Introduction: Nivolumab (nivo) is a fully human IgG4 monoclonal antibody (mAb) targeting programmed death receptor-1 (PD-1). Nivo has demonstrated clinical activity and an acceptable safety profile in a phase 1b study (NCT01592370; CheckMate 039) in patients (pts) with relapsed/refractory hematologic malignancies. In pts diagnosed with Hodgkin lymphoma (HL), after a median 86 weeks of follow-up, 7/20 responders maintained a response for >1.5 years (Ansell S et al. Blood 2015;126:583), and after a median follow-up of 67 weeks, clinical activity (investigator-assessed objective response rate) was demonstrated in follicular lymphoma (FL; 40%), diffuse large B-cell lymphoma (DLBCL; 36%), mycosis fungoides (15%), and peripheral T-cell lymphoma (PTCL; 40%) (Lesokhin AM et al. J Clin Oncol 2016;34:2698). CheckMate 039 also included a cohort of pts who had received nivo in combination with ipilimumab (ipi), a fully human mAb targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4). Combination of CTLA-4 and PD-1 blockade has shown superior efficacy compared with nivo or ipi alone in preclinical studies and solid tumor malignancies (Wolchok JD et al. N Engl J Med 2013;369:122; Larkin JM et al. N Engl J Med 2015;373:22; Antonia SJ et al. Lancet Oncol 2016;17:883). The aim of this cohort study was to evaluate the safety and efficacy of combined immune checkpoint blockade (nivo+ipi) in pts with the following hematologic malignancies: HL, B-cell non-Hodgkin lymphoma (B-NHL; FL and DLBCL), T-cell NHL (T-NHL; cutaneous T-cell lymphoma [CTCL] and PTCL]), and multiple myeloma (MM). Methods: Nivo+ipi were given at 3 mg/kg IV and 1 mg/kg IV, respectively, every 3 weeks for 4 doses, followed by nivo monotherapy (3 mg/kg) every 2 weeks for up to 2 years. Pts with any of the above histologies, relapsed or refractory disease after ≥2 prior lines of therapy, and adequate organ function were included in the study. Prior systemic therapy may have included chemotherapy and autologous hematopoietic stem cell transplantation (auto-HSCT). Prior anti-PD-1 therapy and allogeneic (allo)-HSCT were not permitted. The primary endpoint was safety. Secondary endpoints included investigator-assessed objective response rate (ORR), best overall response, duration of response (DOR), and progression-free survival (PFS). Results: In total, 65 pts were treated with nivo+ipi (31 HL, 15 B-NHL, 11 T-NHL, 7 MM, and 1 with primary mediastinal B-cell lymphoma [PMBL] who was included in the overall safety cohort only). Median (range) number of prior systemic therapies was 4 (2, 10; HL), 3, (1, 16; B-NHL), 4 (1, 11; T-NHL), and 5 (2, 20; MM). Among patients with HL, only 13% (4/31) had prior auto-HSCT. 2 pts with HL and 1 with T-NHL proceeded to allo-HSCT after stopping study therapy. Across all cohorts, median follow-up was 11.4 months. 5 pts (8%) discontinued due to a drug-related adverse event (AE). The most common drug-related AEs of any grade were fatigue (17 pts [26%]), pyrexia (15 [23%]), and diarrhea (12 [18%]). 19 pts (29%) had a drug-related AE of grade ≥3. 31 pts (48%) had a serious AE. 24 pts (37%) died: HL 2 pts, B-NHL 11, T-NHL 6, MM 4, PMBL 1. Among those pts, 22 (34%) were from disease progression (HL 2 pts, B-NHL 10, T-NHL 5, MM 4, PMBL 1); no deaths were due to an AE. Clinical outcome data are presented (Table). Conclusions: These are the first reported data of combination checkpoint blockade therapy in hematologic malignancies. Overall, the combination of nivo+ipi in these heavily pretreated patients demonstrated a safety and efficacy profile similar to that previously reported for nivo monotherapy in HL, NHL, and MM. Additional follow-up may further clarify the role of ipi in this cohort of patients. In this predominantly transplant-naïve group of patients with HL, the efficacy of nivo+ipi was similar to that seen in patients with relapsed/refractory HL treated with nivo alone. Funding: Bristol-Myers Squibb (BMS). Medical writing: S Addison, Caudex, funded by BMS Disclosures Ansell: BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Gutierrez:Bayer Health Care Pharmaceuticals, Inc.: Other: Traveling and Lodging- Food and Beverage; E.R. Squibb & Sons, LLC (Bristol Myers Squibb): Consultancy, Other: Travel and Lodging; Incyte Corporation: Consultancy; Pfizer Inc: Consultancy; Merck Sharp & Dohme Corporation: Consultancy, Other: Travel and Lodging; Pharmacyclics LLC, An AbbVie Company: Other: Food and Beverage. Shipp:Cell Signaling: Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Bayer: Research Funding; Merck, Gilead, Takeda: Other: Scientific Advisory Board. Moskowitz:Seattle Genetics: Research Funding; Seattle Genetics, Merck: Consultancy. Borello:Bristol-Myers Squibb: Research Funding, Speakers Bureau. Popa-Mckiver:Bristol-Myers Squibb: Employment, Equity Ownership. Farsaci:Bristol-Myers Squibb: Employment. Zhu:Bristol-Myers Squibb: Employment. Armand:Sequenta Inc: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Infinity Pharmaceuticals: Consultancy; Roche: Research Funding; Merck: Consultancy, Research Funding.
TPS8555 Background: Adoptive cellular therapy may be practice-changing in relapsed/refractory multiple myeloma (MM). NY-ESO-1 TCR T (GSK3377794) are autologous polyclonal T cells transduced by a self-inactivating lentiviral vector to express an affinity-enhanced TCR capable of recognizing NY-ESO-1 or LAGE-1a antigenic peptides in complex with HLA-A*02. GSK3377794 has shown clinical activity in synovial sarcoma, melanoma, myxoid/round cell liposarcoma, and MM after autologous stem cell transplant. NY-ESO-1 and LAGE-1a are cancer/testis antigens frequently overexpressed in MM and linked to poor clinical outcome. PD-1 expression on CD8 T cells, which has been observed in MM patients previously treated with GSK3377794 as well as with CD19 CAR T-cell therapy, can limit adaptive immune response. We hypothesize that GSK3377794 alone, or in combination with the anti-PD-1 inhibitor pembrolizumab, may result in an antitumor effect in MM. Methods: This is an open-label, pilot study (NCT03168438) of GSK3377794 in patients with relapsed/refractory MM positive for HLA-A*02:01, HLA-A*02:05, ± HLA-A*02:06 and NY-ESO-1/LAGE-1a. Patients (n = 20) who have received ≥3 prior therapies containing ≥1 immunomodulatory imide, proteasome inhibitor, alkylator, CD38 monoclonal antibody, or glucocorticoid will be assigned to either single-infusion GSK3377794 (Arm 1, n = 10) or single-infusion GSK3377794 + pembrolizumab 200 mg IV every 3 weeks (Arm 2, n = 10). Arm 1 enrollment will be completed first. In Arm 2, pembrolizumab will begin in Week 3 (Week 6 if precluded by toxicity). Patients in both arms will provide cells via leukapheresis to manufacture autologous NY-ESO-1–specific T cells, undergo lymphodepletion (fludarabine + cyclophosphamide), and then receive GSK3377794 infusion (1−8x109 transduced T cells). Primary and secondary objectives are to assess safety/tolerability and antitumor activity, respectively, of GSK3377794 (± pembrolizumab). Arm 2 enrollment will pause for a 3-week safety review after 3 patients have received a first dose of pembrolizumab. Efficacy, safety, and biomarkers will be assessed every visit. The treatment phase will last 108 weeks, or until disease progression; follow-up will last ≤15 years. As of January 2020, 3 patients have been treated. Funding: GlaxoSmithKline (208470) Clinical trial information: NCT03168438 .
31 Background: Therapeutic vaccine is emerging as a potentially efficacious and safe treatment for cancer patients. However, markers are not available to identify patients more likely to benefit from this treatment. Aim of this retrospective study was to analyze before treatment immune subsets that correlated with clinical outcome in metastatic breast cancer patients treated with docetaxel alone or in combination with vaccine. Methods: We applied multi-color flow cytometry analysis of PBMCs harvested prior to treatment from patients (n=43) enrolled in a small randomized phase II study of docetaxel alone (n=20) or in combination with PANVAC-V (Vaccinia) and PANVAC-F (Fowlpox) encoding for the tumor-associated antigens CEA and MUC-1, along with a TRIad of COstimulatory Molecules (B7-1, ICAM-1, and LFA-3; called TRICOM) (n=23). Frequency of more than 200 immune sub-populations before treatment was measured by flow cytometry. Each of the resulting subsets was ranked in tertiles. For immune subsets that correlated directly with PFS, 2 points were assigned if the frequency fell in the highest tertile, 1 point if in the middle, and 0 if in the lowest tertile. For subsets that correlated inversely with PFS, the points were assigned in the opposite order. An immunoscore was calculated based on the sum of points assigned to each subset. Log-Rank analysis, with the cutoff based on the median of the immunoscores, was performed to evaluate differences in PFS between patients with a low and high immunoscore. Results: In vaccine plus docetaxel arm, 10 immune subsets from PBMCs before treatment correlated with PFS and were used for the calculation of the immunoscore. Patients with an immunoscore above the median showed a statistically significant longer PFS compared to those with lower score in vaccine plus docetaxel arm (p<0.001, HR=0.1466, 95% CI= 0.0478-0.4375) but not in docetaxel alone arm (p=0.097, HR=0.418, 95% CI=0.147-1.172). Conclusions: Calculation of an immunoscore from PBMCs before treatment based on flow cytometry screening of immune subsets may identify patients that will most likely benefit from vaccine combination immunotherapy.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.