Clinical Efficacy Of Combination Research Articles

Abstract 2697: Simultaneous activation of innate immune suppressive components impairs antitumor efficacy of immunotherapy against the innate immune system

Abstract Cancer immunotherapy has shown noticeable clinical efficacy in many cancer types, while clinical benefits are only observed in 20-40% of treated patients. Therefore, combination cancer immunotherapy targeting multiple factors that limit antitumor immunity has been tested in the clinic. Accumulating evidence reveals that cancers that harbor limited immune cell infiltration (so-called immunologically cold tumors) respond poorly to current immunotherapy. Preclinical studies using animal models have shown that activation of innate immunity by TLR agonists or STING agonists can successfully remodel the TME to effectively induce antitumor immunity in those immunologically cold tumors. However, unexpectedly, all TLR agonists and STING agonists tested have not shown clinical efficacy in combination with immune checkpoint blockade therapy, including PD-1/PD-L1 blockade therapy. Hence, we addressed the mechanism(s) why stimulators of innate immunity failed to elicit effective antitumor immunity in cancer patients. We then employed OK-432, which reportedly stimulates TLR-2, TLR-4, and/or TLR-9, as OK-432 is widely used in Japan in the clinic. In vitro OK-432 treatment accelerated the maturation DCs, and efficiently induced CD8+ T cells in humans. However, the combination treatment with anti-PD-1 mAb and OK-432 failed to augment antitumor immunity in animal models using anti-PD-1 mAb monotherapy-resistant tumors; the data mirrors the failure of clinical trials of combination therapy with immune checkpoint blockade and TLR agonists or STING agonists in humans. Therefore, using the animal models, we explored the acquired resistance mechanism developed after combination treatment. While OK-432 treatment effectively stimulated DCs, innate immune suppressive cells, such as MDSCs, were concurrently accumulated in the TME. The accumulation of PMN-MDSCs after OK-432 treatment was induced in a CXCL1-CXCR2-dependent fashion. Accordingly, triple combination treatment with a PMN-MDSC inhibitor along with OK-432 and anti-PD-1 mAb attenuated the accumulation of PMN-MDSCs in the TME and improved the antitumor effect of the combination treatment. Taken together, we propose that successful combination treatment stimulating innate immunity against immunogenically cold cancers requires controlling the unwanted co-activation of innate immune suppressive cells. This study clearly demonstrates the mechanism of acquired resistance after administration of reagents that activate innate immunity, such as TLR agonists or STING agonists, and provides the basis for future successful combination therapy. Citation Format: Hitomi Nishinakamura, Sayoko Shinya, Takuma Irie, Shugo Sakihama, Tadaaki Ioroi, Takeo Naito, Keisuke Watanabe, Daisuke Sugiyama, Motohiro Tamiya, Tatsuya Yoshida, Tetsunari Hase, Takao Yoshida, Kennosuke Karube, Yuka Maeda, Shohei Koyama, Hiroyoshi Nishikawa. Simultaneous activation of innate immune suppressive components impairs antitumor efficacy of immunotherapy against the innate immune system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2697.

Subgroup Analyses of Progression-Free Survival from the Phase 3 Octans and Alcyone Studies in Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma Treated with Bortezomib, Melphalan, and Prednisone with or without Daratumumab

Introduction:Daratumumab, a human IgGκ monoclonal antibody targeting CD38, has shown clinical efficacy in combination with standard-of-care regimens in patients with newly diagnosed multiple myeloma (NDMM). The addition of daratumumab to bortezomib, melphalan, and prednisone (D-VMP) significantly improved clinical outcomes vs bortezomib, melphalan, and prednisone (VMP) in phase 3 studies in Asian patients (OCTANS) and a global population (ALCYONE) with transplant-ineligible (TIE) NDMM. Here, we present subgroup analyses of progression-free survival (PFS) by measurable residual disease (MRD) and cytogenetic risk status from OCTANS and ALCYONE. Methods: Eligible patients from OCTANS (NCT03217812) and ALCYONE (NCT02195479) had a diagnosis of NDMM and were TIE due to age or comorbidities. Patients were randomized to receive up to nine 42-day cycles of VMP (bortezomib 1.3 mg/m 2 SC twice weekly in Cycle 1 and weekly in Cycles 2-9, and melphalan 9 mg/m 2 and prednisone 60 mg/m 2 orally on Days 1-4 of each cycle) or D-VMP (VMP + daratumumab 16 mg/kg IV weekly in Cycle 1, every 3 wk in Cycles 2-9, and every 4 wk thereafter until disease progression or unacceptable toxicity). MRD negativity (10 -5) was assessed by multi-parameter flow cytometry in OCTANS and next-generation sequencing in ALCYONE. Cytogenetic risk was assessed by FISH or karyotype testing. Results:A total of 220 Asian patients were randomized (D-VMP, n = 146; VMP, n = 74) in OCTANS, and 706 global patients were randomized (D-VMP, n = 350; VMP, n = 356) in ALCYONE. With a median follow-up of 41.2 mo (range, 0.0-59.9) in OCTANS, the median PFS was 38.7 mo with D-VMP and 19.2 mo with VMP (HR, 0.35; 95% CI, 0.23-0.52; P <0.0001). With a median follow-up of 40.1 mo (range, 0.0-52.1) in ALCYONE, the median PFS was 36.4 mo with D-VMP and 19.3 mo with VMP (HR, 0.42; 95% CI, 0.34-0.51; P <0.0001). The rates of overall and sustained MRD negativity were higher with D-VMP vs VMP. In OCTANS, the MRD-negativity rate was 40.4% with D-VMP vs 10.8% with VMP ( P <0.0001), and more patients in the D-VMP group had sustained MRD negativity lasting ≥12 mo (24.7% vs 1.4%; P <0.0001) and ≥18 mo (15.1% vs 1.4%; P = 0.0008). Similarly, in ALCYONE, the MRD-negativity rate was 28.3% with D-VMP vs 7.0% with VMP ( P <0.0001), with more patients in the D-VMP group having sustained MRD negativity lasting ≥12 mo (14.0% vs 2.8%; P <0.0001) and ≥18 mo (8.9% vs 1.7%: P <0.0001). In both studies, longer PFS was observed for patients who achieved MRD negativity vs those who did not within each treatment group; however, the PFS benefit observed for D-VMP vs VMP was maintained irrespective of MRD status ( Figure). In multivariate analyses, achievement of sustained MRD negativity lasting ≥12 mo was associated with longer PFS vs MRD negativity <12 mo in both OCTANS (HR, 0.23; 95% CI, 0.09-0.62; P = 0.004) and ALCYONE (HR, 0.13; 95% CI, 0.06-0.32; P <0.0001). No other factors showed a significant association with PFS in the multivariate analysis for OCTANS; other factors associated with longer PFS in ALCYONE included age <75 vs ≥75 y (HR, 0.38; 95% CI, 0.20-0.75; P = 0.005) and ISS disease stage I vs II (HR, 0.20; 95% CI, 0.05-0.86; P = 0.03). Data from OCTANS and ALCYONE were pooled for an analysis of PFS by cytogenetic risk subgroup (D-VMP, n = 496; VMP, n = 430). D-VMP prolonged median PFS vs VMP in patients with standard cytogenetic risk (not estimable vs 18.9 mo; HR, 0.33; 95% CI, 0.26-0.42) and high cytogenetic risk (25.6 vs 18.9 mo; HR, 0.54; 95% CI, 0.41-0.71), defined by the presence of t(4;14), t(14;16), del(17p), t(14;20), gain(1q21), and/or amp(1q21). Median PFS was also longer with D-VMP vs VMP for patients with gain and/or amp(1q21) (31.9 vs 18.9 mo; HR, 0.45; 95% CI, 0.32-0.63), 1 high-risk cytogenetic abnormality (HRCA; 24.4 vs 19.3 mo; HR, 0.62; 95% CI, 0.44-0.86), and ≥2 HRCA (28.2 vs 17.5 mo; HR, 0.36; 95% CI, 0.20-0.63). Conclusions:In this subgroup analysis of OCTANS and ALCYONE, the prolonged PFS observed with D-VMP vs VMP in the overall study populations was maintained irrespective of the achievement of MRD negativity or the presence of high cytogenetic risk. In addition, the rates of MRD negativity and sustained MRD negativity were higher with D-VMP vs VMP, and achievement of these deep responses translated into longer PFS, consistent with a prior pooled analysis of the MAIA and ALCYONE studies. These results further support the use of daratumumab in combination with VMP in both Asian and global patients with TIE NDMM.

Tumor and Stromal Cell Targeting with Nintedanib and Alpelisib Overcomes Intrinsic Bladder Cancer Resistance.

Bladder cancer is a highly prevalent tumor, requiring the urgent development of novel therapies, especially for locally advanced and metastatic disease. Nintedanib is a potent antifibrotic angio-kinase inhibitor, which has shown clinical efficacy in combination with chemotherapy in patients with locally advanced muscle-invasive bladder cancer. Nintedanib inhibits fibroblast growth factor receptors (FGFRs), validated targets in patients with bladder cancer harboring FGFR3/2 genetic alterations. Here, we aimed at studying its mechanisms of action to understand therapy resistance, identify markers predictive of response, and improve the design of future clinical trials. We have used a panel of genetically well-characterized human bladder cancer cells to identify the molecular and transcriptomic changes induced upon treatment with nintedanib, in vitro and in vivo, at the tumor and stroma cell levels. We showed that bladder cancer cells display an intrinsic resistance to nintedanib treatment in vitro, independently of their FGFR3 status. However, nintedanib has higher antitumor activity on mouse xenografts. We have identified PI3K activation as a resistance mechanism against nintedanib in bladder cancer and evidenced that the combination of nintedanib with the PI3K inhibitor alpelisib has synergistic antitumor activity. Treatment with this combination is associated with cell-cycle inhibition at the tumoral and stromal levels and potent nontumor cell autonomous effects on α-smooth muscle actin-positive tumor infiltrating cells and tumor vasculature. The combination of nintedanib with PI3K inhibitors not only reversed bladder cancer resistance to nintedanib but also enhanced its antiangiogenic effects.

Clinical efficacy of combination of oxaliplatin and vascular intervention in treatment of advanced cervical cancer and related prognostic factors

Purpose: To investigate the therapeutic effect of combination of oxaliplatin and vascular intervention in patients with advanced cervical cancer (ACC), and its influence on the prognosis of patients.Methods: One hundred ACC patients were selected and equally assigned to control (oxaliplatin) and combination or study (oxaliplatin plus vascular intervention) groups. The patients in control group received oxaliplatin, while those in study group were treated with oxaliplatin combined with vascular intervention. Clinical efficacy, levels of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor-2 (VEGFR-2), fibroblast growth factor-2 (FGF-2), BFGF and platelet-derived growth factor (PDGF) before and after therapy, and survival rate at 3, 6, 12 and 18 months after therapy were determined compared between the two groups. The prognostic factors were analyzed with logistic factor analysis.Results: The clinical efficacy and survival rate at 3, 6, 12 and 18 months after therapy in the combination group were higher when compared with those of the control group (p < 0.05). After therapy, the levels of VEGF, VEGFR-2, FGF-2, BFGF and PDGF were lower in the combination group than in control group. Age, short-term efficacy and basic diseases were identified as the influencing factors for the prognosis of patients with advanced cervical cancer (p < 0.05).Conclusion: The combination of oxaliplatin and vascular intervention significantly improved clinical treatment efficacy and survival rate in ACC patients. Age, short-term efficacy and basic diseases affected the prognosis of patients.

Clinical efficacy of mouse nerve growth factor plus nimodipine in neonatal intracranial hemorrhage and its effect on plasma PAF, CNP, MMP-2, and neurological function.

To investigate the clinical efficacy of combination of mouse nerve growth factor (NGF) and nimodipine in the treatment of neonatal intracranial hemorrhage (NICH) and its effect on plasma platelet-activating factor (PAF), C-type natriuretic peptide (CNP), matrix metalloproteinase-2 (MMP-2), and neurological function. A total of 90 infants with severe ICH admitted to our hospital from December 2016 to December 2018 were enrolled for retrospective study. According to different treatment schemes, they were assigned into 2 groups: group A (n=40) treated with mouse NGF plus nimodipine; group B (n=50) treated with nimodipine. The recovery time, serum indexes (PAF, MMP-2, CNP), neurological function (neonatal behavioral neurological assessment (NBNA) score), complications, and total effective rate of patients were recorded, and the satisfaction degree of family members was statistically analyzed. Patients in group A showed shorter recovery time, down-regulated PAF and MMP-2, evidently up-regulated CNP, and significantly increased NBNA score after one/two weeks of treatment, as well as fewer complications, higher total effective rate and higher satisfaction of family members. To sum up, the combination of mouse NGF and nimodipine achieves good clinical efficacy in NICH, which down-regulates plasma PAF and MMP-2, up-regulates CNP, and improves neurological function. Therefore, it is suitable for clinical promotion.

Phase Ib study of CPX-351 lower-intensity therapy (LIT) plus venetoclax as first-line treatment for patients with AML who are unfit for intensive chemotherapy (IC).

TPS7567 Background: CPX-351 (Vyxeos; daunorubicin and cytarabine liposome for injection) is approved by the FDA and EMA for the treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. In a phase 3 study in patients (pts) aged 60-75 y with newly diagnosed high-risk/secondary AML who were fit for IC, CPX-351 significantly improved median survival versus 7+3 cytarabine/daunorubicin and had a comparable safety profile. However, it may not be appropriate to administer CPX-351 at the label dosage in pts unfit for IC. Venetoclax, a BCL-2 inhibitor, has clinical efficacy in combination with low-dose cytarabine in AML pts unfit for IC, and preclinical data suggest a rationale for combining CPX-351 and venetoclax. This study thus evaluates CPX-351 LIT in combination with venetoclax in AML pts unfit for IC. Methods: This is an open-label, multicenter, 2-part, phase 1b study (NCT04038437) to determine the maximum tolerated dose (MTD) and evaluate the safety, efficacy, and pharmacokinetics of CPX-351 LIT plus venetoclax. Key eligibility criteria are shown in the Table. In the dose-escalation phase (3+3 design), up to 24 pts will receive CPX-351 (dose levels: 20, 40, 60, and 75 units/m2) on Days 1 and 3 plus venetoclax 400 mg on Days 2-21 of each cycle to determine the MTD, with each dose escalation confirmed by a safety assessment committee. Pts who achieve complete or partial remission after 1 or 2 cycles may receive up to 4 similar cycles of CPX-351 plus venetoclax. In the expansion phase, an additional 20 pts will be treated at the MTD. All pts are assessed for response by morphology and minimal residual disease testing, and are monitored for safety (until 1 month after end of treatment) and survival (up to 1 year after start of treatment). The study is ongoing and actively enrolling pts. Clinical trial information: NCT04038437 . [Table: see text]

A meta-analysis of the clinical efficacy of the combination of acupuncture and Chinese medicine in the treatment of haemorrhoids

At present, surgical resection is the main method of the treatment of haemorrhoids, but is easy to recur after surgery. Recently, it is reported that acupuncture has a beneficial influence on haemorrhoids. Thus, whether acupuncture is effective in the treatment of haemorrhoids is the key in this meta-analysis. To evaluate the clinical efficacy of the treatment of combination of acupuncture and Chinese medicine in haemorrhoids by meta-analysis, which provide a scientific, effective and feasible evidence for clinical decision-making and practice. A systematic review and meta-analysis of randomized clinical trials (RCTs). A meta-analysis was performed by using Review Manager 5.3. All RCTs about combination of acupuncture and Chinese medicine versus Chinese medicine alone were selected and assessed for inclusion. The effective rate (ER), recurrence rate(RR), Symptom score before and after treatment (perianal edema, hemafecia, perianal pain, pruritus ani, prolapse of haemorrhoids) were the outcomes analyzed in this meta-analysis. 11 RCTs and 976 patients were included. The methodological quality of most included trials was low to moderate. In this meta-analysis, the clinical efficacy of combination of acupuncture and Chinese medicine was more effective than only Chinese medicine used in haemorrhoids. The effective rate [OR=5.24,95%CI(3.72,7.40), P<0.0000I], recurrence rate [OR=0.29, 95%CI(0.11, 0.73), P=0.009], perianal edema [WMD=-0.74,95%CI-0.90 to -0.59, P<0.00001], hemafecia[WMD=-0.78,95%CI-0.89 to -0.67. P<0.00001], perianal pain[WMD=-0.72,95%CI-0.94 to -0.50, P<0.00001], pruritus ani[WMD=-0.75,95%CI-0.92 to -0.58, P<0.00001] and prolapse of haemorrhoids[WMD=-0.43,95%CI-0.84 to -0.02, P=0.04] were shown in this meta-analysis.(OR:odds ratio; CI:confidence interval; WMD:weighted mean difference). There was about 96% of the clinical efficiency in the treatment of acupuncture plus Chinese medicine in haemorrhoids and 89% of that used in Chinese medicine alone, which indicates clearly that 7% higher efficiency in the experimental group compared with the control group. The treatment of combination of acupuncture and Chinese medicine in haemorrhoids is more useful than Chinese medicine alone applied in piles, which is shown in 91% of clinical effects in average.

Evaluating the Regulatory Immunomodulation Effect of Irreversible Electroporation (IRE) in Pancreatic Adenocarcinoma.

Irreversible electroporation (IRE) has been demonstrated as an effective local method for locally advanced (stage 3) pancreatic adenocarcinoma. Immune regulatory T cells (Tregs) induce immunosuppression of tumors by inhibiting patients' anti-tumor adaptive immune response. This study aimed to evaluate the immunomodulation effect of IRE to identify an ideal time point for potential adjuvant immunotherapy. This study prospectively evaluated an institutional review board-approved study of patients undergoing either in situ IRE or pancreatectomy. Patient blood samples were collected at different time points (before surgery [preOP] and on postoperative day [POD] 1, POD3, and POD5). Peripheral blood mononuclear cells (PBMCs) were isolated and evaluated for three different CD4 + Treg subsets (CD25 + CD4 +, CD4 + CD25 + FoxP3 +, CD4 + CD25 + FoxP3 -) by flow cytometry and analyzed for median fold change (MFC) between each two consecutive time points (MFC = log2(T2/T1)). The study analyzed 15 patients with in situ IRE (n = 11) or pancreatectomy (PAN) (n = 4). In both groups, CD25 + CD4 + Tregs decreased on POD1 followed by a steady increase in pancreatectomy, whereas the trend in the IRE group reversed between D3 and D5 (MFC: IRE [- 0.01], PAN [+ 0.39]). For each period, CD4 + CD25 + FoxP3 + Tregs showed the most dramatic inverse effect, with D3 to D5 showing the most change (MFC: IRE [- 0.18], PAN [+ 0.39]). Also, CD4 + CD25 + FoxP3 - Tregs showed an inverse effect between D3 and D5 (MFC: IRE [- 0.25], PAN [+ 0.49]). Altogether, the Treg trend was inversely affected by the in situ IRE procedure, with the greatest cumulative significant change for all three Treg subsets between D3 and D5 (MFC ± SEM: IRE [- 0.24 ± 0.05], PAN [+ 0.37 ± 0.02]; p = 0.016). The study data suggest that in situ IRE procedure-mediated Treg attenuation between POD3 and POD5 can provide a clinical window of opportunity for potentiating clinical efficacy in combination with immunotherapy.

Antibodies in Development for Multiple Myeloma: A Systematic Review

IntroductionImmunotherapy using monoclonal antibodies (mAbs) have been gaining significance in the treatment of multiple myeloma (MM). These include naked antibodies, checkpoint inhibitors (CPIs), novel bispecific mAbs targeting two epitopes and antibody-drug conjugates (ADCs) having a mAb conjugated to a cytotoxic drug. This review aims to summarize phase I and I/II clinical trials using mABs for the treatment of MM.MethodsA comprehensive literature search using data from PubMed, Embase, AdisInsight and Clinicaltrials.gov was performed for identification of early phase (I and I/II) trials of mAbs in MM treatment (January 2008 to December 2017). Studies involving mAbs including targeting antibodies, ADCs, CPIs and bispecific mAbs were included, without considering the geo-location, age, sex or specific eligibility criteria. Drugs already approved by FDA were excluded.ResultsTotal of 2537 phase I and phase I/II studies were identified. After screening by two reviewers and categorization by their mechanism of action, 74 clinical trials (CTs) that involved mAbs as monotherapy or in combination with other chemotherapeutic drugs for the treatment of newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM). 41 CTs are active, completed or discontinued (Table 1) and 33 CTs are recruiting, approved for recruitment or planned. Most explored mechanism of action in these trials was mAb therapy directed against CD38, IL-6, huCD40, PD-L1 and PD-1.Isatuximab (Anti-CD38) has shown objective response rate (ORR) of >50% in combination with lenalidomide (R) or pomalidomide (P) plus dexamethasone (d) in ongoing phase I trials NCT01749969 (n=57) and NCT02283775 (n=89) respectively. According to Vij et al. (2016) and Mikhael et al. (2018), 54% ORR (n=31) and 62% ORR (n=28) was shown by combination of isatuximab with Rd and Pd in 57 and 45 evaluable RRMM patients, respectively. In Vij et al. (2016) study, stringent complete response (sCR) in 2 (3%) patients, very good partial response (VGPR) in 13 (23%) and partial response (PR) in 16 (28%) patients was observed. In Mikhael et al. (2018) study, sCR in 1 (2%) patient, CR in 1 (2%), VGPR in 10 (21%) and PR in 16 (34%) patients was observed. In comparison, Martin et al. (2014) mentioned ORR of only 24% with isatuximab monotherapy in 34 RRMM patients. Grade (G) ≥3 pneumonia (n=4) was the most common high-grade adverse events (AEs) being reported (Table 2).Siltuximab (Anti-IL-6) has shown clinical efficacy in combination with bortezomib (V) + d and RVd in phase I and I/II CTs. Shah et al. (2016) and Suzuki et al. (2015) found ORR to be 90.9% and 67% in 11 (NDMM) and 9 (RRMM) patients when siltuximab was given combined with RVd and Vd, respectively. Clinical benefit response (CBR) i.e. ≥ minimal response (MR) was 100% with siltuximab + RVd in NDMM patients. In comparison, siltuximab monotherapy in 13 RRMM patients yielded an ORR of 15% (2 CR) as reported by Kurzrock et al. (2012). G≥3 neutropenia (n=9), G≥3 thrombocytopenia (n=6) and G≥3 lymphopenia (n=8) were most common reported high-grade AEs.Checkpoint inhibitors including pembrolizumab (anti-PD-1) and pidilizumab (anti-PD-L1) are being investigated in RRMM treatment. According to Otero et al. (2017) and Ribrag et al. (2017), 50% ORR was obtained with pembrolizumab combined with Rd compared to 0% with monotherapy, respectively. However, combination therapy was associated with G≥3 neutropenia (n=17), thrombocytopenia (n=9) and anemia (n=6) while no high-grade AEs were observed with monotherapy.Antibody-Drug conjugates including lorvotuzumab mertansine and indatuximab ravtansine have been investigated in CTs for MM treatment. Lorvotuzumab mertansine has shown clinical efficacy in combination with Rd in a phase I trial (NCT00991562). Berdeja et al. (2012) reported an ORR of 59% (1 sCR, 1 CR, 8 VGPR, 9 PR) in 32 RRMM patients. In a phase I/II trial (NCT01638936) of indatuximab ravtansine combined with either Rd or Pd, Kelly et al. (2016) showed ORR of 77% with Rd (n=43) including at least 1 CR and 4 VGPR and 79% with Pd (n=14) including 4 VGPR in total 57 RRMM patients.ConclusionCombination regimens including monoclonal antibodies, CPIs and ADCs have shown clinically significant response in RRMM and NDMM patients. The mAbs caused hematological and nonhematological AEs like cytopenias and infections which needs to be monitored closely. DisclosuresNo relevant conflicts of interest to declare.

Evaluation of the efficacy of combination of biapenem and levofloxacin in the treatment of severe pneumonia in patients with multidrug-resistant Pseudomonas aeruginosa

Objective To observe the clinical efficacy of combination of biapenem and levofloxacin in the treatment of severe pneumonia caused by multi-drug resistant Pseudomonas albuginea.In order to provide effective treatment for the patients with severe pneumonia resulted from resistant Pseudomonas albuginea. Methods Sixty patients with severe pneumonia were enrolled in this study.All patients had multiple drug resistant Pseudomonas aeruginosa infection.They were randomly divided into two groups according to the digital table method, 30cases in each group.All patients were treated with mechanical ventilation, anti-infection, phlegm, asthma and hemodynamic stability.The control group was treated with cefperazone-sulbactam and levofloxacin.The treatment group was treated with biapenem and levofloxacin.The body temperature, white blood cell count(WBC) and procalcitonin(PCT) level, oxygenation index(PaO2/FiO2), the total clinical effective rate, pulmonary rales disappeared time and the time of chest radiograph showing the pulmonary exudate absorption significantly were compared before treatment and 7 days after treatment. Results After treatment, the WBC, body temperature, PCT, PaO2/FiO2 of the control group were (13.16±2.89)109/L, (37.58±0.92)℃, (195.36±10.63), (9.36±1.56)μg/L, respectively, which of the treatment group were (5.36±2.65)×109/L, (36.41±0.52)℃, (235.14±8.65), (5.63±1.69)μg/L, respectively, and the differences between the two groups were statistically significant(t=2.72, 2.93, 2.82, 3.25, all P<0.05). The total effective rate was 40.0% in the control group and 56.7% in the treatment group.The difference was statistically significant(χ2=12.64, P<0.01). The time of reduction of lung rales in the lungs and the obvious absorption time of chest radiographs in the control group were (9.35±3.25)d, (10.63±1.57)d, respectively, which in the treatment group were (5.87±1.46)d, (7.65±1.87)d, respectively, the differences between the two groups were statistically significant (t=2.31, 2.45, all P<0.05). Conclusion The clinical effect of biapenem and levofloxacin is better than cefoperazone sulbactam combined with levofloxacin in the treatment of patients with severe pneumonia result from multidrug-resistant Pseudomonas aeruginosa. Key words: Pneumonia; Drug therapy, combination; Pseudomonas aeruginosa; Biapenem; Levofloxacin

Clinical efficacy of the combination of transjugular intrahepatic portosystemic shunt and catheter-directed thrombolysis in the treatment of acute portal vein thrombosis accompanied by Budd-Chiari syndrome with extensive occlusion of hepatic veins

Objective To evaluate the clinical efficacy of combination of transjugular intrahepatic portosystemic shunt (TIPS) and catheter-directed thrombolysis (CDT) in the treatment of acute portal vein thrombosis (PVT) accompanied by Budd-Chiari syndrome (BCS) with extensive occlusion of the hepatic veins. Methods From March 2013 to December 2015, nine patients of acute PVT accompanied by BCS with extensive occlusion of the hepatic veins were collected, and the patients were treated by the combination of TIPS and CDT. The clinical symptoms, liver function and portal vein hemodynamics of patients were observed. After operation, portal vein and shunt patency was followed up by Doppler ultrasound. The patients were followed up seven days, one, three, six months, and every six months after the operation. Paired sample t test was performed for statistically analysis. Results The study enrolled nine patients, six male and three female, with an average age of (41.6±10.9) years old. Operation was successfully performed in eight patients, and of whom three were completed under the assist of perctaneous transhepatic approach. After operation, the blood flow of portal vein was unobstructed and clinical symptoms of portal vein hypertension were obviously improved. There was no significant difference in portal vein diameter between pre-operation ((13.6±2.1) cm) and seven days ((12.5±1.7) cm), one month ((12.1±2.9) cm), three months ((12.9±3.2) cm), six months ((11.6±1.8) cm) after operation (all P>0.05). And the portal vein velocity after operation were (79.3±14.6), (84.4±17.3), (87.3±21.4) and (80.1±12.6) cm/s, respectively, which were higher than that before operation ((9.8±3.1) cm/s), and the differences were statistically significant (t=28.169, 34.713, 36.519, 30.314, all P<0.01). The maximum cross sectional area ratios of the thrombus to the lumen after operation were (17.1±6.9)%, (19.1±6.2)%, (16.2±5.5)% and (16.7±5.1)%, respectively, which were lower than that before operation ((78.2±14.5)%), and the differences were statistically significant (t=26.182, 23.931, 29.371, 27.471, all P<0.01). At the seventh day after operation, the pressure of portal vein decreased from (42.2±8.9) cmH2O (1 cmH2O=0.098 kPa) to (19.6±4.2) cmH2O (t=17.410, P<0.01). At seven days, one month, three months and six months after operation, albumin levels ((30.7±3.9), (30.9±4.2), (29.9±3.1) and (33.1±4.7) g/L) were all higher than that before operation ((26.5±4.8) g/L), and the differences were statistically significant (t=4.785, 4.874, 2.874, 5.402, all P<0.05). The levels of transaminase after operation (32.9±21.6), (39.5±22.4), (24.8±19.8), (37.1±26.9) U/L) were all lower than that before operation ((99.6±31.7) U/L), and the differences were statistically significant (t=27.624, 24.913, 33.671 and 25.019, all P<0.01). During eight to 17 months follow-up, TIPS stent shunt stenosis was found in one case at three months after operation and the blood flow recovered after treatment of balloon dilation. The shunt and blood flow of portal vein of the other seven cases were clear. None of the eight patients had the symptoms of hepatic encephalopathy and pulmonary embolism. Operation was not successfully performed in one case, and 29 days later the patient died of hepatic and renal failure. Conclusion The combination of TIPS and CDT is safe and effective in the treatment of acute PVT accompanied by BCS with extensive occlusion of the hepatic veins, which maintain the blood flow of portal vein clear during short-and medium-term follow-up. Key words: Budd-Chiari syndrome; Portal vein thrombosis; Portasystemic shunt, transjugular intrahepatic

Influence of the number and interval of treatment cycles on cytokine-induced killer cells and their adjuvant therapeutic effects in advanced non-small-cell lung cancer (NSCLC)

ObjectiveCytokine-induced killer (CIK) cells have important therapeutic effects in adoptive cell transfer (ACT) for the treatment of various malignancies. In this study, we focused on in vitro expansion of CIK cells and their clinical efficacy in combination with chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). MethodsA total of 64 patients with NSCLC (enrolled from 2011 to 2012), including 32 patients who received chemotherapy alone or with sequential radiotherapy (conventional treatment, control group) and 32 patients who received conventional treatment and sequential CIK infusion (study group), were retrospectively analyzed. The time to progression (TTP), overall survival (OS) and adverse effects were analyzed and the phenotype of lymphocytes in CIK population was also determined by flow cytometry. ResultsAfter in vitro expansion, the average percentage of CIK cells was 26.35%. During the 54-month follow up, the median OS and TTP were significantly longer in the study group than in the control group (P=0.0189 and P=0.0129, respectively). The median OS of the ACT≥4cycles subgroup was significantly longer than that of the ACT<4cycles subgroup (P=0.0316). The percentage of CIK cells in patients who received ≥4cycles of ACT was higher than that in patients treated with <4cycles of ACT (P=0.0376). Notably, CIK cells were difficult to expand in vitro in some patients after the first ACT cycle but became much easier as the treatment cycles increased monthly. Longer treatment interval negatively impacted the expansion of CIK cells. ConclusionsSystematic immune levels can be increasingly boosted by reinfusion of ACT. Conventional treatment plus CIK cells is an effective therapeutic strategy to prevent progression and prolong survival of patients with advanced NSCLC.

Abstract 4201: Combination of palbociclib with enzalutamide shows in vitro activity in RB-proficient and androgen receptor-positive triple-negative breast cancer cells

Abstract Background Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors have in vitro synergistic effects and significant clinical efficacy in combination with hormone therapy for estrogen receptor (ER)-positive advanced breast cancer. However, the effects of CDK4/6 inhibitors in triple negative breast cancer (TNBC) are not well-elucidated. Retinoblastoma (RB, a known substrate of CDK4/6) protein pathway deregulation is a frequent occurrence in TNBC and in vitro studies have revealed that pharmacological CDK4/6 inhibition yields a cooperative cytostatic effect with doxorubicin in RB-proficient TNBC models, suggesting that RB may be a biomarker for selecting patients receiving CDK4/6 inhibitors. In addition, anti-androgen therapy have been shown preclinical efficacy in androgen-receptor (AR) positive TNBC cells. Here we tested the combination effect of a CDK4/6 inhibitor palbociclib with an AR antagonist enzalutamide in TNBC cells. Methods MDA-MB-231, MDA-MB-468 and MDA-MB-453 TNBC cell lines were used for in vitro studies. Cell viability was examined by MTT assay. Apoptotic effects were examined by flow cytometry. Signal transduction pathways in cells were assessed by Western blot. Results We correlated the expressions of AR and pRB status in these TNBC cells and identified that MDA-MB-453 were AR-positive/pRB-positive, MDA-MB-231 were AR-negative/pRB-positive, and MDA-MB-468 were AR-negative/pRB-negative cells. Since CDK4/6 inhibition leads to dephosphorylation of pRB, we examined effects of palbociclib and found that palbociclib significantly inhibited the cell growth of pRB-positive cell lines MDA-MB-453 and MDA-MB-231, but did not affect pRB-negative MDA-MB-468 cells. Further combining palbociclib with enzalutamide showed that the growth inhibitory effects of combination therapy were additive in AR-positive/pRB-positive MDA-MB-453 cells, but not in AR-negative/pRB-positive MDA-MB-231 cells, nor AR/pRB double negative MDA-MB-468 cells. Moreover, palbociclib-induced G1/S arrest only exhibited in pRB-proficient MDA-MB-453 and MDA-MB-231 cells. In contrast, enzalutamide did not affect the cell cycle on any of these TNBC cell lines but inhibited phosphorylation of AR signaling in AR-positive MDA-MB-453 cells. In addition, both palbociclib and enzalutamide induced little apoptosis, suggesting cytostatic effects of these agents. Conclusions In summary, both pRB and AR status are important for response of TNBC cells to palbociclib. Combination of palbociclib with enzalutamide shows more prominent cytostatic effects in RB proficient and AR positive TNBC cells, comparing to AR-negative/pRB-positive or AR/pRB double negative TNBC cells. Our data provide a preclinical rationale in selecting patients who might have therapeutic benefit from combining CDK4/6 inhibitors with AR antagonists. Citation Format: Ling-Ming Tseng, Tzu-Ting Huang, Chun-Teng Huang, Ka-Yi Lau, Chun-Yu Liu, Chung-Wai Shiau, Kuen-Feng Chen. Combination of palbociclib with enzalutamide shows in vitro activity in RB-proficient and androgen receptor-positive triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4201. doi:10.1158/1538-7445.AM2017-4201

PI3Kδ Inhibition Elicits Anti-Leukemic Effects through Bim-Dependent Apoptosis

Introduction: Phosphatidylinositol-3-kinase δ (PI3Kδ)-signaling provides key maintenance, proliferation, and survival cues during both normal and malignant B-lymphocyte development. Consequently, isoform-selective PI3Kδ inhibitors (PI3Kδi) have generated huge interest as a potential treatment for lymphoid malignancies. In particular, PI3Kδi demonstrate impressive clinical efficacy in combination with anti-CD20 monoclonal antibodies (mAbs) for relapsed chronic lymphocytic leukemia (CLL). However, these combinations function primarily to delay disease progression, but are not curative. With the ever-rising number of new targeted therapeutics, the challenge is to identify combinations that will ultimately deliver curative regimes. In order to guide these selections, a detailed mechanistic understanding is required. To date, only limited data are available regarding the exact in vivo therapeutic mechanism of PI3Kδi. Currently, studies identify immunomodulation, inhibition of BCR-, chemokine/cytokine-signaling, and induction of apoptosis as putative therapeutic mechanisms. Here we characterize the molecular mechanisms responsible for PI3Kδi-induced cytotoxicity and determine the relative contribution toward in vivo therapeutic responses utilizing the Eµ-TCL1-Tg mouse model of CLL alongside human CLL samples.Methods: The molecular mechanisms of PI3Kδi alone or in combination with anti-CD20 mAbs were assessed using the Eµ-TCL1-Tg mouse model, an in vivo model system of CLL. To inhibit PI3Kδ, the δ isoform-selective inhibitor GS-9820 was chosen, as it is highly structurally related to idelalisib, and critically demonstrates improved pharmacokinetic properties in the mouse in comparison to idelalisib. In vitro GS-9820 IC50 are as follows: PI3Kδ 27 nM; PI3Kα 83,424 nM; PI3Kβ 14,899 nM; and PI3Kγ 15,606 nM. Assays to measure its effects on BCR-mediated kinase activation, chemokine signaling/chemotaxis, and cytokine- and cell-mediated support were performed. GS-9820 was administered in vivo at 10 mg/kg per os BID (formulated in 0.5% methylcellulose, 0.05% tween-80), once leukemias were detected, and maintained throughout the treatment period (GS-9820 Cmax 3114 nM, Ctrough 48.6 nM).Results: GS-9820 induced substantive in vitro cell death and disruptedBCR-mediated kinase activation, chemokine signaling/chemotaxis, and inhibited both cytokine- and cell-mediated support in murine (Eµ-TCL1) and human CLL cells. In vivo administration of GS-9820 imparted significant therapeutic responses in Eµ-TCL1-bearing animals, reducing leukemic burden by 75% and splenic tumor deposits by 66% 4 weeks posttreatment. GS-9820 appeared well tolerated in recipient animals with no obvious toxicity apparent (e.g. weight loss or behavioral symptoms). When in combination with anti-CD20 mAbs, GS-9820 extended leukemia depletion by several weeks. GS-9820 enhanced overall survival by 66% in comparison with vehicle control-recipient animals and enhanced the survival benefit of anti-CD20 mAb therapy. These therapeutic responses were associated with a 2-fold increase in expression of the pro-apoptotic BH3-only Bcl-2 family member Bim and a 3-fold increase in the extent of Bim/Bcl-2 interaction. Accordingly, Bim-/- Eµ-TCL1-Tg leukaemias exhibited profound resistance to PI3Kδi-induced cytotoxicity, were refractory to PI3Kδi in vivo, and failed to display combination efficacy with anti-CD20 mAbs. These findings informed the rational design of a GS-9820 + ABT199 (Venetoclax) complementary drug combination strategy. Combinations of GS-9820 and ABT199 were well tolerated with an absence of weight loss or altered behavioral symptoms. The GS-9820 + ABT199 combination effectively halted leukemia progression in vivo with increased efficacy compared to monotherapy regimes, resulting in a 90% reduction in leukemic burden at the end of the treatment period.Conclusions: Bim-dependent apoptosis represents the key in vivo effector mechanism for PI3Kδi in the Eµ-TCL1-Tg mouse model, both alone and in combination with anti-CD20 mAbs. As such, combinations of PI3Kδ and Bcl-2 inhibitors may represent an efficacious drug combination strategy. DisclosuresTannheimer:Gilead Sciences: Employment. Packham:Karus Therapeutics: Other: Share Holder & Founder; Aquinox Pharmaceuticals: Research Funding. Cragg:Baxalta: Consultancy; Roche: Consultancy, Research Funding; Bioinvent International: Consultancy, Research Funding; Gilead Sciences: Research Funding; GSK: Research Funding.

Study of the effect of menopausal hormone therapy in women with psoriasis type 2 in postmenopause

The results of comparative analysis of the hormonal status from 75 women aged from 49 to 60 years old (average age 54.04 ± 1.28 year) in postmenopause with psoriasis type 2 (study group) and 50 women of control group of the same age and menstrual status without psoriasis are presented. There were two subgroups in the main group: subgroup 1 received basic therapy in combination with menopausal hormone therapy (MHT) (estradiol 1 mg + drospirenone 2 mg), subgroup 2 - basic therapy. Psoriatic process was assessed according to PASI index and was evaluated by the dermatology quality of the life index (DIQL) and the content of gonadotropic and sex hormones before treatment and after 3 and 6 months of starting treatment in patients of both subgroups. More pronounced clinical efficacy in combination with reduced FSH level is 13.2% (p &lt; 0.001), increased content of estradiol 69.3% (p &lt; 0.001) was observed in patients from 1 subgroup. MHT supplement to the basic treatment decreased the PASI index after 3 months of starting treatment for 50.9% (p fter 6 months - at 94% (p &lt; 0.001), and reduced DIQL in subgroup 1 compared to 2 subgroup after 3 months - 15.3% (p &lt; 0.05) and after 6 months - 20.8% (p &lt; 0.05). In postmenopausal women with psoriasis favorable changes of indexes reflecting the clinical manifestations of the disease were associated with the correction of hormonal status in MHT estradiol 1 mg + drospirenone 2 mg.

Metformin increases antitumor activity of MEK inhibitors through GLI1 downregulation in LKB1 positive human NSCLC cancer cells.

PurposeMetformin, widely used as antidiabetic drug, showed antitumoral effects expecially in combination with chemotherapy. Our group recently has demonstrated that metformin and gefitinib are synergistic in LKB1-wild-type NSCLC cells. In these models, metformin as single agent induced an activation and phosphorylation of mitogen-activated-protein-kinase (MAPK) through an increased C-RAF/B-RAF heterodimerization.Experimental designSince single agent metformin enhances proliferating signals through the RAS/RAF/MAPK pathway, and several MEK inhibitors (MEK-I) demonstrated clinical efficacy in combination with other agents in NSCLC, we tested the effects of metformin plus MEK-I (selumetinib or pimasertib) on proliferation, invasiveness, migration abilities in vitro and in vivo in LKB1 positive NSCLC models harboring KRAS wild type and mutated gene.ResultsThe combination of metformin with MEK-I showed a strong anti-proliferative and proapoptotic effect in Calu-3, H1299, H358 and H1975 human NSCLC cell lines, independently from the KRAS mutational status. The combination reduced the metastatic behaviour of NSCLC cells, via a downregulation of GLI1 trascritional activity, thus affecting the transition from an epithelial to a mesenchymal phenotype. Metformin and MEK-Is combinations also decreased the production and activity of MMP-2 and MMP-9 by reducing the NF-jB (p65) binding to MMP-2 and MMP-9 promoters.ConclusionsMetformin potentiates the antitumor activity of MEK-Is in human LKB1-wild-type NSCLC cell lines, independently from the KRAS mutational status, through GLI1 downregulation and by reducing the NF-jB (p65)-mediated transcription of MMP-2 and MMP-9.

Profile of nintedanib in the treatment of solid tumors: the evidence to date.

Angiogenesis is an essential process for tumor growth and metastasis, and remains a promising therapeutic target process in cancer treatment for several cancer types. Bevacizumab, a monoclonal antibody that targets vascular endothelial growth factor (VEGF), was the first antiangiogenic agent approved for cancer therapy. Novel antiangiogenic agents, such as sunitinib, sorafenib, pazopanib, or vandetanib that target additional proangiogenic signaling pathways beyond VEGF, have also been approved for the treatment of various malignant diseases. While most of these agents are approved in combination with cytotoxic chemotherapy for indications including metastatic colorectal cancer, non-small-cell lung cancer, breast cancer, renal cell carcinoma (RCC), and gastric cancer, some are used as approved monotherapy for advanced RCC, hepatocellular carcinoma and medullary thyroid cancer. Major challenges to the success of antiangiogenic therapy include associated toxicity risks, limitation of efficacy through the possible development of resistance and induction or promotion of metastatic progression. Nintedanib (formally known as BIBF 1120) is a triple angiokinase inhibitor of VEGF, fibroblast growth factor, platelet-derived growth factor signaling with lesser activity against RET, Flt-3, and Src. Through this unique targeting profile nintedanib has demonstrated significant antitumor activity in several tumor types in preclinical studies. Nintedanib has also shown promising clinical efficacy in combination with docetaxel and has been approved for treating patients with locally advanced and metastatic non-small-cell lung cancer in Europe. Nintedanib has also been found to be clinically promising in terms of efficacy and safety in several other solid tumors including ovarian cancer (Phase III), RCC (Phase II), and prostate cancer (Phase II). This review article provides a comprehensive summary of the preclinical and clinical efficacy of nintedanib in the treatment of solid tumors.

AB37. The combination of I brachytherapy with intermittent androgen deprivation in treating locally advanced prostate cancer

ObjectiveTo evaluate the clinical efficacy of combination of intermittent androgen deprivation and I brachytherapy (BT) for the treatment of locally advanced prostate cancer.MethodA total of 31 patients with locally advanced prostate cance were treated with the Combination Of I Brachytherapy and Intermittent Androgen Deprivation. Bicalutamide 50 mg Qd and Goserelin 3.6 mg every 28 days were given after surgery. When PSA fell to 0.1 ng/mL and stabilized for two months, treatment was stopped (off phase). A PSA relapse was defined according to the ASTRO consensus definition (PSA was more than 0.5 ng/mL and three successive PSA elevations after a post-operation nadir was achieved). When the PSA relapse happened, hormonal therapy was restarted.ResultsAll cases were followed up 12-65 months average 35 months. All the patients’ PSA fell to the normal range (≤4 ng/mL) 3 to 5 months after operation. A total of 28 patients’ PSA decreased to <0.1 ng/mL and stopped hormonal therapy. Three cases did not reach standard, so they maintained the hormonal therapy. A total of 7 of the 28 patients suffered the PSA relapse 5 to 26 months after stopping hormonal therapy. Hormonal therapy was restarted and the PSA decreased to 0 ng/mL again in 5 cases of the 7 PSA relapse patients. A total of 21 of the 31 patients did not suffer the PSA relapse during the follow up. The duration of first off phase was 12-57 months, averaging about 26.9 months. Bone metastasis happened in two patients. One patient was diagnosed as bone metastasis 16 months after operation. One patient was diagnosed as bone metastasis and died 42 months after operation.ConclusionCombination of intermittent androgen deprivation and I brachytherapy is an effective and safe treatment for locally advanced prostate cancer. Our results need to be approved by multicenter prospective randomized trial.

Smac mimetics and innate immune stimuli synergize to promote tumor death

Smac mimetic compounds (SMC), a class of drugs that sensitize cells to apoptosis by counteracting the activity of inhibitor of apoptosis (IAP) proteins, have proven safe in Phase I clinical trials in cancer patients. However, because SMCs act by enabling transduction of pro-apoptotic signals, SMC monotherapy may only be efficacious in the subset of patients whose tumors produce large quantities of death-inducing proteins such as inflammatory cytokines. As such, we reasoned that SMCs would synergize with agents that stimulate a potent yet safe “cytokine storm”. Here we show that oncolytic viruses and adjuvants such as poly(I:C) and CpG induce bystander death of cancer cells treated with SMCs that is mediated by interferon beta (IFNβ), tumor necrosis factor alpha (TNFα) and/or TNF-related apoptosis-inducing ligand (TRAIL). This combinatorial treatment resulted in tumor regression and extended survival in two mouse models of cancer. As these and other adjuvants have been proven safe in clinical trials, it may be worthwhile to explore their clinical efficacy in combination with SMCs.

Imprime PGG, a yeast β-glucan immunomodulator, has the potential to repolarize human monocyte-derived M2 macrophages to M1 phenotype

Meeting abstracts Imprime PGG (IPGG) has shown promising clinical efficacy in combination with monoclonal antibody treatment of cancer [[1][1]]. In mice, complement receptor 3 (CR3) on innate immune cells (neutrophils and macrophages) is required for IPGG's anti-tumor activity [[2][2], [3][3]]. In