Biopharmaceutical Report III
NY-ESO-1 targeting immunotherapies are seeing renewed clinical development interest as the antigen is widely expressed in certain solid tumors and sarcomas, experts said. They noted recent checkpoint inhibitor approvals and modified T cell receptor (TCR) research underscore the enthusiasm, experts said.
Combinations with checkpoint inhibitors and other immune modulators have the potential to increase response rates seen with existing NYESO-1 directed vaccines, and TCR approaches offer newer strategies to exploit the NY-ESO-1 antigen over-expression in cancers. There is some caution on how well the approaches will pan out. Furthermore, experts expressed the need to target multiple additional antigens besides NY-ESO-1 to induce significant immune responses.
While Adaptimmune (NASDAQ:ADAP) and Immune Design (NASDAQ:IMDZ) are using a modified TCR approach with a Phase I/II NYESO TCR, and Phase I LV305 with CMB305, respectively, for multiple cancers, Celldex (NASDAQ:CLDX) is exploring a vaccine approach in different cancers with the Phase II CDX-1401, an NY-ESO-1-targeting vaccine. Early trials at academic centers like Memorial Sloan Kettering, New York and Roswell Park Cancer Institute are also underway.
Adaptimmune, Immune Design, Celldex did not respond to a request for comment.
NY-ESO-1 antigen expression
NY-ESO-1 expression in normal tissues is relatively narrow and from an antigen standpoint, it is a wonderful antigen to start research with, said Dr Paul Sabbatini, deputy physician-in-chief for clinical research, Memorial Sloan Kettering Cancer Center, New York.
The NY-ESO-1 antigen is widely expressed in synovial sarcoma (SS), myxoid round-cell liposarcoma (LPS), melanoma, ovarian cancer, glioblastoma (GBM) and other tumors, but it has the most potential in sarcomas and melanoma due to their being immunogenic in nature, experts said.
NY-ESO-1 is expressed highly in SS and myxoid round-cell LPS in about 60-70% of tumors, said Dr Sant Chawla, director, Sarcoma Oncology Center, Santa Monica, California. NY-ESO1-targeting seem to especially benefit SS, and there have been remissions observed in these patients, said Dr Sebastian Bauer, professor of medicine, West German Cancer Center, Germany.
Among 24 patients in a Phase I study of Immune Design’s LV305 in sarcomas, one had a partial response, and 13 had stable disease (SD), with a median progression-free survival (PFS) of 4.6 months, according to data presented at the ASCO annual meeting. Among 14 patients receiving CMB305, 10 had SD, with a median 5.5-month PFS.
NY-ESO-1 expression in ovarian cancer is said to be in the range of 42- 60%, said Sabbatini and Dr Oliver Dorigo, associate professor, obstetrics and gynecology, Stanford University Medical Center, Palo Alto, California. The NYESO-1 antigen has been of particular interest in ovarian cancer since as patients have had their ovaries removed, NY-ESO-1 expression in normal ovarian tissue is not a clinical issue, added Dorigo.
However, it’s not necessarily the expression of the antigen, but also the tumor immunogenicity that’s important, said Dr Brent Hanks, assistant professor of medicine, Duke University School of Medicine, Durham, North Carolina. Melanomas are just more responsive to immunotherapies than gastric or colon cancer, he added. NYESO-1 expression in melanoma can range from 25-50+%, depending on which research study is considered, he added.
Though melanomas do overexpress the antigen, it is unknown if that is enough to drive T cell responses, cautioned Dr Jason Luke, assistant professor of medicine, University of Chicago. Therapies that target NY-ESO-1 have been around for many years, he and Dr Anthony Olszanski, co-director, cutaneous oncology and melanoma, Fox Chase Cancer Center, Philadelphia agreed. Luke noted most researchers would find it unlikely that targeted NY-ESO-1 would be a particularly efficacious way to move forward. Previous studies have not shown any significant response rate in melanoma, Olszanski added. However, now with the introduction of PD-1 inhibitors, the hope is that a combination approach can capitalize on the antigen recognition and improve the efficacy of these therapies, he said.
Ultimately, future research will focus on combination approach in the form of a vaccine with the checkpoint inhibitor
Across indications, it still needs to be explored if the ideal patient population would be one in remission with a lower disease burden, or those with active disease and a higher antigenic load, said Sabbatini.
NY-ESO-1 vaccinations have induced mild immune responses in a disease like ovarian cancer, but the question is always on how to enhance those responses across all tumor types, said Sabbatini. If the focus is on just one antigen and the induced immune response is not potent enough to generate T-cell responses to other antigens, then the tumor can simply downregulate the expression or processing of those antigens, agreed Hanks and Dorigo. NY-ESO-1 expression in ovarian cancer is more heterogeneous and patchy than in others, and it might be necessary to target a second or third antigen or add another other antitumor treatment for a clinical response, Dorigo explained.
New co-stimulatory molecules and checkpoint inhibitors could modulate these immune responses, said Sabbatini. Ultimately, future research will focus on combination approach in the form of a vaccine with the checkpoint inhibitor, agreed Hanks. Other agents that have been designed to reverse immune suppression or reverse immune invasion by the cancer could be combined as well, he added. The next generation of therapies is looking at the addition of these immune molecules to elicit a robust immune response, said Sabbatini.
Immune Design is studying (NCT02609984) CMB305, a dendritic cell-targeting vector that expressed NY-ESO-1 and a NY-ESO-1 recombinant protein in combination with Roche’s (VTX:ROG) Tecentriq (atezolizumab). An investigator sponsored Phase I trial (NCT02737787) at MSKCC will explore Bristol-Myers Squibb’s (NYSE:BMY) Opdivo (nivolumab) in combination with a dual NY-ESO-1 and WT1-directed vaccine. Celldex is also evaluating CDX-1401 in a Phase I/ II (NCT02413827) study in Stage III/IV melanoma patients in combination with its anti-CD27 antibody, varlilumab, and BMS’ anti-CTLA4 antibody Yervoy (ipilimumab).
However, it is not clear if there’s a role for NYESO-1-based vaccines and combination with checkpoint inhibitors have not proven to be particularly efficacious, differed Luke.
TCRs or vaccines
The best way to target the antigen may depend on the host immune response, said Liau, adding that TCRs or vaccines could be potential strategies to use NY-ESO-1. For patients who are able to mount an active immune response, a vaccine may be optimal, while adoptive immunotherapy with engineered T cells may be preferable for those who cannot, she added.
By tailoring the antigen-targeting treatment to each patient, researchers can look at individual tumor presentation and customize T cell directed therapy, said Dorigo. One reason for the recent focus on TCRs is that chimeric antigen receptor T-cells (CAR-Ts) haven’t been shown to be effective in solid tumors yet, said Dorigo, though they could be in the future. Adaptimmune is running multiple clinical trials where a patient’s T cells are extracted and modified to identify NY-ESO-1 in ovarian cancer and certain sarcomas. However, with a TCR approach, the impact of induced myelosuppression on heavily pretreated ovarian cancer patients is not yet known, said Dorigo.
Modifying T cells is a newer approach than vaccines, but vaccines have not been studied in combination with immune-modulating agents before, said Sabbatini. It is still too early to determine which approach would work best or how effective it would be, said Dorigo.
Alaric DeArment covers cancer drug development for BioPharm Insight. He served as associate editor of Drug Store News from 2008 to 2014, covering branded and generic drugs from development to distribution, retail and specialty pharmacy and regulatory affairs. In 2011-2012, he edited the book Contestation and Adaption: The Politics of National Identity in China. A native of Seattle, he graduated with honors with a bachelor degree in journalism from Ball State University and also lived in China from 2001-2004. Follow Alaric on Twitter @AlaricD_BPI
Indrani Datta covers cancer drug development for BioPharm Insight. She holds a B.E. in Biochemical Engineering, a BS in Computer Science and a Masters in Journalism with a concentration in Health and Science Reporting from CUNY Graduate School of Journalism. Prior to joining BioPharm Insight, Indrani performed experimental lab work in a startup biotech company, worked as a bioinformatics statistician in academia and a LIMS (laboratory information management system) developer for various pharmaceutical companies. She also built interactives for The New York Times before founding a news web startup. Indrani has written about hospital finance and politics for various publications.
Manasi Vaidya has a Masters degree in biotechnology. After a stint in a research lab, she spent two years as correspondent in India for BioSpectrum, a publication focused on the Asian biotechnology industry. She then moved to the United States to pursue a Masters degree in Science, Health and Environmental Reporting at New York University. Manasi has reported primarily on topics that combine health and policy, and her work has appeared in Nature Medicine, Nautilus and Scienceline. Her coverage at BioPharm Insight focuses on cancer.