19 research outputs found
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Antimetastatic vaccination of tumor-bearing mice with two types of IFN-γ gene-inserted tumor cells
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Anti‐metastatic vaccination of tumor‐bearing mice with il‐2‐gene‐inserted tumor cells
IL‐2 gene was introduced through retroviral vectors into the highly malignant and poorly immunogenic 3LL‐D122 clone. Both high and low D122‐11‐2 secretors showed elimination of tumorigenicity in syngeneic immune‐competent mice; however, in nude mice only the high IL‐2 secretor showed reduced tumorigenicity as compared with parental D 122 cells. Also, following intravenous inoculation, only the high IL‐2 secretor showed reduced generation of metastases, whereas the low IL‐2 secretors were as highly metastatic as parental cells. These results seem to indicate that low levels of IL‐2 secreted by tumor cells are sufficient to activate T cells, while higher levels are needed in order to activate non‐T‐cell effectors. D122‐IL‐2 secretors induced high levels of anti‐tumor CTL, while their sensitivity to the lytic activity of these CTL was similar to the sensitivity of D122 cells, thus indicating that the elevation of immunogenicity of IL‐2 secretors was essentially due to the secreted IL‐2. In accordance with CTL induction, pre‐immunization with IL‐2 secretors protected mice against subsequent challenge of parental cells. Moreover, immunization in an “immunotherapy protocol” i.e., vaccination of mice carrying an established tumor of parental D122 cells with inactivated D122‐IL‐2 infectants, almost completely eliminated the generation of lung metastases by D122 cells, thus providing a rationale for the use of IL‐2 gene transferred tumor cells as a modality for treatment of metastasis
Pembrolizumab plus dinaciclib in patients with hematologic malignancies: the phase 1b KEYNOTE-155 study.
Preclinical data demonstrated that combining an anti-programmed cell death 1 (PD-1) inhibitor with a cyclin-dependent kinase 9 (CDK9) inhibitor provided enhanced antitumor activity with no significant toxicities, suggesting this combination may be a potential therapeutic option. The multicohort, phase 1 KEYNOTE-155 study evaluated the safety and antitumor activity of the PD-1 inhibitor pembrolizumab plus the CDK9 inhibitor dinaciclib in patients with relapsed or refractory (rr) chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM). Patients enrolled were ≥18 years of age with a confirmed diagnosis of CLL, DLBCL, or MM. The study included 2 phases: a dose-evaluation phase to determine dose-limiting toxicities and a signal-detection phase. Patients received pembrolizumab 200 mg every 3 weeks plus dinaciclib 7 mg/m2 on day 1 and 10 mg/m2 on day 8 of cycle 1 and 14 mg/m2 on days 1 and 8 of cycles 2 and later. Primary endpoint was safety, and a key secondary endpoint was objective response rate (ORR). Seventy-two patients were enrolled and received ≥1 dose of study treatment (CLL, n = 17; DLBCL, n = 38; MM, n = 17). Pembrolizumab plus dinaciclib was generally well tolerated and produced no unexpected toxicities. The ORRs were 29.4% (5/17, rrCLL), 21.1% (8/38, rrDLBCL), and 0% (0/17, rrMM), respectively. At data cutoff, all 72 patients had discontinued treatment, 38 (52.8%) because of progressive disease. These findings demonstrate activity with combination pembrolizumab plus dinaciclib and suggest that a careful and comprehensive approach to explore anti-PD-1 and CDK9 inhibitor combinations is warranted. This trial was registered at www.clinicaltrials.gov as NCT02684617