Immunet Plus 3 Serial Key
Study participants were randomly assigned to one of four arms: once-daily maraviroc alone, maraviroc plus TDF, maraviroc plus emtricitabine, or TDF and emtricitabine (FTC). The study participants and the study researchers were blinded to the study arm randomizations.
Immunet Plus 3 Serial Key
The preliminary results from a phase III IMpower131 study showed that atezolizumab plus chemotherapy (carboplatin and nab-paclitaxel) reduced the risk of disease worsening or death (PFS) by 29% compared with chemotherapy (carboplatin and nab-paclitaxel) in previously untreated patients with advanced squamous NSCLC [46]. At the time of the interim analysis, the overall survival benefit was not observed and the study will continue as planned [46].
Correspondingly, the addition of tremelimumab to durvalumab did not meet the primary endpoint of improving OS compared to standard chemotherapy in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) who progressed after platinum-based chemotherapy whose tumors express PD-L1 on 25% or more of their cancer cells [63]. This open-label phase III EAGLE trial randomized patients to single-agent durvalumab, durvalumab plus tremelimumab, or standard-of-care chemotherapy [63]. While the EAGLE trial did not meet the primary endpoint, the results of the phase III KESTREL trial of durvalumab and tremelimumab in patients who have not received prior chemotherapy for recurrent or metastatic HNSCC are awaited in the first half of 2019 [63].
A phase III GEMSTONE-303 study evaluating the efficacy and safety of CS1001 plus oxaliplatin and capecitabine (XELOX) chemotherapy for the first-line treatment in patients with unresectable, locally advanced, or metastatic gastric adenocarcinoma or GEJ adenocarcinoma is currently accruing. Additionally, there are two pivotal phase II studies for patients with relapsed/refractory extranodal natural killer/T cell lymphoma (NKTL) (NCT03595657) and relapsed/refractory classical Hodgkin lymphoma (rr-cHL)(NCT03505996) and two phase III studies for patients with stage IV non-small cell lung cancer (NCT03789604) and locally advanced/unresectable (stage III) non-small cell lung cancer that has not progressed after prior concurrent/sequential chemoradiotherapy (NCT03728556) have been initiated in China.
Clinically, glioblastoma tumors are treated with surgical resection, followed by temozolomide (TMZ)-based chemotherapy plus local radiation. IDO-blockade has been shown to enhance the effects of both chemotherapy and radiation [14]. We tested the hypothesis that blocking IDO synergizes with TMZ plus radiation therapy (RT) to enhance survival in a murine model of glioblastoma. We employed the mouse glioblastoma cell line GL261 which becomes a highly aggressive tumor with short survival time, so treatment was focused on a single cycle of therapy, and a synergistic effect was defined as prolongation of survival relative to controls.
The large perivascular cuffs from tumors harvested 7 days after TMZ (Additional file 1: Figure S7A) were predominantly comprised of CD68+ macrophages (CD45+) and microglia (CD45-lo), as well as substantial numbers of CD4+ T cells (Additional file 1: Figure S7B). A large proportion of the CD4 T cells co-stained for nuclear Foxp3, indicating a Treg cell phenotype (Additional file 1: Figure S7C). CD8 T cells were notably sparse in these leukocyte collections (Additional file 1: Figure S7B). Treating tumor-bearing mice with high dose chemotherapy plus RT caused the perivascular leukocyte cuffs and vessels to become disorganized with downregulation of endothelial CD31 expression (data not shown). Thus, while a single modest dose of TMZ alone had only minimal effect on survival, the intervention initiated a process of macrophage, microglia, and Treg cell aggregation at vascular sites within the tumor.
Allo-HSCT plus Sorafenib maintenance was an effective strategy to improve recurrence free survival and decrease relapse probability in FLT3-ITD AML patients. It had benefits to AML patients regardless of ITD mutant ratio, and to those with long ITD length instead of the short ITD length [62]. A prospective study of patients with FLT3-ITD AML undergoing allo-HSCT was conducted to evaluate the safety, tolerability, and outcome of Sorafenib administered peritransplant. Sorafenib dosing was individualized in the post-transplantation setting according to patient tolerability. Results indicate that Sorafenib is effective in vivo FLT3 inhibition and yields encouraging survival results [63].
Another study showed Sorafenib plus intensive chemotherapy improves survival in patients with newly diagnosed FLT3-ITD mutated AML regardless of whether they undergo allo-HSCT [64]. Addition of Sorafenib to chemotherapy not only nullifies the negative prognostic impact of higher allele burden, but also improves outcome of FLT3-ITD mutated AML patients regardless of the allele burden [65]. Sorafenib therapy is associated with improved outcomes for FLT3-ITD AML relapsing after allo-HSCT. Sorafenib combined with chemotherapy followed by donor lymphocyte infusion reveals an optimal efficacy [66]. Combination of Sorafenib with hypomethylating agents (azacitidine or decitabine) has resulted in high response rates in patients with FLT3 mutant AML inappropriate for intensive chemotherapy. FLT3 inhibitors are being explored in combination with other targeted agents [67]. Sorafenib has been approved and widely used in solid tumors, such as renal cell cancer, hepatocellular cancer, etc. [68, 69].
We are pleased to report that the FDA has accepted for review our BLA for N-803 + BCG for BCG-Unresponsive NMIBC CIS. If approved, N-803 plus BCG would be the first immunotherapy combination for this indication in 23 years that can be delivered directly to the bladder to induce natural killer cells and T cells.