Citations

Background: BCMA targeted immunotherapy has yielded promising results for relapsed/refractory multiple myeloma (RRMM). TNB-383B is a BCMA x CD3 bispecific T-cell redirecting antibody incorporating a unique anti-CD3 moiety that preferentially activates effector over regulatory T-cells and uncouples cytokine release from anti-tumor activity, as well as 2 heavy-chain-only anti-BCMA moieties for a 2:1 tumor associated antigen to CD3 stoichiometry. Results from the ongoing phase 1 dose escalation and expansion First-in-Human (FIH) study of TNB-383B are presented (NCT03933735). Methods: Eligible patients have RRMM and have been exposed to at least 3 prior lines of therapy including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody. Patients have been treated with escalating doses of TNB-383B infused IV over 1-2 hours Q3W (without step-up dosing). The primary objectives are to determine the safety/tolerability and clinical pharmacology of TNB-383B and to identify the MTD/RP2D. The study used a 3+3 design for dose escalation, with additional patients enrolled on cleared dose levels. Patients on earlier dose cohorts were allowed to increase to the highest cleared dose with investigator consensus. Responses were assessed by IMWG criteria and Adverse Events (AEs) were graded according to CTCAE v5.0. Minimal residual disease (MRD) assessment was performed via NGS on bone marrow samples in patients achieving a complete response (CR). Results: As of 13 July 2020, 38 subjects have been dosed with TNB-383B (0.025 - 40 mg). Demographics and disease characteristics at study entry are summarized in Table 1. The most common Gr 3/4 AEs were anemia (6/38; 16%) and thrombocytopenia (5/38; 13%). The most common drug-related AEs were CRS (8/38; 21%) and headache (5/38; 13%). One case of Gr 2 CRS was observed at 0.075 mg; all other CRS events were seen at 5.4 mg and above. Cases of CRS were grade 1 (5/8) or 2 (3/8) and occurred only after the first dose of TNB-383B. All but 3 subjects were managed with fluids and acetaminophen (the other 3 received 1 dose each of tocilizumab). One DLT, Gr3 confusion that resolved within 6 hours without sequelae was seen at the 20 mg dose in an additional patient enrolled on this cohort. No IRRs were observed. Dose modification was necessary in 1 subject for Gr 3 neutropenia associated with CRS; the subject escalated to their full dose after tolerating subsequent doses without incident. 5 subjects died from their underlying disease during follow-up. 15 subjects discontinued treatment, all of them for progressive disease. Preliminary PK data support Q3W dosing of TNB-383B. Activity was observed in one patient each at 0.2 mg and 1.8 mg; at doses of 5.4 - 40 mg an ORR of 52% (12/23) was observed. Depth and duration of response are summarized in Table 2. Conclusions: TNB-383B is well tolerated at doses up to 40 mg, without the need for step/split dosing. A preliminary ORR of 52% (12/23) was observed at doses ≥ 5.4 mg, including deep (6 PR / 3 VGPR / 3 CR) and durable (up to 24 weeks) responses despite dosing only every 3 weeks. Enrollment into the dose escalation arm is ongoing; updated data will be presented at the meeting. Disclosures Rodriguez: BMS, Takeda, Amgen: Consultancy, Speakers Bureau. D'Souza:Amgen: Research Funding; Akcea: Consultancy; Pfizer: Consultancy; Teneobio: Research Funding; Imbrium: Consultancy; Merck: Research Funding; Janssen: Consultancy. Shah:GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy; BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding. Voorhees:Bristol-Myers Squibb: Other: Personal fees; Adaptive Biotechnologies: Other: Personal fees; Novartis: Other: Personal fees; Celgene: Other: Personal fees; Janssen: Other: Personal fees; Oncopeptides: Other: Personal fees; TeneoBio: Other: Personal fees; Levine Cancer Institute, Atrium Health: Current Employment. Buelow:Teneobio, Inc.: Current Employment, Current equity holder in private company. Kumar:Karyopharm: Consultancy; Tenebio: Other, Research Funding; Sanofi: Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genecentrix: Consultancy; Dr. Reddy's Laboratories: Honoraria; Adaptive Biotechnologies: Consultancy; Merck: Consultancy, Research Funding; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Cellectar: Other; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Carsgen: Other, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding; MedImmune: Research Funding; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Kite Pharma: Consultancy, Research Funding.

BackgroundMultiple myeloma (MM) with the translocation t(11;14) may have inferior outcomes in comparison with other standard‐risk MM, and it has been suggested to portend a worse prognosis in African Americans in comparison with Whites. This study used the Center for International Blood and Marrow Transplant Research (CIBMTR) database to examine the impact of t(11;14) on the clinical outcomes of patients with MM of African American and White descent.MethodsThis study evaluated 3538 patients who underwent autologous hematopoietic cell transplantation (autoHCT) for MM from 2008 to 2016 and were reported to the CIBMTR. Patients were analyzed in 4 groups: African Americans with t(11;14) (n = 117), African Americans without t(11;14) (n = 968), Whites with t(11;14) (n = 266), and Whites without t(11;14) (n = 2187).ResultsAfrican Americans with t(11;14) were younger, had lower Karnofsky scores, and had more advanced stage MM with a higher Hematopoietic Cell Transplantation–Comorbidity Index (HCT‐CI). Fewer African Americans with t(11;14) (21%) had a coexistent high‐risk marker in comparison with Whites with t(11;14) (27%). In a multivariate analysis, race and t(11;14) had no association with progression‐free survival. However, overall survival was superior among African Americans with t(11;14) in comparison with Whites with t(11;14) (hazard ratio, 0.53; 95% confidence interval, 0.30‐0.93; P = .03). Survival was also associated with female sex, stage, time from diagnosis to transplant, a low HCT‐CI, and receipt of maintenance.ConclusionsRace may have a differential impact on the survival of patients with t(11;14) MM who undergo autoHCT and needs to be further studied.

Head and neck cancer is the sixth leading cancer by incidence worldwide. Unfortunately, drug resistance and relapse are the principal limitations of clinical oncology for many patients, and the failure of conventional treatments is an extremely demoralizing experience. It is therefore crucial to find new therapeutic targets and drugs to enhance the cytotoxic effects of conventional treatments without potentiating or offsetting the adverse effects. Melatonin has oncostatic effects, although the mechanisms involved and doses required remain unclear. The purpose of this study is to determine the precise underlying mitochondrial mechanisms of melatonin, which increase the cytotoxicity of oncological treatments, and also to propose new melatonin treatments in order to alleviate and reverse radio- and chemoresistant processes. We analyzed the effects of melatonin on head and neck squamous cell carcinoma (HNSCC) cell lines (Cal-27 and SCC-9), which were treated with 0.1, 0.5, 1, and 1.5 mM melatonin combined with 8 Gy irradiation or 10 μM cisplatin. Clonogenic and MTT assays, as well as autophagy and apoptosis, involving flow cytometry and western blot, were performed in order to determine the cytotoxic effects of the treatments. Mitochondrial function was evaluated by measuring mitochondrial respiration, mtDNA content (RT-PCR), and mitochondrial mass (NAO). ROS production, antioxidant enzyme activity, and GSH/GSSG levels were analyzed using a fluorometric method. We show that high concentrations of melatonin potentiate the cytotoxic effects of radiotherapy and CDDP in HNSCC, which are associated with increased mitochondrial function in these cells. In HNSCC, melatonin induces intracellular ROS, whose accumulation plays an upstream role in mitochondria-mediated apoptosis and autophagy. Our findings indicate that melatonin, at high concentrations, combined with cisplatin and radiotherapy to improve its effectiveness, is a potential adjuvant agent.