ABSTRACT
Background AgenT-797 is a novel allogeneic iNKT cell therapy demonstrating activity in malignances and serious viral infections (i.e., SARS-CoV-2). In response to inflammatory injury, iNKTs home to critical organs, including lungs, dampen proinflammatory cytokines and protect epithelial tissues. INKTs drive response through activation of innate and adaptive immunity, recruitment/trans-activation of NK, B, and T cells, and myeloid cells via contact and soluble mediators. iNKTs represent a novel and attractive potential immunotherapy for viral ARDS. This analysis presents results from an ongoing phase 1/2 study of agenT-797 in mechanically ventilated patients with moderate to severe ARDS secondary to COVID- 19;NCT04582201. Methods As of February 2022, patients on mechanical ventilation with confirmed moderate to severe (Berlin Definition) ARDS, secondary to COVID-19 were treated with a single infusion of agenT-797 at 100, 300, or 1000 x 106 iNKT cells. Primary endpoint was safety and secondarily, time to extubation, prevention of secondary infections, persistence and alloimmunity were evaluated. Clinical benefit was defined as improvement/resolution of viral ARDS evaluated as time to extubation and survival at 30 days post-infusion. Results Twenty evaluable patients were treated with agenT-797 with a median age of 66 years (range 26-77;85% >=65y). Patients enrolled early in pandemic (pre-vaccines) and were heavily pre-treated with remdesivir, steroids and/or tocilizumab. No dose-limiting toxicities were observed. Tolerability was favorable with no cytokine release syndrome (CRS), neurotoxicity, or severe immune-related AEs. One SAE was deemed possibly related to agenT-797 (Dyspnea, Grade 4). The most frequent AEs deemed possibly related was pyrexia (grade 1;n=6). Survival was 70% (14/20) in this predominantly elderly, mechanically ventilated population. Early signals of reduction in ARDS symptoms, rapid extubation, and reduction in secondary infections were observed. AgenT-797 was detected in peripheral blood up to day 6 post-infusion, consistent with a rapid translocation from blood to tissue. Spikes in the blood during D1 and D2 showed a dose-proportional relationship, however, increased dose did not lead to prolonged peripheral persistence. Additional translational and biomarker evaluation is underway. Conclusions In patients with severe viral ARDS secondary to SARS-COV-2, agenT-797 demonstrated encouraging survival and disease mitigating benefit with a favorable tolerability profile. The deep and broad activity observed is likely attributed to iNKT cells' ability to promote viral clearance, home to the lungs, and reduce inflammation. These findings support the potential for a variant-agnostic therapy for patients with viral ARDS, a condition for which there are currently no effective therapies.
ABSTRACT
Background We are developing MiNK-413;a novel allogeneic CAR-iNKT product targeting BCMA and secreting soluble IL-15 for treatment of relapsed/refractory Multiple Myeloma (rrMM). Chimeric Antigen Receptor (CAR)-T cell therapy has revolutionized treatment of rrMM with two autologous products already approved by the FDA. However, current treatments come with significant toxicity, cost, and logistical challenge and many patients relapse, with 60% of relapsed patients still expressing BCMA. To address these, we propose the use of invariant Natural Killer T (iNKT) cells as a platform for BCMA-targeted allogenic cell therapy for rrMM. iNKT cells have potent immunostimulatory activity and intrinsic CD1d-and NK receptor ligand targeted cytotoxicity, and do not cause Graft versus Host Disease due to their invariant T cell receptor. In our native iNKT cell (agenT-797) clinical trials for COVID, solid tumors and Multiple Myeloma we observe excellent tolerability to up to 1 billion cell dosing with minimal treatment-related adverse events, absence of signs of CRS or peripheral neuropathy, and early signs of biological activity. AgenT-797 is administered without prior lymphodepletion, which is an approach we intend to pursue with MiNK-413. Methods Our proprietary CARDISTM platform consists of highly diverse (>1010) scFv library screening followed by library-based direct functional selection in CAR format using mammalian display. Candidates can be further optimized using affinity tuning to ensure optimal and highly selective on-target/ on-tumor activity. We developed a manufacturing approach to engineer and specifically expand CAR and soluble IL-15-expressing allogeneic iNKT cells. Lead candidates are assessed in vitro and in vivo for cytotoxicity, cytokine secretion, exhaustion, tumor homing and persistence. Results Discovery using our CARDISTM platform generated a fully human, potent, and specific anti-BCMA CAR which forms the basis for MiNK-413. Xenograft in vivo studies demonstrate effective bone marrow homing, and potent cytotoxic activity, with soluble IL-15 prolonging persistence. In vitro data show potent immunomodulatory activity and lack of exhaustion against BCMA+ human hematologic tumor cell lines in vitro and in vivo. Conclusions Combination of our proprietary CARDISTM and iNKT platforms enabled rapid discovery and development of MiNK-413, a next generation armored allogeneic BCMA-targeting CAR therapies. MiNK-413 is eligible to target a broader rrMM patient population due to intrinsic iNKT cell properties such as effective bone-marrow homing, high BCMA specific activity augmented by natural CD1d and NK receptorligand mediated activity. We believe MiNK-413 will provide additional benefits to rrMM patients beyond currently available treatments.