top of page
General Sarcoma Studies
B cells are Associated with Survival and Immunotherapy Response in Sarcoma
Publication Date:
January 15, 2020
Abstract:
Soft-tissue sarcomas represent a heterogeneous group of cancer, with more than 50 histological subtypes1,2. The clinical presentation of patients with diferent subtypes is often atypical, and responses to therapies such as immune checkpoint blockade vary widely3,4. To explain this clinical variability, here we study gene expression profiles in 608 tumours across subtypes of soft-tissue sarcoma. We establish an immune-based classification on the basis of the composition of the tumour microenvironment and identify five distinct phenotypes: immune-low (A and B), immune-high (D and E), and highly vascularized (C) groups. In situ analysis of an independent validation cohort shows that class E was characterized by the presence of tertiary lymphoid structures that contain T cells and follicular dendritic cells and are particularly rich in B cells. B cells are the strongest prognostic factor even in the context of high or low CD8+ T cells and cytotoxic contents. The class-E group demonstrated improved survival and a high response rate to PD1 blockade with pembrolizumab in a phase 2 clinical trial. Together, this work confirms the immune subtypes in patients with soft-tissue sarcoma, and unravels the potential of B-cell rich tertiary lymphoid structures to guide clinical decision-making and treatments, which could have broader applications in other diseases.
Author(s)
Florent Petitprez 1,2,3,4, Aurélien de Reyniès 4,24, Emily Z. Keung 5,24, Tom Wei-Wu Chen 6,7,8,9,
Cheng-Ming Sun 1,2,3, Julien Calderaro 1,10,11, Yung-Ming Jeng 9,12, Li-Ping Hsiao 7, Laetitia Lacroix 1,2,3, Antoine Bougoüin 1,2,3, Marco Moreira 1,2,3, Guillaume Lacroix 1,2,3, Ivo Natario 1,2,3, Julien Adam 13, Carlo Lucchesi 14,15, Yec′han Laizet 14,15, Maud Toulmonde 14,16, Melissa A. Burgess 17, Vanessa Bolejack 18, Denise Reinke 19, Khalid M. Wani 20, Wei-Lien Wang 20, Alexander J. Lazar 20,21, Christina L. Roland 5, Jennifer A. Wargo 5,21, Antoine Italiano 14,16,22, Catherine Sautès-Fridman 1,2,3, Hussein A. Tawbi 23* & Wolf H. Fridman 1,2,3*
B cells and Tertiary Lymphoid Structures Promote Immunotherapy
Response
Publication Date:
January 15, 2020
Abstract:
Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers1,2,3,4,5,6,7,8,9,10 and strategies to augment clinical response have largely focused on the T cell compartment. However, other immune subsets may also contribute to anti-tumour immunity11,12,13,14,15, although these have been less well-studied in ICB treatment16. A previously conducted neoadjuvant ICB trial in patients with melanoma showed via targeted expression profiling17 that B cell signatures were enriched in the tumours of patients who respond to treatment versus non-responding patients. To build on this, here we performed bulk RNA sequencing and found that B cell markers were the most differentially expressed genes in the tumours of responders versus non-responders. Our findings were corroborated using a computational method (MCP-counter18) to estimate the immune and stromal composition in this and two other ICB-treated cohorts (patients with melanoma and renal cell carcinoma). Histological evaluation highlighted the localization of B cells within tertiary lymphoid structures. We assessed the potential functional contributions of B cells via bulk and single-cell RNA sequencing, which demonstrate clonal expansion and unique functional states of B cells in responders. Mass cytometry showed that switched memory B cells were enriched in the tumours of responders. Together, these data provide insights into the potential role of B cells and tertiary lymphoid structures in the response to ICB treatment, with implications for the development of biomarkers and therapeutic targets.
Author(s)
Beth A. Helmink, Sangeetha M. Reddy, Jianjun Gao, Shaojun Zhang, Rafet Basar, Rohit Thakur, Keren Yizhak, Moshe Sade-Feldman, Jorge Blando, Guangchun Han, Vancheswaran Gopalakrishnan, Yuanxin Xi, Hao Zhao, Rodabe N. Amaria, Hussein A. Tawbi, Alex P. Cogdill, Wenbin Liu, Valerie S. LeBleu, Fernanda G. Kugeratski, Sapna Patel, Michael A. Davies, Patrick Hwu, Jeffrey E. Lee, Jeffrey E. Gershenwald, Anthony Lucci, Reetakshi Arora, Scott Woodman, Emily Z. Keung, Pierre-Olivier Gaudreau, Alexandre Reuben, Christine N. Spencer, Elizabeth M. Burton, Lauren E. Haydu, Alexander J. Lazar, Roberta Zapassodi, Courtney W. Hudgens, Deborah A. Ledesma, SuFey Ong, Michael Bailey, Sarah Warren, Disha Rao, Oscar Krijgsman, Elisa A. Rozeman, Daniel Peeper, Christian U. Blank, Ton N. Schumacher, Lisa H. Butterfield, Monika A. Zelazowska, Kevin M. McBride, Raghu Kalluri, James Allison, Florent Petitprez, Wolf Herman Fridman, Catherine Sautès-Fridman, Nir Hacohen, Katayoun Rezvani, Padmanee Sharma, Michael T. Tetzlaff, Linghua Wang & Jennifer A. Wargo
Recent success and limitations of immune checkpoint inhibitors for cancer: a lesson from melanoma
Publication Date:
February 12, 2019
Abstract:
Several researches have been carried over the last few decades to understand of how cancer evades the immune system and thus to identify therapies that could directly act on patient's immune system in the way of restore or induce a response to cancer. As a consequence, "cancer immunotherapy" is conquering predominantly the modern scenario of the fight against cancer. The recent clinical success of immune checkpoint inhibitors (ICIs) has created an entire new class of anti-cancer drugs and restored interest in the field of immuno-oncology, leading to regulatory approvals of several agents for the treatment of a variety of malignancies. The first to be approved in 2011 was the anti-CTLA-4 antibody ipilimumab for the treatment of unresectable or metastatic melanoma. Subsequently, the anti-PD-1s, nivolumab and pembrolizumab, received regulatory approvals for the treatment of melanoma and several other cancers. More recently, three anti-PD-L1 antibodies have received approval: atezolizumab and durvalumab for locally advanced or metastatic urothelial carcinoma and metastatic non-small cell lung cancer (NSCLC) and avelumab for the treatment of locally advanced or metastatic urothelial carcinoma and metastatic Merkel cell carcinoma. This review, starting from the results of melanoma trials, highlights in turn different ICIs and data for different indications in several malignancies are included under each drug class.
Author(s)
Margaret Ottaviano 1, Sabino De Placido 2, Paolo Antonio Ascierto 3
Phase III Soft Tissue Sarcoma Trials: Success or Failure?
Publication Date:
March 23, 2017
Abstract:
Opinion Statement:
Two recently reported phase III randomised control trials (RCTs) have resulted in the registration of two new systemic therapies for advanced soft tissue sarcoma. Both of these trials’ designs were informed by phase II data that guided the selection of sensitive STS diagnoses, enabling the demonstration of benefit in certain subtypes. A number of other phase III trials reported in the last 18 months have seemingly fit into a recurrent pattern of failure—promising efficacy signals in earlier phase studies being lost in the survival follow-up of large, highly heterogeneous cohorts. Greater effort is needed to identify histological and molecularly defined subgroups associated with differential treatment response in order to avoid the tremendous disappointment and loss of resources associated with a failed phase III trial. Additionally, improvements in available treatment of advanced STS have underpinned a prolongation in overall survival (OS). Consequently, surrogate efficacy endpoints are of increasing importance to STS drug trials. Whilst progression-free survival (PFS) should arguably replace overall survival as the primary endpoint of choice in first-line studies, more work is required to provide definitive validation of surrogacy, as well as developing more sophisticated techniques of assessing radiological response and expanding the inclusion of quality-of-life-related endpoints.
Author(s)
Alexander T. J. Lee, MBChB 1,2, Seth M. Pollack, MD 3,4, Paul Huang, PhD 2, Robin L. Jones, PhD, MBBS 1,5,6,*
Progression-free Rate as the Principal End-point for Phase II Trials in Soft-tissue Sarcomas
Publication Date:
October 9, 2001
Abstract:
We have estimated progression-free rates (PFR) for various groups of soft-tissue sarcoma patients from our clinical trials database, to provide reference values for conducting phase II studies with PFR as the principal end-point. In 146 pretreated patients receiving an active agent, the PFR estimates were 39 and 14% at 3 and 6 months; with inactive regimens (234 patients), those estimates were 21 and 8% respectively. In 1154-non pretreated patients, PFR estimates varied from 77% (synovial sarcoma) to 57% (malignant fibrous histiocytoma (MFH)) at 3 months, and from 56% (synovial sarcoma) to 38% (MFH) at 6 months. In 61 leiomyosarcomas from gastrointestinal origin, the corresponding figures were 44 and 30%, respectively. Consequently, for first-line therapy, a 6-month PFR of 530–56% (depending on histology) can be considered as a reference value to suggest drug activity; for second-line therapy, a 3-month PFR of 540% would suggest a drug activity, and 420% would suggest inactivity.
Author(s)
a EORTC Data Center, Av Mounier 83/11, B1200, Brussels, Belgium
b Rotterdam Cancer Institute and University Hospital, Groene Hilledijk 301, Rotterdam, The Netherlands
c Royal Marsden Hospital, Fulham Road 203, London, UK
d Aarhus Kommunehospital, Noerrebrogade 44, Aarhus, Denmark
Get updates on CCSF happenings
bottom of page