Eve Rodler

NY-ESO-1 is a ubiquitous immunotherapeutic target antigen for patients with myxoid/round cell liposarcoma

Myxoid/round cell liposarcoma (MRCL) is the second most common liposarcoma subtype, accounting for >33% of liposarcomas and approximately 10% of all soft tissue sarcomas. Although MRCL is a chemosensitive subtype, patients with metastatic disease have a poor outcome. NY‐ESO‐1 is a cancer‐testis antigen (also known as cancer germ cell antigen) that has been successfully targeted in vaccine trials and in adoptive T‐cell therapy trials for the treatment of several solid tumors.

Current treatment options in triple negative breast cancer.

Triple negative breast cancer (TNBC) refers to a subgroup of breast carcinomas that do not express the estrogen receptor, progesterone receptor, or human epidermal growth factor receptor type 2. This heterogeneous group of tumors has significant overlap with both basal-like tumors (defined through gene expression array) and BRCA1 mutation-associated tumors. Due to a lack of well defined clinical targets, chemotherapy is the standard of care treatment for TNBC. When compared with other breast cancer subtypes, TNBC exhibits at least equivalent, or often superior sensitivity to chemotherapy. However, despite this increased chemosensitivity, TNBC has a worse clinical outcome than other breast cancer subtypes. This has led to the investigation of DNA damaging chemotherapy agents, including platinum drugs, angiogenesis inhibitors, poly(ADP-ribose) polymerase inhibitors, novel microtubule inhibitors, and other targeted therapies in an effort to improve the outcome for patients with these high-risk tumors. Treatment decisions for patients with TNBC should be based on the best currently available evidence, which consists mainly of retrospective and prospective subgroup analyses and phase II prospective data. This review summarizes data from select neoadjuvant, adjuvant, and metastatic chemotherapy clinical trials which included analyses of treatment effects and outcomes in TNBC and/or basal-like breast cancer.

NYESO-1/LAGE-1s and prame are targets for antigen specific t cells in chondrosarcoma following treatment with 5-Aza-2-deoxycitabine

Background Chondrosarcoma has no proven systemic option in the metastatic setting. The development of a non-cross-resistant strategy, such as cellular immunotherapy using antigen-specific T cells would be highly desirable. NY-ESO-1 and PRAME are members of the Cancer Testis Antigen (CTA) family that have been identified as promising targets for T cell therapy. LAGE-1 is a cancer testis antigen 90% homologous to NY-ESO-1, sharing the 157–165 A*0201 NY-ESO-1 epitope with its transcript variant, LAGE-1s. A number of CTAs have been induced using 5-Aza-2-Deoxycitabine (5-Aza-dC) in other cancers. We sought to evaluate the feasibility of targeting chondrosarcoma tumors using NY-ESO-1/LAGE-1s and PRAME specific T cells using 5-Aza-dC to induce antigen expression. Methods We used 11 flash frozen tumors from the University of Washington tumor bank to test for the expression of NY-ESO-1, PRAME, LAGE-1s and LAGE-1L in chondrosarcoma tumors. Using four chondrosarcoma cell lines we tested the expression of these CTAs with and without 5-Aza-dC treatments. Finally, using NY-ESO-1/LAGE-1s and PRAME specific effectors that we generated from sarcoma patients, we evaluated the ability of these T cells to lyse A*0201 expressing chondrosarcoma cell lines in vitro both with and without 5-Aza-dC treatment. Results A minority (36%) of chondrosarcoma tumors expressed either NY-ESO-1 or LAGE-1s at >10% of our reference value and none expressed PRAME at that level. However, in all four of the chondrosarcoma cell lines tested, NY-ESO-1 and PRAME expression could be induced following treatment with 5-Aza-dC including in cell lines where expression was absent or barely detectable. Furthermore, NY-ESO-1/LAGE-1s and PRAME specific CD8+ effector T cells were able to specifically recognize and lyse A*0201 expressing chondrosarcoma cell lines following 5-Aza-dC treatment. Conclusion These data suggest that adoptive immunotherapy in combination with 5-Aza-dC may be a potential strategy to treat unresectable or metastatic chondrosarcoma patients where no proven systemic therapies exist.

Phase I Study of Veliparib (ABT-888) Combined with Cisplatin and Vinorelbine in Advanced Triple-Negative Breast Cancer and/or BRCA Mutation–Associated Breast Cancer

Purpose: Cisplatin is synergistic with vinorelbine and the PARP inhibitor veliparib, and has antineoplastic activity in triple-negative breast cancer (TNBC) and BRCA mutation–associated breast cancer. This phase I study assessed veliparib with cisplatin and vinorelbine. Experimental Design: A 3+3 dose-escalation design evaluated veliparib administered twice daily for 14 days with cisplatin (75 mg/m2 day 1) and vinorelbine (25 mg/m2 days 1, 8) every 21 days, for 6 to 10 cycles, followed by veliparib monotherapy. Pharmacokinetics, measurement of poly(ADP-ribose) in peripheral blood mononuclear cells, and preliminary efficacy were assessed. IHC and gene-expression profiling were evaluated as potential predictors of response. Results: Forty-five patients enrolled in nine dose cohorts plus five in an expansion cohort at the highest dose level and recommended phase II dose, 300 mg twice daily. The MTD of veliparib was not reached. Neutropenia (36%), anemia (30%), and thrombocytopenia (12%) were the most common grade 3/4 adverse events. Best overall response for 48 patients was radiologic response with 9-week confirmation for 17 (35%; 2 complete, 15 partial), and stable disease for 21 (44%). Germline BRCA mutation presence versus absence was associated with 6-month progression-free survival [PFS; 10 of 14 (71%) vs. 8 of 27 (30%), mid-P = 0.01]. Median PFS for all 50 patients was 5.5 months (95% confidence interval, 4.1–6.7). Conclusions: Veliparib at 300 mg twice daily combined with cisplatin and vinorelbine is well tolerated with encouraging response rates. A phase II randomized trial is planned to assess veliparibs contribution to cisplatin chemotherapy in metastatic TNBC and BRCA mutation–associated breast cancer. Clin Cancer Res; 22(12); 2855–64. ©2016 AACR.

Immune-Based Therapies for Sarcoma

Immunotherapy has shown promise in a number of tumor types, but its exact role in sarcoma remains to be defined. Advanced bone and soft tissue sarcomas are challenging diseases to treat with an unmet need for effective systemic therapy. Previous reports have suggested that immune-based treatments may be effective in sarcoma, but such approaches have not yet become part of standard clinical practice. A number of sarcoma subtypes express targets known as cancer testis antigens and hence may be excellent targets for immunotherapy. This paper will focus on the recent advances and understanding of cancer testis antigens in sarcoma and also clinical data of immunotherapeutic approaches in these diseases.

Feasibility study of FDG PET as an indicator of early response to aromatase inhibitors and trastuzumab in a heterogeneous group of breast cancer patients

BackgroundIn breast cancer endocrine therapy, post-therapy Ki-67 assay of biopsy material predicts recurrence-free survival but is invasive and prone to sampling error. [18F]Fluorodeoxyglucose (FDG) positron emission tomography (PET) has shown an early agonist or ‘flare’ response to tamoxifen and estradiol, but has not been tested in response to estrogen-lowering aromatase inhibitors (AIs). We hypothesized that decreased agonistic response to AIs would result in early FDG uptake decline. We also measured early response to trastuzumab (T), another targeted agent for breast cancer with differing mechanisms of action. Our study was designed to test for an early decline in FDG uptake in response to AI or T and to examine association with Ki-67 measures of early response.MethodsPatients with any stage of newly diagnosed or recurrent breast cancer were eligible and enrolled prior to initiation (or resumption) of AI or T therapy. FDG PET and tissue biopsy were planned before and after 2 weeks of AI or T therapy, with pretreatment archival tissue permitted. Cutoffs of ≥20% decline in standardized uptake value (SUV) as FDG PET early response and ≤5% post-treatment expression as Ki-67 early response were defined prior to analysis.ResultsForty-two patients enrolled, and 40 (28 AI, 12 T) completed serial FDG-PET imaging. Twenty-two patients (17 AI, 5 T) had newly diagnosed disease, and 23 (14 AI, 9 T) had metastatic disease (5 newly diagnosed). Post-treatment biopsy was performed in 25 patients (63%) and was either refused or not feasible in 15. Post-treatment biopsy yielded tumor in only 17/25 cases (14 AI, 3 T). Eleven of 14 AI patients with post-therapy tissue showed FDG PET early response, and there was 100% concordance of PET and post-therapy Ki-67 early response. For the T group, 6/12 showed an FDG PET early response, including 2/3 patients with post-therapy biopsy, all with Ki-67 >5%.ConclusionsSubstantial changes in FDG PET SUV occurred over 2 weeks of AI therapy and were associated with low post-therapy proliferation. SUV decline was seen in response to T, but few tissue samples were available to test association with Ki-67. Our results support further investigation of FDG PET as a biomarker for early response to AI therapy.

The evolution of systemic therapy in sarcoma

Approximately 50% of patients with localized soft tissue sarcomas will develop recurrent disease after complete surgical resection, requiring alternative means of treatment. Conventional chemotherapy comprising of doxorubicin and ifosfamide has shown benefit in advanced disease, however, there remains a clear need for more effective, less toxic, therapies for the treatment of this heterogeneous group of mesenchymal malignancies. Recently, greater emphasis has been placed on the underlying biology of individual sarcoma subtypes, with the development and evaluation of novel therapies both in common and in rare subtypes. In addition, there is a greater specificity in the selection of chemotherapy agents based on activity in individual histological subtypes. Despite these advances the management of sarcoma, and in particular of rare subtypes, remains a major challenge. Some histological subtypes are resistant to conventional chemotherapy and patients with these diseases should be offered participation in early phase clinical trials of novel drugs.

Treatment of chest wall sarcomas: a single-institution experience over 20 years.

Objective:To evaluate the impact on the outcome of radiation therapy and chemotherapy in the treatment of localized chest wall sarcomas. Methods:A retrospective review of 65 patients with stage IIB and III chest wall sarcomas seen over 20 years at the University of Washington Medical Center. Overall and disease-free survival outcomes were analyzed on the basis of the treatment received: surgery alone; surgery and radiation therapy; surgery and chemotherapy; and surgery, radiation therapy, and chemotherapy. Results:Disease recurrence was observed in 32.3%, and, of these, 33.3% were local only, 42.9% distant only, and 23.8% were both local and distant. As compared with surgery alone, disease-free survival at both 5 and 10 years improved by 92% with the addition of radiation therapy to surgery, by 82% with the addition of chemotherapy to surgery, and by 89% and 90% with the addition of both chemotherapy and radiation therapy at 5 and 10 years, respectively. Overall survival also improved with radiation therapy, chemotherapy, or the combination of both, with the greatest improvement seen in patients treated with both radiation therapy and chemotherapy, which showed reduced mortality at 5 and 10 years of 49% and 45%, respectively, compared with surgery alone. Conclusions:The addition of radiation therapy, chemotherapy, or both to surgery in localized chest wall sarcoma improves outcome and should strongly be considered for patients with acceptable comorbidities. A trend toward improvement in overall survival was also shown with the use of radiation therapy and chemotherapy. As chest wall sarcomas are rare and histologically heterogenous, larger studies are necessary to elucidate which histologic subtypes may gain the most benefit from radiation therapy and chemotherapy.