MAGE-A3 Is a Clinically Relevant Target in Undifferentiated Pleomorphic Sarcoma/Myxofibrosarcoma

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Abstract

Melanoma-associated antigen 3 (MAGE-A3) expression is generally restricted to the placenta and germline cells of the testis, but it may also be expressed in sarcoma and other cancers and is associated with poor prognosis. Immunotherapy approaches targeting MAGE-A3 in other cancers have shown mixed results in the clinic, however, use of cancer testis antigens such as MAGE-A3 may have therapeutic value in the treatment of soft tissue sarcomas. Based on the recent success of anti-programmed death-1 (PD-1) therapy in undifferentiated pleomorphic sarcoma, we hypothesize that MAGE-A3-based immunotherapies may also provide benefits in this sarcoma type. We analyzed MAGE-A3 expression of sarcoma subtypes available in the Cancer Genome Atlas and Cancer Cell Line Encyclopedia and show that undifferentiated pleomorphic sarcoma/myxofibrosarcoma (UPS/MFS) expresses this potential target gene. We have identified high protein expression by tissue microarray of 106 UPS cores. We also found that high MAGE-A3 mRNA and protein expression is associated with worse overall survival in UPS/MFS. Furthermore, our results show no human leukocyte antigen (HLA) expression loss and relatively high lymphocyte infiltration by lymphocyte specific protein tyrosine kinase (LCK) marker expression. Based on these results, we propose targeting MAGE-A3 in UPS/MFS by immunotherapy techniques.

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Most cited references 22

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Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma.

Gerald P. Linette, Edward A Stadtmauer, Marcela Maus … (2013)

An obstacle to cancer immunotherapy has been that the affinity of T-cell receptors (TCRs) for antigens expressed in tumors is generally low. We initiated clinical testing of engineered T cells expressing an affinity-enhanced TCR against HLA-A*01-restricted MAGE-A3. Open-label protocols to test the TCRs for patients with myeloma and melanoma were initiated. The first two treated patients developed cardiogenic shock and died within a few days of T-cell infusion, events not predicted by preclinical studies of the high-affinity TCRs. Gross findings at autopsy revealed severe myocardial damage, and histopathological analysis revealed T-cell infiltration. No MAGE-A3 expression was detected in heart autopsy tissues. Robust proliferation of the engineered T cells in vivo was documented in both patients. A beating cardiomyocyte culture generated from induced pluripotent stem cells triggered T-cell killing, which was due to recognition of an unrelated peptide derived from the striated muscle-specific protein titin. These patients demonstrate that TCR-engineered T cells can have serious and not readily predictable off-target and organ-specific toxicities and highlight the need for improved methods to define the specificity of engineered TCRs.

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Identification of a Titin-derived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE A3-directed T cells.

Brian Cameron, Andrew Gerry, Joseph Dukes … (2013)

MAGE A3, which belongs to the family of cancer-testis antigens, is an attractive target for adoptive therapy given its reactivation in various tumors and limited expression in normal tissues. We developed an affinity-enhanced T cell receptor (TCR) directed to a human leukocyte antigen (HLA)-A*01-restricted MAGE A3 antigen (EVDPIGHLY) for use in adoptive therapy. Extensive preclinical investigations revealed no off-target antigen recognition concerns; nonetheless, administration to patients of T cells expressing the affinity-enhanced MAGE A3 TCR resulted in a serious adverse event (SAE) and fatal toxicity against cardiac tissue. We present a description of the preclinical in vitro functional analysis of the MAGE A3 TCR, which failed to reveal any evidence of off-target activity, and a full analysis of the post-SAE in vitro investigations, which reveal cross-recognition of an off-target peptide. Using an amino acid scanning approach, a peptide from the muscle protein Titin (ESDPIVAQY) was identified as an alternative target for the MAGE A3 TCR and the most likely cause of in vivo toxicity. These results demonstrate that affinity-enhanced TCRs have considerable effector functions in vivo and highlight the potential safety concerns for TCR-engineered T cells. Strategies such as peptide scanning and the use of more complex cell cultures are recommended in preclinical studies to mitigate the risk of off-target toxicity in future clinical investigations.

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Antitumor Activity Associated with Prolonged Persistence of Adoptively Transferred NY-ESO-1c259T cells in Synovial Sarcoma

Gabor Kari, Tom Holdich, Lini N Pandite … (2018)

We evaluated the safety and activity of autologous T cells expressing NY-ESO-1c259, an affinity-enhanced T-cell receptor (TCR) recognizing an HLA-A2-restricted NY-ESO-1/LAGE1a-derived peptide, in patients with metastatic synovial sarcoma (NY-ESO-1c259T cells). Confirmed antitumor responses occurred in 50% of patients (6/12) and were characterized by tumor shrinkage over several months. Circulating NY-ESO-1c259T cells were present postinfusion in all patients and persisted for at least 6 months in all responders. Most of the infused NY-ESO-1c259T cells exhibited an effector memory phenotype following ex vivo expansion, but the persisting pools comprised largely central memory and stem-cell memory subsets, which remained polyfunctional and showed no evidence of T-cell exhaustion despite persistent tumor burdens. Next-generation sequencing of endogenous TCRs in CD8+ NY-ESO-1c259T cells revealed clonal diversity without contraction over time. These data suggest that regenerative pools of NY-ESO-1c259T cells produced a continuing supply of effector cells to mediate sustained, clinically meaningful antitumor effects.Significance: Metastatic synovial sarcoma is incurable with standard therapy. We employed engineered T cells targeting NY-ESO-1, and the data suggest that robust, self-regenerating pools of CD8+ NY-ESO-1c259T cells produce a continuing supply of effector cells over several months that mediate clinically meaningful antitumor effects despite prolonged exposure to antigen. Cancer Discov; 8(8); 944-57. ©2018 AACR.See related commentary by Keung and Tawbi, p. 914This article is highlighted in the In This Issue feature, p. 899.

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Author and article information

Journal

Journal ID (nlm-ta): Cancers (Basel)

Journal ID (iso-abbrev): Cancers (Basel)

Journal ID (publisher-id): cancers

Title: Cancers

Publisher: MDPI

ISSN (Electronic): 2072-6694

Publication date (Electronic): 15 May 2019

Publication date Collection: May 2019

Volume: 11

Issue: 5

Electronic Location Identifier: 677

Affiliations

[1 ]Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA; JALivingston@ 123456mdanderson.org (J.A.L.); vravi@ 123456mdanderson.org (V.R.); NSomaiah@ 123456mdanderson.org (N.S.); spatel@ 123456mdanderson.org (S.P.)

[2 ]Department of Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA; wlwang@ 123456mdanderson.org (W.-L.W.); jwtsai0317@ 123456gmail.com (J.-W.T.); ali.ali@ 123456bcm.edu (A.A.); DRIngram@ 123456mdanderson.org (D.R.I.); caitlin.d.may@ 123456gmail.com (C.D.L.); alazar@ 123456mdanderson.org (A.J.L.)

[3 ]Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA; CLRoland@ 123456mdanderson.org

[4 ]Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA; phwu@ 123456mdanderson.org (P.H.); CYee@ 123456mdanderson.org (C.Y.)

[5 ]Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA; VSubbiah@ 123456mdanderson.org

[6 ]Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA; AFutreal@ 123456mdanderson.org

Author notes

[* ]Correspondence: aconley@ 123456mdanderson.org (A.P.C.); jroszik@ 123456mdanderson.org (J.R.); Tel.: +713-792-3626 (A.P.C.); +713-745-2641 (J.R.); Fax: +713-794-1934 (A.P.C.); +713-745-1046 (J.R.)

Author information

Vivek Subbiah https://orcid.org/0000-0002-6064-6837

Jason Roszik https://orcid.org/0000-0002-4561-6170

Article

Publisher ID: cancers-11-00677

DOI: 10.3390/cancers11050677

PMC ID: 6562561

PubMed ID: 31096717

SO-VID: ede5998a-641b-4ad3-9edc-4312b62eb0e5

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

MAGE-A3 Is a Clinically Relevant Target in Undifferentiated Pleomorphic Sarcoma/Myxofibrosarcoma

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Abstract

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Cancer Immunotherapy

Most cited references 22

Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma.

Identification of a Titin-derived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE A3-directed T cells.

Antitumor Activity Associated with Prolonged Persistence of Adoptively Transferred NY-ESO-1c259T cells in Synovial Sarcoma

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