Death receptor agonist therapies have exhibited limited clinical benefit to date. Investigations into why Apo2L/TRAIL and AMG 655 preclinical data were not predictive of clinical response revealed that coadministration of Apo2L/TRAIL with AMG 655 leads to increased antitumor activity in vitro and in vivo. The combination of Apo2L/TRAIL and AMG 655 results in enhanced signaling and can sensitize Apo2L/TRAIL-resistant cells. Structure determination of the Apo2L/TRAIL-DR5-AMG 655 ternary complex illustrates how higher order clustering of DR5 is achieved when both agents are combined. Enhanced agonism generated by combining Apo2L/TRAIL and AMG 655 provides insight into the limited efficacy observed in previous clinical trials and suggests testable hypotheses to reconsider death receptor agonism as a therapeutic strategy.

Ide-cel or Standard Regimens in Relapsed and Refractory Multiple MyelomaTable of Contents KarMMa-3 Study Countries and Sites. Methods Study Design and Patients Long-term Follow-up Endpoints and Assessments Statistical Analyses Results Patients and Treatment Odds Ratio for Overall Response Rate Cellular Kinetics-Pharmacokinetics BCMA Expression KarMMa-3 Study Countries and Sites.

Talimogene laherparepvec, a new oncolytic immunotherapy, has been recently approved for the treatment of melanoma. Using a murine version of the virus, we characterized local and systemic antitumor immune responses driving efficacy in murine syngeneic models. The activity of talimogene laherparepvec was characterized against melanoma cell lines using an viability assay. Efficacy of OncoVEX (talimogene laherparepvec with the mouse granulocyte-macrophage colony-stimulating factor transgene) alone or in combination with checkpoint blockade was characterized in A20 and CT-26 contralateral murine tumor models. CD8 depletion, adoptive T-cell transfers, and Enzyme-Linked ImmunoSpot assays were used to study the mechanism of action (MOA) of systemic immune responses. Treatment with OncoVEX cured all injected A20 tumors and half of contralateral tumors. Viral presence was limited to injected tumors and was not responsible for systemic efficacy. A significant increase in T cells (CD3/CD8) was observed in injected and contralateral tumors at 168 hours. analyses showed these cytotoxic T lymphocytes were tumor-specific. Increased neutrophils, monocytes, and chemokines were observed in injected tumors only. Importantly, depletion of CD8 T cells abolished all systemic efficacy and significantly decreased local efficacy. In addition, immune cell transfer from OncoVEX-cured mice significantly protected from tumor challenge. Finally, combination of OncoVEX and checkpoint blockade resulted in increased tumor-specific CD8 anti-AH1 T cells and systemic efficacy. The data support a dual MOA for OncoVEX that involves direct oncolysis of injected tumors and activation of a CD8-dependent systemic response that clears injected and contralateral tumors when combined with checkpoint inhibition. .

Introduction: B-cell maturation antigen (BCMA) is expressed on malignant plasma cells and is an attractive therapeutic target for multiple myeloma. BCMA CAR T-cells, antibody drug conjugates and bispecific T-cell engagers have demonstrated substantial preclinical and clinical activity to date. JCARH125 is a BCMA-targeting CAR T product containing a lentiviral CAR construct with a fully human scFv, optimized spacer, 4-1BB co-stimulatory and CD3z activation domains. The construct has shown minimal tonic signaling and lack of inhibition by soluble BCMA. JCARH125 is generated using a manufacturing process developed to optimize various aspects, including increased consistency of cell health, in the drug product. Methods: EVOLVE (NCT03430011) is a multi-center, phase 1/2 trial of JCARH125 in patients with relapsed and/or refractory multiple myeloma, who have received 3 or more prior regimens, which must include autologous stem cell transplant, a proteasome inhibitor, immunomodulatory drug and an anti-CD38 monoclonal antibody, unless not a candidate (i.e. contraindicated) to receive one or more of the above treatments. Lymphodepleting chemotherapy (LDC) consisting of 3 days of fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2) is given 2 to 7 days prior to JCARH125 infusion. A single dose of JCARH125 is given on day 1. Dose escalation is determined using the modified toxicity probability interval 2 (mTPI-2). A minimum of 3 patients are evaluated at each dose level (DL). The first 2 DLs evaluated were 50 and 150x 106 CAR+ T cells. Additional DLs are planned, followed by an expansion at the recommended phase 2 dose (RP2D). The primary objectives of the phase 1 portion are safety and identifying a RP2D. Results: At the time of the July 12, 2018 data analysis, 19 patients have been enrolled (i.e. apheresed) and 13 patients dosed with JCARH125. Only one patient was unable to receive JCARH125, due to sepsis after LDC, leading to death before JCARH125 administration. Eight patients were evaluable for safety (≥ 1 mo follow-up). (n = 5 DL1; n = 3 DL2). Three patients (all from DL1) were evaluable for confirmed response (≥ 2 mo follow-up) per International Myeloma Working Group (IMWG) criteria. Data reported here are from these initial 8 patients. Median follow-up is 5 weeks (range 4 - 13 weeks). Median age is 53 years (range 36 - 66) with a median time from diagnosis of 4 years (range 2 - 12). Patients had received a median of 10 prior regimens (range 4 - 15). Of these 8 patients, 4 (50%) were refractory (no response or progression within 60 days of last therapy) to bortezomib, carfilzomib, lenalidomide, pomalidomide and an anti-CD38 monoclonal antibody. Seven of 8 (88%) had prior autologous stem cell transplant and 4 of 8 (50%) have IMWG high risk cytogenetics. As of the data cut, no DLTs have been observed at the first 2 DLs. Cytokine release syndrome (CRS), all grade 1 or 2, was observed in 6 of 8 (75%) patients. Median onset of CRS was 9 days (range 4 - 10) with a median duration of 4.5 days (range 2 - 19 days). None of the patients with grade 2 CRS required vasopressor support and only 1 patient received tocilizumab. No patients had grade ≥ 3 CRS. Three of 8 (38%) patients experienced neurologic adverse events (AE). Two patients had grade 1 events, and 1 had a grade 3 event (lethargy), which resolved within 24 hours after receiving steroids. Onset of neurologic AEs was 9,11 and 12 days with a duration of 2, 3 and 1 days respectively. Notably, the patient who experienced grade 3 neurotoxicity (NT), developed secondary plasma cell leukemia (PCL) just prior to receiving LDC. All 8 patients have evidence of objective response (≥ MR), including the patient with secondary PCL. 3 patients, all treated at DL1 (50 x 106 CAR+ T-cells), have confirmed responses (1 PR, 2 sCR) with the remainder unconfirmed (1 CR, 2 VGPR, 1 PR, 1 MR). As of the data cut, no patients have progressed. Additional clinical and translational data on at least 30 patients and additional follow up of at least 4 months will be available at time of presentation. Conclusion: At initial lower dose levels, JCARH125 showed an acceptable safety profile with no DLTs reported thus far. Incidence of grade ≥ 3 NT was low and no grade ≥ 3 CRS has occurred with clear clinical activity. Although durability of response and response rate in a greater number of patients remain to be determined, early experience with JCARH125 support a favorable risk-benefit profile and rapid clinical development. Disclosures Mailankody: Takeda: Research Funding; Janssen: Research Funding; Physician Education Resource: Honoraria; Juno: Research Funding. Bensinger:celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Speakers Bureau; Takeda: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Devries:Junot Therapeutics: Employment. Piasecki:Juno Therapeutics: Employment, Equity Ownership; Cascadian Therapeutics: Patents & Royalties; Amgen: Patents & Royalties. Ziyad:Juno Therapeutics: Employment, Equity Ownership. Blake:Celgene: Employment, Equity Ownership. Byon:Juno Therapeutics: Employment, Equity Ownership. Jakubowiak:Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; SkylineDx: Consultancy, Honoraria.

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