One form of cell-based immunotherapy uses exogenously modified autologous T cells to specifically target and eliminate the tumor cells. Another approach is to elicit the development of these cells in vivo in the patient using a cancer vaccine. Drs. Seth Pollack (Clinical Research Division) and Robin Jones (formerly of the Clinical Research Division and currently at the Royal Marsden Hospital in London) collaborated with researchers from the University of Washington, Mount Sinai School of Medicine, MD Anderson Cancer Center and Immune Design to investigate the ability of a lentivirus to drive an immune response against a specific antigen. The targeted antigen, NY-ESO-1, a member of the Cancer Testis Antigens family, is expressed in various cancers such as myeloma, melanoma or sarcoma, and is not detected in healthy tissues except the testis and trophoblast. NY-ESO1 function remains unknown but its high immunogenic potential makes it an appealing target for immunotherapies.
The tested lentivirus, called LV305, is a replication incompetent and integration deficient lentivirus encoding the NY-ESO-1 antigen. LV305 is issued from the “Zvex” platform engineering recombinant lentiviruses for dendritic cells (DC) targeted vaccines. LV305 targets DC by specific binding between a modified Envelope from Sindbis virus and the CD209 receptor. DC cells in turn present the antigenic peptide allowing lymphocyte activation and targeting of NY-ESO-1 cancer cells by the elicitation of humoral and cytotoxic responses. In a study published in The Journal of Immunotherapy, Dr. Pollack and colleagues report the results of the first patient administered LV305 for synovial sarcoma treatment. Soft tissue sarcoma constitute 1% of adult cancers and develop in fat, muscle or fibrous tissues. The average survival of patients in advanced stage varies from 12 to 18 months.
The patient underwent 8 intradermal injections of the virus administered at Days 1, 21 and 42. Draining lymph nodes in close proximity to the skin contain many DCs, optimizing the chance for efficient in vivo transduction. Besides low grade toxicities (ie. pain at the injection site or fatigue), no significant adverse events were reported. As early as 8 weeks following treatment initiation, the tumor growth stabilized and further presented a 10% size reduction at 16 weeks. At 5 months, the size was reduced by 24.7 % and by 84.8 % at Month 24. No recurrence was observed at the time of publication.
Functional analyses to establish the correlation between treatment efficiency and the type of immune response involved demonstrating that prior to the treatment there was a pre-existing population of T cells directed against NY-ESO-1. After treatment, this population increased by 49% as demonstrated by the analysis of the frequency of T cell receptor sequences in tumor infiltrating lymphocytes. More CD8+ T cells bound to a NY-ESO-1 peptide ex vivo following treatment, and this increase was also associated with a higher interferon gamma production relative to the same cells pre-treatment. CD4+ and CD8+ T cell activation by exposure to NY-ESO-1 peptide pool was greater post-treatment and was time-dependent for CD8+ but not CD4+ T cells. No humoral response increase was noted against NY-ESO-1 in ELISA assays, suggesting that the treatment efficiency was mediated by a T cell-mediated rather than B-cell mediated humoral immune response.
Overall, this study demonstrates a sustained tumor regression for over two years following tumor vaccination associated with very moderate side effects. Previous studies in mice reported a low inflammatory response against lentiviruses relative to other viruses such as adeno- or poxviruses, associated with the induction of an early memory response. Additionally, it was observed that LV305 persisted in the lymph nodes for 28 days post-injection, where DC – T cell interaction occurs. Such mechanisms, if confirmed in human patients, could explain the prolonged anti-tumor efficiency.
These results are very promising for the treatment of synovial sarcoma patients of whom over 80% are NY-ESO-1 positive, but also for other cancer patients such as malignant melanoma which include 25% of NY-ESO-1+ cancers (read the article). Additionally, such a strategy has broad applications as tumor vaccine treatment using such lentiviruses could be extended to a variety of cancer antigens expressed specifically in different types of cancer.
Funding for this study was provided by the Sarcoma Alliance for Research through Collaboration (SARC), the Sarcoma Foundation for America, the Gilman Sarcoma Foundation and Immune Design company.
Pollack SM,Lu H,Gnjatic S,Somaiah N,O'Malley RB,Jones RL,Hsu FJ,Ter Meulen J. 2017. First-in-Human Treatment With a Dendritic Cell-targeting Lentiviral Vector-expressing NY-ESO-1, LV305, Induces Deep, Durable Response in Refractory Metastatic Synovial Sarcoma Patient. Journal of Immunotherapy, 40(8), 302-306.