This study in patients with relapsed, refractory, or high-risk multiple myeloma (MM) evaluated the safety and activity of autologous T cells engineered to express an affinity-enhanced T-cell receptor (TCR) that recognizes a peptide shared by cancer antigens New York esophageal squamous cell carcinoma-1 (NY-ESO-1) and L-antigen family member 1 (LAGE-1) and presented by HLA-A*02:01.
The expression of New York oesophageal squamous cell carcinoma 1 (NY-ESO-1), one of the most immunogenic cancer-testicular antigens, is largely restricted to cancer and germ cells/placental trophoblasts, with little to no expression in normal adult somatic cells.
We employed engineered T cells targeting NY-ESO-1, and the data suggest that robust, self-regenerating pools of CD8<sup>+</sup> NY-ESO-1<sup>c259</sup>T cells produce a continuing supply of effector cells over several months that mediate clinically meaningful antitumor effects despite prolonged exposure to antigen.<i>Cancer Discov; 8(8); 944-57.
Vaccine responses were associated with a detectable population of CD141<sup>Hi</sup> conventional dendritic cells, which are critical for the uptake of NY-ESO-1 vaccine and have a recognized role in antitumor immune responses.<b>Conclusions:</b> These data indicate that vaccination against induced NY-ESO-1 expression can produce an antigen-specific immune response in a relatively nonimmunogenic myeloid cancer and highlight the potential for induced antigen-directed immunotherapy in a group of patients with limited options.<i>Clin Cancer Res; 24(5); 1019-29.
In this issue, D'Angelo and colleagues confirm the safety and feasibility of adoptive T-cell therapy with autologous T cells engineered to express NY-ESO-1<sup>c259</sup>, an affinity-enhanced T-cell receptor recognizing an HLA-A2-restricted NY-ESO-1-derived peptide, and demonstrate encouraging antitumor responses in 50% of treated patients, particularly in the setting of persistence of polyfunctional NY-ESO-1<sup>c259</sup>-expressing T cells in circulation for at least 6 months.<i>Cancer Discov; 8(8); 914-7.
Furthermore, NY-ESO-1-specific immune responses have been observed in various cancer types; however, their utility as biomarkers are not well determined.
Clinical trials testing broad range of cancer therapeutic vaccines against antigens of MAGEA and NY-ESO-1 families for treating various cancers have shown mixed clinical efficiency, safety and tolerability, suggesting the requirement of in-depth research of CTA expression in normal and cancer stem cells and extensive clinical trials for improving cancer immunotherapy technologies.
Nevertheless, some autoantibodies, such as anti-MAGEA4, anti-CTAG1 or anti-TP53 and their combinations could possibly contribute to the development of cancer early detection tests (not necessarily restricted to gastric cancer) when being combined with other markers.
Our study demonstrated that the MAGE-A family may be of greater utility than NY-ESO-1 for targeted immunotherapy in a variety of cancer histologies, in particular metastatic melanomas and squamous cell carcinomas.
The observation that the cancer germline (CG) antigen NY-ESO-1 is expressed in 70% to 80% and in approximately 25% of patients with synovial cell sarcoma and melanoma, respectively, prompted us to perform this first-in-man clinical trial using the adoptive transfer of autologous peripheral blood mononuclear cells that were retrovirally transduced with an NY-ESO-1-reactive T-cell receptor (TCR) to heavily pretreated patients bearing these metastatic cancers.
The cancer-testis/cancer-germline antigen NY-ESO-1 is a vaccine target in epithelial ovarian cancer (EOC), but its limited expression is a barrier to vaccine efficacy.
We illustrated the usage of our platform by monitoring the response of a melanoma patient cohort to an experimental therapeutic NY-ESO-1-based cancer vaccine; inter alia, we found evidence of determinant spreading in individual patients, as well as differential CT antigen expression and epitope usage.
We conducted a clinical trial of an NY-ESO-1 cancer vaccine using 4 synthetic overlapping long peptides (OLP; peptides #1, 79-108; #2, 100-129; #3, 121-150; and #4, 142-173) that include a highly immunogenic region of the NY-ESO-1 molecule.
Here, we demonstrate the in vivo generation of functional effector T cells from CD34-enriched human peripheral blood stem cells modified with a lentiviral vector designed for clinical use encoding a TCR recognizing the cancer/testes antigen NY-ESO-1, coexpressing the PET/suicide gene sr39TK.
SGI-110 induced/up-regulated the expression of investigated cancer/testis antigens (CTA) (i.e., MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A10, GAGE 1-2, GAGE 1-6, NY-ESO-1, and SSX 1-5) in all cancer cell lines studied, both at mRNA and at protein levels.
The potential for cancer-testis (CT) antigens as targets for immunotherapy in cancer patients has been heavily investigated, and currently cancer vaccine trials based on the CT antigens, MAGE-A3 and NY-ESO-1, are being carried out.
These technologies have aided in the advancement of cancer vaccine development, as illustrated in examples including NY-ESO-1 originally defined by SEREX, and HER2/neu peptides analyzed via high-throughput epitope prediction methods.
Analyses of NY-ESO-1-specific spontaneous immune responses in cancer patients revealed that antibody and both CD4(+) and CD8(+) T cell responses were induced together in cancer patients.