients (age range 6-17yo) and fifteen adult patients (age range 18-35yo) underwent image-guided biopsy. Tumor procurement included multiple core needle biopsies (n= 2), fine needle aspirations (FNA) (n= 11), or both (n= 20). The majority of the biopsies involved tumors of the bone or soft tissue; however, four tumors in the thoracic cavity and five in the abdominal cavity were biopsied. Of the 31 biopsies that involved an FNA, an average of 11 passes were performed. Of the 22 biopsies that involved a core needle biopsy, an average of 4 passes were performed. Adverse events included one episode of fluid-responsive hypotension due to anesthesia, and 6 patients who reported Grade 1 pain the day following procedure. Of the 35 biopsies performed in 34 patients, 2 biopsies did not yield enough protein to create the tumor vaccine. Conclusions: FNA and core needle biopsies were found to be safe in this experience of 35 percutaneous, image-guided biopsies of sarcomas in pediatric and young adult patients. This is despite the use of multiple passes to obtain adequate tissue. These results suggest that biopsies may be performed safely for research endpoints in molecularly targeted trials for pediatric solid tumors. Clinical trial information: nct00923351.

10075 Background: Childhood melanoma is rare with an incidence of ~300 cases/yr in the United States. Stage IV disease is detected in 1-10% of reported pediatric melanomas. The treatment of this chemoresistant disease in pediatric patients can be quite challenging, even with access to recently approved therapies for melanoma. Limited numbers have made it difficult to determine if the presentation and characteristics of pediatric metastatic melanoma are similar to the disease seen in adults. Methods: In a retrospective chart review, we identified sixteen pediatric patients with metastatic melanoma who were referred to the Pediatric Oncology Branch. Molecular status of tumors was determined by CLIA certified tests. Patient overall survival data was collected while patients were treated with ongoing immunotherapy protocols or with treatment using approved agents. Results: A total of 16 patients aged 2-21yo were evaluated from January 2009 to January 2014. Fifteen patients had cutaneous melanoma and one teen ...