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Development of JCARH125: Optimization of a Fully Human Anti-Bcma CAR for Use in the Treatment of Multiple Myeloma
Multiple myeloma (MM) is the second most common hematologic malignancy in the US, characterized by uncontrolled proliferation of monoclonal plasma cells in the bone marrow. Although recent treatment options for MM patients have resulted in increased survival rates, MM remains incurable. There continue to be opportunities for advancement in treatment, and B-cell maturation antigen (BCMA) has emerged as a promising target for MM. BCMA is heterogeneously expressed on malignant plasma cells from all relapsed or newly diagnosed myeloma patients, with little expression on normal tissues. Several clinical trials using BCMA-targeting CAR T cells have shown promising results with no observed off target effects reported to date. Juno Therapeutics is developing a (CAR) T-cell product candidate, comprised of autologous CD4+ and CD8+ T-cells transduced with a genetically-engineered lentiviral vector to express a BCMA-specific CAR. The construct comprises a BCMA-specific single chain variable fragment (scFv) with human variable regions, CD137 [4 1BB] co-stimulatory domain, and CD3ζ signaling domain. The binding domain was observed to specifically bind to BCMA with high affinity. No off target cell membrane staining was observed in assays for potential binding of the scFV to cryosections across a range of human tissues. BCMA CAR T cells did not bind unexpectedly to samples with an array of human plasma membrane proteins. When the CAR was expressed on primary T cells, the cells activated, proliferated and had high lytic activity against BCMA-positive targets, with no activity against BCMA-negative targets. We compared the activity of the construct against constructs having a series of different spacer lengths between the scFV and the transmembrane domain, as well as different signaling domains and observed advantageous qualities with the specific combination of the particular components of this CAR construct. When incubated with target cells, over a range effector to target ratios (from 10 to 1 to 1 to 10), primary cells transduced with the CAR construct had comparatively robust lytic activity and produced high levels of multiple effector cytokines. These cells showed similar activity with a range of antigen densities from 100,000 mol./cell (NCI-H929,). We observed similar activity against both BCMA+ cell lines and primary CD138+ multiple myeloma cells. Additionally, the CAR-expressing primary T cells showed comparable activity against BCMA-expressing cells in the presence and absence of soluble recombinant or natural BCMA (up to 1000ng/ml). T cells engineered with the CAR derived from MM patients demonstrated similar expression, expansion and antigen-specific activities as compared to cells expressing the CAR derived from normal human donors. Additionally, in an in vitro assay, no evidence of tonic signaling was observed in the absence of antigen, in contrast to other BCMA-specific CARs that were observed to have variable levels of tonic signaling in this assay. In the presence of increasing amounts of antigen-either plate bound or endogenously expressed on cell lines-efficient signaling through the CAR was observed, with strong signaling observed at low levels of antigen ( Function of the construct in vivo was evaluated in NSG mouse models generated by injecting OPM2 or RPMI-8226 MM cells. Significantly improved survival and tumor growth were observed in mice in both models treated with the anti-BCMA CAR+ cells, as compared to mock T cells. In the RPMI-8226 model, mice administered both tested doses of the anti-BCMA CAR T cells exhibited complete regression of tumor growth by 20 days post CAR T-cell transfer which continued up to Day 60. Total circulating BCMA CAR T cells peaked at Day 14 post CAR T-cell transfer and greater numbers of CD8+ CAR+ T cells were observed compared to CD4+ CAR T cells. Taken together, these results support the development of a fully human BCMA-specific CAR T cell product candidate with a binder exhibiting little or no off target activity and observed to kill myeloma cells over a range of antigen densities and to the same degree regardless of the presence of soluble BCMA. Phase 1 clinical studies in MM patients with a BCMA CAR T cell clinical candidate, JCARH125, are planned for early 2018. Disclosures Harrington: Juno Therapeutics: Employment, Equity Ownership. Hauskins: Juno therapeutics: Employment, Equity Ownership. Amin: Juno therapeutics: Employment, Equity Ownership. Long: Juno Therapeutics, Inc.: Employment, Equity Ownership. Chen: Juno Therapeutics: Employment, Equity Ownership. Rahardjo: Juno Therapeutics: Employment, Equity Ownership. Thayer: Juno Therapeutics: Employment, Equity Ownership. Jones: Juno Therapeutics: Employment, Equity Ownership. Baturevych: Juno Therapeutics: Employment, Equity Ownership. Morkowski: Juno Therapeutics: Employment, Equity Ownership. Salmon: Juno Therapeutics: Employment, Equity Ownership. Bond: Juno Therapeutics: Employment, Equity Ownership. Liu: Eureka Therpeutics Inc.: Employment, Equity Ownership, Membership on an entity9s Board of Directors or advisory committees, Patents & Royalties. Liu: Eureka Therapeutics, Inc: Employment, Equity Ownership. Xu: Eureka Therapeutics, Inc: Employment, Equity Ownership. Wang: Eureka Therapeutics Inc.: Employment, Equity Ownership. Brentjens: Juno Therapeutics: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Patents & Royalties, Research Funding. Smith: Juno Therapeutics: Membership on an entity9s Board of Directors or advisory committees, Patents & Royalties: BCMA targeted CAR T cells, Research Funding. Sather: Juno Therapeutics: Employment, Equity Ownership
A phase 1/2 clinical trial of invariant natural killer T cell therapy in moderate-severe acute respiratory distress syndrome
Abstract Invariant natural killer T (iNKT) cells, a unique T cell population, lend themselves for use as adoptive therapy due to diverse roles in orchestrating immune responses. Originally developed for use in cancer, agenT-797 is a donor-unrestricted allogeneic ex vivo expanded iNKT cell therapy. We conducted an open-label study in virally induced acute respiratory distress syndrome (ARDS) caused by the severe acute respiratory syndrome-2 virus (trial registration NCT04582201). Here we show that agenT-797 rescues exhausted T cells and rapidly activates both innate and adaptive immunity. In 21 ventilated patients including 5 individuals receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO), there are no dose-limiting toxicities. We observe an anti-inflammatory systemic cytokine response and infused iNKT cells are persistent during follow-up, inducing only transient donor-specific antibodies. Clinical signals of associated survival and prevention of secondary infections are evident. Cellular therapy using off-the-shelf iNKT cells is safe, can be rapidly scaled and is associated with an anti-inflammatory response. The safety and therapeutic potential of iNKT cells across diseases including infections and cancer, warrants randomized-controlled trials
A phase 1/2 clinical trial of invariant natural killer T cell therapy in moderate-severe acute respiratory distress syndrome
Invariant natural killer T (iNKT) cells, a unique T cell population, lend themselves for use as adoptive therapy due to diverse roles in orchestrating immune responses. Originally developed for use in cancer, agenT-797 is a donor-unrestricted allogeneic ex vivo expanded iNKT cell therapy. We conducted an open-label study in virally induced acute respiratory distress syndrome (ARDS) caused by the severe acute respiratory syndrome-2 virus (trial registration NCT04582201). Here we show that agenT-797 rescues exhausted T cells and rapidly activates both innate and adaptive immunity. In 21 ventilated patients including 5 individuals receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO), there are no dose-limiting toxicities. We observe an anti-inflammatory systemic cytokine response and infused iNKT cells are persistent during follow-up, inducing only transient donor-specific antibodies. Clinical signals of associated survival and prevention of secondary infections are evident. Cellular therapy using off-the-shelf iNKT cells is safe, can be rapidly scaled and is associated with an anti-inflammatory response. The safety and therapeutic potential of iNKT cells across diseases including infections and cancer, warrants randomized-controlled trials.</p