bims-myxlip 2022-07-17 papers

Issue of 2022–07–17
three papers selected by
Laura Mannarino, Humanitas Research

Curr Opin Oncol. 2022 Jul 01. 34(4): 362-370

Immunotherapy of sarcomas with modified T cells.

Preethika Mahalingam, Maximilian Julve, Paul Huang, Andrew J S Furness, Seth M Pollack, Robin L Jones.

PURPOSE OF REVIEW: To summarize the development of modified T-cell therapies in sarcomas and discuss relevant published and ongoing clinical trials to date.
RECENT FINDINGS: Numerous clinical trials are underway evaluating tumor-specific chimeric antigen receptor T cells and high affinity T-cell receptor (TCR)-transduced T cells in sarcomas. Notably, translocation-dependent synovial sarcoma and myxoid/round cell liposarcoma are the subject of several phase II trials evaluating TCRs targeting cancer testis antigens New York esophageal squamous cell carcinoma-1 (NY-ESO-1) and melanoma antigen-A4 (MAGE A4), and response rates of up to 60% have been observed for NY-ESO-1 directed, modified T cells in synovial sarcoma. Challenges posed by modified T-cell therapy include limitations conferred by HLA-restriction, non-immunogenic tumor microenvironments (TME), aggressive lymphodepletion and immune-mediated toxicities restricting coinfusion of cytokines.
SUMMARY: Cellular therapy to augment the adaptive immune response through delivery of modified T cells is an area of novel therapeutic development in sarcomas where a reliably expressed, ubiquitous target antigen can be identified. Therapeutic tools to improve the specificity, signaling, proliferation and persistence of modified TCRs and augment clinical responses through safe manipulation of the sarcoma TME will be necessary to harness the full potential of this approach.

DOI: https://doi.org/10.1097/CCO.0000000000000843

Clin Transl Med. 2022 Jul;12(7): e961

Functional genomic analysis of epithelioid sarcoma reveals distinct proximal and distal subtype biology.

BACKGROUND: Metastatic epithelioid sarcoma (EPS) remains a largely unmet clinical need in children, adolescents and young adults despite the advent of EZH2 inhibitor tazemetostat.
METHODS: In order to realise consistently effective drug therapies, a functional genomics approach was used to identify key signalling pathway vulnerabilities in a spectrum of EPS patient samples. EPS biopsies/surgical resections and cell lines were studied by next-generation DNA exome and RNA deep sequencing, then EPS cell cultures were tested against a panel of chemical probes to discover signalling pathway targets with the most significant contributions to EPS tumour cell maintenance.
RESULTS: Other biologically inspired functional interrogations of EPS cultures using gene knockdown or chemical probes demonstrated only limited to modest efficacy in vitro. However, our molecular studies uncovered distinguishing features (including retained dysfunctional SMARCB1 expression and elevated GLI3, FYN and CXCL12 expression) of distal, paediatric/young adult-associated EPS versus proximal, adult-associated EPS.
CONCLUSIONS: Overall results highlight the complexity of the disease and a limited chemical space for therapeutic advancement. However, subtle differences between the two EPS subtypes highlight the biological disparities between younger and older EPS patients and emphasise the need to approach the two subtypes as molecularly and clinically distinct diseases.

Keywords: SMARCB1; distal; epithelioid sarcoma; functional genomics; proximal

DOI: https://doi.org/10.1002/ctm2.961

J Natl Compr Canc Netw. 2022 07;pii: jnccn220049. [Epub ahead of print]20(7): 834-844

The Role of Immunotherapy in the Management of Soft Tissue Sarcomas: Current Landscape and Future Outlook.

Lauren B Banks, Sandra P D'Angelo.

Soft tissue sarcomas (STS) are a subset of sarcoma, a rare group of heterogeneous malignancies of mesenchymal origin. Current standard of care involves surgical resection with systemic chemotherapy used to treat high-risk localized and metastatic disease. Though classically thought to be immunologically quiet tumors, STS interact with the immune system, undergoing immunoediting that alters tumor immunogenicity and the tumor microenvironment. Recent advances with immune checkpoint inhibition have led to clinical trials exploring the efficacy of immunotherapy in treating STS. Results from these trials point to histologic subtype-specific clinical activity of immune checkpoint blockade. In addition, combinatorial strategies adding immune checkpoint inhibition to local or systemic therapies for STS have further increased their efficacy. Targeted immunotherapies using engineered T-cell receptor-based approaches also show increasing promise as treatment options for some patients with STS. Adoptive transfer of autologous T cells targeting NY-ESO-1 and MAGE-A4 have high response rates in sarcomas expressing these antigens, although recurrence is often seen in responding patients. Future work must focus on identifying primary and acquired mechanisms of resistance to these therapies, and extend T-cell receptor discovery to other tumor-associated antigens.

DOI: https://doi.org/10.6004/jnccn.2022.7027