Success Of Combination Therapy Research Articles

Synergistic and antagonistic drug interactions are prevalent but not conserved across acute myeloid leukemia cell lines.

Acute myeloid leukemia (AML) is the most prevalent type of leukemia in adults. Its heterogeneity, both between patients and within the same patient, is often a factor contributing to poor treatment outcomes. Despite advancements in AML biology and medicine in general, the standard AML treatment, the combination of cytarabine and daunorubicin, has remained the same for decades. Combination drug therapies are proven effective in achieving targeted efficacy while minimizing drug dosage and unintended side effects, a common problem for older AML patients. However, a systematic survey of the synergistic potential of drug-drug interactions in the context of AML pathology is lacking. Here, we examine the interactions between 15 commonly used cancer drugs across distinct AML cell lines and demonstrate that synergistic and antagonistic drug-drug interactions are widespread but not conserved across these cell lines. Notably, enasidenib and venetoclax, recently approved anticancer agents, exhibited the highest counts of synergistic interactions and the fewest antagonistic ones. In contrast, 6-Thioguanine, a purine analog, was involved in the highest number of antagonistic interactions. The interactions we report here cannot be attributed solely to the inherent natures of these three drugs, as each drug we examined was involved in several synergistic or antagonistic interactions in the cell lines we tested. Importantly, these drug-drug interactions are not conserved across cell lines, suggesting that the success of combination therapies might vary significantly depending on AML genotypes. For instance, we found that a single mutation in the TF1 cell line could dramatically alter drug-drug interactions, even turning synergistic interactions into antagonistic ones. Our findings provide a preclinical survey of drug-drug interactions, revealing the complexity of the problem.

Success of Combination Therapy with Isavuconazole in a Pediatric Patient with Breakthrough Invasive Aspergillosis

AbstractThe increasing incidence of invasive fungal infections, coupled with the growing population of immunocompromised patients, has led to an increased need for antifungal agents. The newest azole, isavuconazole, plays an important role in the treatment of invasive aspergillosis in adults due to its broad spectrum, tolerability, and no need for therapeutic drug monitoring. This agent, which has not yet been approved for use in children, has significant problems with drug supply in Türkiye. We present the treatment response to isavuconazole combination therapy used in salvage treatment in a patient with breakthrough invasive aspergillosis, who had treatment failure with different antifungal combination treatment options and surgical resection.

Evolution, control and success of combination therapy with Ampicilin-sulbactam/Ceftazidime-Avibactam during a Carbapenem-Resistant Acinetobacter baumannii outbreak in burn Intensive Care Unit.

We present our findings on interpatient transmission, epidemic control measures, and the outcomes of a series of ten critically ill burn patients who were either colonized or infected with carbapenem-resistant Acinetobacter baumannii (CRAB). None of the five infected patients achieved clinical cure, and all experienced relapses. Microbiological failure was observed in 40% of the infected patients. The isolated CRAB strains were found to carry blaOXA-23 and armA resistance genes. Despite the lack of clinical cure, all five infected patients survived and were discharged from the Burn Intensive Care Unit.

Exploring the Molecular Players behind the Potentiation of Chemotherapy Effects by Durvalumab in Lung Adenocarcinoma Cell Lines.

Immune checkpoint inhibitors are increasingly used in combination with chemotherapy for the treatment of non-small cell lung cancer, yet the success of combination therapies is relatively limited. Thus, more detailed insight regarding the tumor molecular markers that may affect the responsiveness of patients to therapy is required. Here, we set out to explore the proteome of two lung adenocarcinoma cell lines (HCC-44 and A549) treated with cisplatin, pemetrexed, durvalumab, and the corresponding mixtures to establish the differences in post-treatment protein expression that can serve as markers of chemosensitivity or resistance. The mass spectrometry study showed that the addition of durvalumab to the treatment mixture resulted in cell line- and chemotherapeutic agent-dependent responses and confirmed the previously reported involvement of DNA repair machinery in the potentiation of the chemotherapy effect. Further validation using immunofluorescence also indicated that the potentiating effect of durvalumab in the case of cisplatin treatment was dependent on the tumor suppressor RB-1 in the PD-L1 weakly positive cells. In addition, we identified aldehyde dehydrogenase ALDH1A3 as the general putative resistance marker. Further studies in patient biopsy samples will be required to confirm the clinical significance of these findings.

Abstract 1907: Combocat: A high-throughput framework for drug combination studies

Abstract Drug combinations are the basis of treatment for modern diseases but arriving at successful combination therapies is fraught with challenges. Decades ago, the limited number of drugs represented a tractable candidate list from which to design combination experiments. However, the current pool of single-agent drugs to potentially combine is far too large to brute-force screen, and purely computational predictions have performed poorly. Suitable screening methods are needed, but the design of experimental approaches has proven to be highly complex; researchers need to carefully balance many variables such as appropriate drug concentration ranges, number of doses, inclusion of replicates, and throughput. Perhaps the most significant obstacle facing these studies is the approach to data analysis, where conflicting definitions of synergy and unintuitive metrics serve to confuse researchers and render largely uninterpretable results. Collectively, these challenges hamper the progress of drug combination research and ultimately translational impact. To overcome these limitations, we have developed a fully self-contained framework to handle both the experimental design and analysis of drug combination experiments. Our method, called Combocat, provides a straightforward way to test and analyze any number of drug combinations and samples, and is suitable for high-throughput. Combocat provides a high-resolution of concentration combinations compared to most current approaches. This is automated by common instruments and uses scripts included within our protocol. Through careful template design, we were able to include 3 replicates of each 10x10 matrix, single-agent drugs, and controls - all within a single 384-well plate. We found our method to work robustly with varying sample types (Human cancer, bacteria, fungi), and readouts. After data generation, files can simply be dragged into our Combocat analysis tool directly. We provide a free, web-based software suite to fully automate the analysis after data collection. The Combocat web tool is intuitive and facilitates interactive exploration of synergy. It also provides a rich array of information such as dose-response curves, IC50 values, synergy matrices, ranked hit plots, and more. Data normalization, synergy algorithms, scoring functions, and other complex calculations are run swiftly and automatically in the background with no need for user input. Notably, we employ statistical testing by taking advantage of experimental replicates, which is a feature we found lacking in most methods. We use a well-documented synergy metric but also decided to formulate our own Combocat score which considers statistical measurements and assay quality. The Combocat score provides an easy interpretation of results and facilitates quick identification of top hits. Collectively, our platform will be used to enhance and expedite the selection of effective drug combinations. Citation Format: William C. Wright, Min Pan, Hyeong-Min Lee, Gregory A. Phelps, Jonathan Low, Duane Currier, Richard E. Lee, Taosheng Chen, Paul Geeleher. Combocat: A high-throughput framework for drug combination studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1907.

Abstract 2739: Defining and evaluating drug additivity in clinical trials of combination cancer therapy

Abstract BACKGROUND The benefits of combination therapy are often attributed to synergy, that is, drug interactions resulting in an anti-cancer effect that is more than the sum of its parts. Accordingly, the rationale for designing new drug combinations is often based on synergy measured in preclinical models. However, preclinical metrics of drug interaction are not applicable to clinical trial data, and there has been no established quantitative method to assess synergy versus additivity in clinical settings. We recently showed that because of extensive patient-to-patient heterogeneity in single drug responsiveness, increasing the chance of a good response to at least one drug was a quantitatively sufficient explanation for the clinical efficacy of many approved combination therapies. Some combinations surpass this ‘highest single-agent’ model, which could be due to either drug additivity or synergy. Here we propose and test a model of drug additivity for Progression-Free Survival (PFS) data from clinical trials, to identify if any approved combinations are clinically synergistic, as compared to additive. METHODS We used PFS from trials as the clinical measure of drug efficacy. We defined ‘clinical drug additivity’ as the sum of PFS times observed from each drug in a combination. Inter-patient heterogeneity in drug responses was simulated by sampling from the joint distribution of drugs’ PFS distributions. For each combination, the clinically observed PFS distribution was compared to the additivity model, or the highest single-agent model (Palmer & Sorger, 2017). Synergy is exhibited if an observed PFS distribution is significantly superior to PFS expected from additivity (by Cox Proportional Hazards). To search for drug synergy in clinical data, we analyzed approved combination therapies where synergy was most likely to explain efficacy, which are combinations where part of the regimen is not approved as monotherapy in the same disease. We analyzed 11 approved combination therapies for advanced cancers in the breast, ovary, pancreas, colon, cervix, and lymphatic system. RESULTS None of the 11 approved combinations analyzed were significantly superior to the model of clinical additivity. For five combinations, the additivity model made the most accurate predictions of clinical efficacy (mean R2=0.97 for additivity, versus R2=0.83 for highest single-agent), and the other six combinations were most accurately described by the highest single-agent model (mean R2=0.97 for highest single-agent, versus R2=0.91 for additivity). CONCLUSIONS Approved combination therapies are rarely ‘more than the sum of their parts’ in quantitative terms. A straightforward definition of clinical drug additivity accurately matched trial results for combination therapies where synergy was expected. This suggests that single-agent efficacy by each drug is usually required for the clinical success of combination therapy. Citation Format: Haeun Hwangbo, Adam C. Palmer. Defining and evaluating drug additivity in clinical trials of combination cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2739.

Keloid Scars: An Updated Review of Combination Therapies.

Keloid scars are a common yet poorly understood complication of wound healing that can cause a diminished quality of life. Currently, there is little agreement amongst the medical community regarding the best treatment modality for keloids. For this reason, we have created an updated review of the most successful combination therapies for keloid scars and compared their efficacy based on rates of recurrence following treatment. Additionally, these combination therapies have been compared with intralesional triamcinolone acetonide corticosteroid (TAC), which is considered the mainstay monotherapy for keloids. All combination therapies included in our review were shown to produce superior outcomes than TAC monotherapy. We have also found that certain combination therapies are known to produce superior results when used in specific anatomic locations. Intralesional TAC plus intralesional cryotherapy appeared to have the most promising results for non-auricular keloids, and the authors suggest considering this as a first-line treatment. Additionally, the use of surgical excision plus compression therapy achieved superior results for auricular keloids and should be considered first-line for keloids in these locations.

Abstract PO-072: Control of inter- and intra-patient cancer heterogeneity is a predictively accurate explanation for the success of many combination therapies for solid and hematological cancers

Abstract Developing optimal drug combinations is one of the central challenges of cancer treatment research: drug combinations are used to treat most types of cancer, and are almost exclusively responsible for cures of advanced cancers. However, historically successful combination therapies were developed empirically, and the mechanistic basis for their efficacy has been largely speculative. I will present experiments, models, and computational analyses of clinical trial data, to investigate the mechanistic basis of clinically successful combination therapies across 12 types of cancer and 30 different therapies. These studies consistently identify the control of cancer heterogeneity between-patients (inter-tumor) and within-patients (intra-tumor) by independently active drugs as critical contributors to the efficacy of combination therapies in human patients. The key approaches for data analysis and modeling in these studies consist of adapting classical pharmacological concepts to the complex situation of populations of cancers with heterogeneous drug sensitivity. Synergistic drug interactions in humans appears uncommon among approved combination therapies, and even curative regimens exhibit drug additivity in experimental measurements and in clinical outcomes. Mathematical descriptions of heterogeneity in cellular or patient populations, and quantitative experimental measurements of how drug combinations address heterogeneity, lead to accurate predictions of clinical trial results for a diverse range of combination therapies, including those with immune checkpoint inhibitors (correlation between observed and expected Progression Free Survival in 14 trials, Pearson r = 0.98, P < 10^-8) and curative chemotherapy regimens for hematological cancers (correlation between observed and expected response rates and cure rates in 40 years of trials in childhood ALL, Pearson r = 0.99, P < 10^-10). These results have broad significance for the treatment of cancers, for the interpretation of clinical trials, and point to new opportunities to use combination therapies with greater precision. Citation Format: Adam C. Palmer, Ben Izar, Haeun Hwangbo, Peter K. Sorger. Control of inter- and intra-patient cancer heterogeneity is a predictively accurate explanation for the success of many combination therapies for solid and hematological cancers [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-072.

The Immuno-Modulatory Effects of Inhibitor of Apoptosis Protein Antagonists in Cancer Immunotherapy.

One of the hallmarks of cancer cells is their ability to evade cell death via apoptosis. The inhibitor of apoptosis proteins (IAPs) are a family of proteins that act to promote cell survival. For this reason, upregulation of IAPs is associated with a number of cancer types as a mechanism of resistance to cell death and chemotherapy. As such, IAPs are considered a promising therapeutic target for cancer treatment, based on the role of IAPs in resistance to apoptosis, tumour progression and poor patient prognosis. The mitochondrial protein smac (second mitochondrial activator of caspases), is an endogenous inhibitor of IAPs, and several small molecule mimetics of smac (smac-mimetics) have been developed in order to antagonise IAPs in cancer cells and restore sensitivity to apoptotic stimuli. However, recent studies have revealed that smac-mimetics have broader effects than was first attributed. It is now understood that they are key regulators of innate immune signalling and have wide reaching immuno-modulatory properties. As such, they are ideal candidates for immunotherapy combinations. Pre-clinically, successful combination therapies incorporating smac-mimetics and oncolytic viruses, as with chimeric antigen receptor (CAR) T cell therapy, have been reported, and clinical trials incorporating smac-mimetics and immune checkpoint blockade are ongoing. Here, the potential of IAP antagonism to enhance immunotherapy strategies for the treatment of cancer will be discussed.

Functional Interactions between Transcription Factors Involved in Myeloma Pathogenesis - Biological and Therapeutic Implications

The clinical success of combination therapies for multiple myeloma (MM) has led our group and others to perform pharmacological screens seeking to identify promising candidates for combination regimens. However, in our genome-scale CRISPR knockout (KO) studies, we have observed that the biological behavior of MM cells is driven by key transcription factors (TFs), including several that represent major preferential dependencies for MM cells compared to other blood cancers or to solid tumors. Most of these TFs are currently considered "undruggable", as they lack identifiable hydrophobic pockets that can be selectively engaged with small-molecule inhibitors and are not thalidomide derivative (IMID)-induced neo-substrates for CRBN. Therefore, pharmacological screens are inherently limited in their ability to probe the functional interactions of MM-related TFs. To bypass this limitation and interrogate in MM cells how key TFs may interact with each other or with other pathways, we performed combinatorial CRISPR-based gene editing studies, in which we examined how MM cell survival/proliferation is impacted by CRISPR KO of each gene individually vs. simultaneous KO of two genes. We applied a combinatorial CRISPR dual knockout (DKO) study in MM.1S or KMS-11 cells, which have been engineered to express 2 orthologous Cas9 nucleases (from S. pyogenes and S. aureus), to increase the efficiency and specificity of combinational KO. Synergy (or antagonism) of the KO of gene pairs was determined by comparing the average (+/-95% CIs) normalized log2-fold change (log2FC) of sgRNA readcounts for each gene pair vs. the sum of log2FC for the respective "singeletons" (pair of sgRNA for one gene and control sgRNA) vs. "double controls"; and focusing on genes pairs with concordant results for sgRNA pairs involving Sp.Cas9-Sa.Cas9 and vice versa. We performed a focused study on ~100 genes, including 45 TFs (including 20 TFs that represent MM-preferential dependencies); additional MM-preferential or broad-spectrum dependencies; tumor suppressors (e.g. TP53, PTEN); as well as TFs and other genes that are not major dependencies for MM cells in single KO studies. We also used this DKO system to study MM.1S cells implanted in "humanized" scaffold-based bone marrow-like model in NSG mice. Both in vitro and in vivo, synergistic combinations of gene KOs were heavily enriched for presence of at least one TF, most often one of the MM-preferentially essential TFs, including IRF4, POU2AF1, TCF3, and NF-kappaB pathway members. Many of these synergistic combinations had greater effect on MM cell survival/proliferation than the combined KO of IKZF1/IKZF3 (IKZF1/ZFP91 or IKZF3/ZFP91 did not result in synergy): these observations suggest that many MM TFs which are not CRBN neo-substrates are involved in synergistic DKO combinations with more potent anti-MM activity compared to all DKOs of the main TFs (IKZF1, IKZF3, ZFP91) degraded by IMIDs. This observation suggests that efforts to advance the therapeutic targeting of currently "undruggable" MM TFs (alone or paired) which do not interact with CRBN may have therapeutic implications that do not overlap with the effect of IMIDs. The results of our DKO studies exhibited a time-dependent effect: in early time-points, strong dependencies (e.g. IRF4) are highly recurrent partners in synergistic pairs, while later time-points uncover interactions between genes with limited, if any, individual roles as essential genes, including TFs (e.g. ZBP1) but also other pathways (the translation regulator ELL2, a gene proposed to be associated with increased risk for myelomagenesis). MM cell "dedifferentiation" (e.g. through suppression of plasma cell-specific TFs such as XBP1) has been proposed as potential mechanism for proteasome inhibitor resistance. However, in our study, loss of XBP1 or other MM-related TFs (alone or in combination with other genes) was not associated with significant resistance to MM.1S or KMS11 cell treated with clinically relevant pulses of bortezomib, suggesting that perturbation of key MM-related TFs can be therapeutically compatible with proteasome inhibition. More broadly, our DKO studies revealed critical interactions between TFs with central roles in MM biology and also others with previously underappreciated effects, pointing to combinatorial effects that may be exploited in the future through novel therapeutic strategies. Disclosures Mitsiades: Ionis Pharmaceuticals: Honoraria; Fate Therapeutics: Honoraria; Arch Oncology: Research Funding; Sanofi: Research Funding; Karyopharm: Research Funding; Abbvie: Research Funding; TEVA: Research Funding; EMD Serono: Research Funding; Janssen/Johnson & Johnson: Research Funding; Takeda: Other: employment of a relative .

Treatment Combinations for Alzheimer's Disease: Current and Future Pharmacotherapy Options.

Although Alzheimer’s disease (AD) is the world’s leading cause of dementia and the population of patients with AD continues to grow, no new therapies have been approved in more than a decade. Many clinical trials of single-agent therapies have failed to affect disease progression or symptoms compared with placebo. The complex pathophysiology of AD may necessitate combination treatments rather than monotherapy. The goal of this narrative literature review is to describe types of combination therapy, review the current clinical evidence for combination therapy regimens (both symptomatic and disease-modifying) in the treatment of AD, describe innovative clinical trial study designs that may be effective in testing combination therapy, and discuss the regulatory and drug development landscape for combination therapy. Successful combination therapies in other complex disorders, such as human immunodeficiency virus, may provide useful examples of a potential path forward for AD treatment.

Long-lasting complete response status of advanced stage IV gall bladder cancer and colon cancer after combined treatment including autologous formalin-fixed tumor vaccine: two case reports

BackgroundThe prognosis of advanced (stage IV) cancer of the digestive organs is very poor. We have previously reported a case of advanced breast cancer with bone metastasis that was successfully treated with combined treatments including autologous formalin-fixed tumor vaccine (AFTV). Herein, we report the success of this approach in advanced stage IV (heavily metastasized) cases of gall bladder cancer and colon cancer.Case presentationCase 1: A 61-year-old woman with stage IV gall bladder cancer (liver metastasis and lymph node metastasis) underwent surgery in May 2011, including partial resection of the liver. She was treated with AFTV as the first-line adjuvant therapy, followed by conventional chemotherapy. This patient is still alive without any recurrence, as confirmed with computed tomography, for more than 5 years.Case 2: A 64-year-old man with stage IV colon cancer (multiple para-aortic lymph node metastases and direct abdominal wall invasion) underwent non-curative surgery in May 2006. Following conventional chemotherapy, two courses of AFTV and radiation therapy were administered sequentially. This patient has had no recurrence for more than 5 years.ConclusionWe report the success of combination therapy including AFTV in cases of liver-metastasized gall bladder cancer and abdominal wall-metastasized colon cancer. Both patients experienced long-lasting, complete remission. Therefore, combination therapies including AFTV should be considered in patients with advanced cancer of the digestive organs.

Final Results and Follow-up of a Phase I Study of the Fc Engineered CD19 Antibody XmAb®5574 (aka MOR00208) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

CD19 is an attractive target in lymphoid malignancies as it is highly expressed in nearly all CLL and non-Hodgkin’s lymphomas. While development of CD19 directed antibodies (abs) had previously been limited by antigen internalization, improved ab modification technology has restored this potential target. XmAb5574 (MOR00208) is a novel humanized IgG1 CD19 monoclonal ab with an engineered Fc region to enhance Fc gamma receptor binding affinity. We have previously presented safety and efficacy data from a first in human trial of this ab in relapsed or refractory (R/R) CLL, and now update these results along with results of a maintenance therapy cohort, follow-up efficacy data on all patients (pts), and correlative studies.This study was a multi-institutional phase I trial of XmAb5574 in pts with R/R CLL. An accelerated titration design was used, with dose levels of 0.3, 1, 3, 6, 9, and 12 mg/kg with an expansion to a total of 16 pts at the maximal tolerated dose (MTD). Patients received 9 intravenous infusions of XmAb5574: days 1, 4, 8, 15, and 22 of cycle 1, and days 1, 8, 15, and 22 of cycle 2. Once 5 patients were treated in the maximal dose cohort, additional patients who had at least stable disease after 2 cycles had the option to receive Xmab5574 every 28 days for an additional 4 infusions. Toxicity was assessed using the National Cancer Institute’s Common Criteria for Adverse Events v4.0 for non-hematologic toxicity, and IWCLL 2008 guidelines for hematologic toxicity. Disease response assessment by physical exam was performed on C1D28, C2D28, and 4, 8, and 12 weeks after the end of Cycle 2. CT assessment was performed C2D28.27 pts were enrolled, with a median age of 66 years (range 40-84). The pts were generally high risk: 14 had high-risk disease by Rai stage, 8 had del(11q22.3) and 10 had del(17p13.1) by FISH, and 24 had IgVH unmutated disease. The median number of prior therapies was 4 (range 1-13). Toxicity with this agent was modest with no MTD identified. 5 pts experienced grade 3 or 4 treatment-related toxicity, which included neutropenia (3 pts), thrombocytopenia (2 pts), increased aspartate aminotransferase (AST; 1 pt), febrile neutropenia (1 pt), and tumor lysis syndrome (1 pt). Grade 1 and 2 toxicities assessed as possibly related to XmAb5574 that occurred in more than 10% of pts included infusion reactions, increased AST, increased alanine aminotransferase, neutropenia, thrombocytopenia, fever, chills, and peripheral neuropathy. Infusion reactions occurred in 67% of patients, however, all were grade 1 or 2, and no reactions were seen following the first infusion.On the basis of physical exam and laboratory studies, 18 patients (66.7%) achieved a partial response (PR), and the remaining 9 patients (33.3%) achieved stable disease (SD). Adding CT criteria, 8 patients (29.6%) achieved a PR with an additional 16 patients (59.3%) achieving SD. Two patients had progressive disease by CT criteria. No patient dosed below 3 mg/kg had an objective response. Of the 16 pts treated at the maximum dose, 12 patients (75%) had a PR by physical exam criteria and 6 patients (37.5%) had a PR by CT criteria, with 2 of these pts achieving a PR during the maintenance phase. Median progression free survival (PFS) for all patients was 199 days (95% CI: 168-299 days). For patients on all dose levels who received 9 doses or less, PFS was 189 days, and for the 8 patients on the extended treatment cohort, PFS was 420 days (95% CI: 168 days-not reached).Flow cytometry was performed for absolute T and NK cell counts as well as activation. During the first 12 weeks, there was no significant change in T or NK cell counts; however, from cycle 1 day 1 pre to end of infusion there was a significant decrease in both T and NK cell number. There was no significant change in T or NK cell activation at any point.PK was best modeled by a two-compartment model. Half-life was 14 days, with clearance 5mL/day/kg that was not dose-dependent. A steady-state was reached at or before infusion 9.In conclusion, this Phase I trial demonstrates safety and preliminary efficacy of a novel Fc engineered CD19 monoclonal antibody XmAb5574 (MOR00208) and justifies movement into the Phase II setting. The modest toxicity combined with preliminary efficacy as a single agent will likely allow for successful combination therapies, and current studies in CLL are investigating XmAb5574 in combination with other active agents. DisclosuresFoster:Xencor, Inc: Employment.

Successful Combination Therapies, Hospital Utilization Improvements among Late-Breaking Clinical Trials

This article reviews multiple late-breaking clinical trials focusing on combination therapy and hospital utilization improvements. Specific trials include the phase 3 AMBITION [NCT01178073], the Comprehensive Respiratory Outcome Management program, as well as trials investigating the use of noninvasive open ventilation, end-of-rotation handoffs, and 2 phase 3 randomized controlled studies [NCT01957163; NCT02119286] looking at umeclidinium for the treatment of COPD.

Insights in Dynamic Kinome Reprogramming As a Consequence of MEK Inhibition in MLL-Rearranged AML.

AbstractAbstract 2338Cancer arises when somatic cells are able to escape the restraints that normally withhold them from unlimited expansion. Cancer progression is thought to be the net result of signaling through various protein-kinase mediated networks driving cell proliferation and survival. The kinome networks can be affected by numerous factors; including acquired or selected mutations as well as environmental cross talk. Additionally, the loss of phosphatases could be a causative factor for activation of multiple tyrosine kinases as well (Cell. 2011 Mar 4;144(5):703–18).Deregulated kinase activity is frequently observed in leukemia, leading to induced proliferation, migration, survival, and chemotherapy resistance of leukemic cells. (Leuk Lymphoma. 2011 Jan;52(1):122–30, Leukemia. 2005 Apr;19(4):586–94, Exp Hematol. 2005 Jun;33(6):660–70) However, single kinase-targeted cancer therapies can default when cancer cells bypass through alternative routes, facilitating therapeutic resistance. In order to circumvent the constraints given by an inihibitor, we need to monitor kinome reprogramming upon mono-treatments to develop the most successful combination therapy approach for disease specific subgroups, as poor prognostic MLL-rearranged AML. Rational designs of kinase inhibitor or RTK antibody combinations require a high-throughput measurement of kinome and proteome activity signatures within this patient subgroup. Figure 1 outlines our approach to explore the intracellular signaling networks and study the dynamic changes resulting in reprogramming of the kinome network, with the goal to define combinational therapeutic strategies.In this study, we succeeded using combined high-throughput approaches for kinomic and proteomic profiling to identify specific aberrant kinase signatures in MLL-rearranged AML as compared to NBM (Fig. 1B/C). The altered activated kinase signatures of a comprehensive set of MLL-rearranged AML patient samples resulted in a detailed map of the overall kinase activity and phosphorylation of signal transduction molecules, which allowed the selection of possible druggable targets i.e. MEK, JNK, and CREB (Fig. 1B/C). Pharmacological MEK inhibition in primary MLL-rearranged AML demonstrated to be most successful in reducing the AML cell survival, without showing cytotoxicity in NBM (mean MEK inhibitor IC50 of 3.5μM +/- 0.7μM in primary MLL-rearranged AML versus a mean IC50 >50μM in NBM), whereas for CREB and JNK inhibitors MLL-rearranged AML cells were equally affected as NBM cells. Dynamic kinome reprogramming of signaling networks in response to MEK therapy did occur, by inducing the activation of RTKs to bypass the initial MEK inhibitory effects in a MLL-rearranged AML cell line. The dynamic escape mechanism allowed us to predict and test the efficacy of novel combination strategies. Combined MEK and VEGFR-2 inhibition demonstrated to induce cell death sufficiently in MLL-rearranged AML (Fig. 1D). This advantageous strategy allows rational design of successful and selective combination therapies for specific target inhibitors. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Abstract 1567: mTERT genetic vaccine chemotherapy combination augment antigen-specific immune response and confer tumor protection in time dependent fashion

Abstract Successful cancer chemotherapy relies on the comprehensive elimination of tumor cells. However, at clinically tolerated doses, chemotherapeutic drugs usually fail to kill all tumor cells in vivo. Theoretically, to achieve complete eradication, partial tumor killing by chemotherapy should be accompanied by a “bystander effect” in which the immune system recognizes, attacks, and eradicates residual tumor cells. Doxorubicin) is an anthracycline antibiotic that intercalates with DNA, inhibiting its replication. It has been shown that treatment of dendritic cells with Doxorubicin increases their ability to present antigen to Ag-specific T cells in vitro and it is accompanied by upregulation of the Ag-processing machinery (APM) proteins and costimulatory molecules. The telomerase reverse transcriptase, TERT, is an attractive target antigen for cancer vaccine because its expression is reactivated in a conspicuous fraction of human tumors. Critical to the success of combination therapy using TERT vaccine and chemotherapy drugs is a positive (synergistic) interaction between chemotherapy drugs and immune effectors mechanisms. Indeed, activation of antitumor immune responses by vaccine could be antagonized by chemotherapy, if the selected drug exerts immune antagonistic effects. Understanding the dose and the schedule of administration of Doxil (pegylated Doxorubicin) is critical for the design of rational combinations of vaccine and chemotherapy. To test the interactions between TERT vaccine and Doxil we performed a series of experiment using six different therapeutic schedules of Doxil/TERT administration. Interestingly, only two of the Doxil/TERT vaccine combinations resulted in a significant tumor growth inhibition delay which was also accompanied by increase in anti-TERT T cell response. This data unveil new facets of “Chemo immune adjuvancy” of Doxorubicin, and demonstrate how the in vivo efficacy of this combination is impacted by the dosing schedule Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1567. doi:1538-7445.AM2012-1567

RNAi strategies to silence HIV-1

RNAi is a sequence-specific gene silencing mechanism induced by double-stranded RNA and a promising tool for the development of a durable gene therapy against HIV-1. Such RNAi attack usually focuses on targets within the HIV-1 RNA genome. Despite potent inhibition, we previously observed the rapid selection of RNAi-resistant HIV-1 variants with a mutated target sequence. A number of strategies were tested to prevent viral escape. Similar to the success of combination therapy with multiple anti-retroviral drugs, one can target HIV-1 with multiple short hairpin RNAs (shRNAs). Alternatively, one can design second-generation shRNAs to target favorite RNAi-resistance mutations in order to block specific viral escape routes. One could also combine RNAi with regular antiviral drug regimens. Another strategy involves the use of RNAi against cellular proteins that are involved in HIV-1 replication. The idea is that viral escape is more difficult in this setting. Many cellular co-factors have been described in literature, e.g. based on large RNAi-screens in cell lines. We have shown that long-term inhibition of HIV-1 replication is possible with RNAi against cellular co-factors. To identify relevant co-factors that are not essential for cellular function, primary cells are to be preferred over T cell lines. We propose that RNAi against both viral and cellular targets could be used as a new therapeutic approach in the combat against HIV-1 infection.

The therapeutic human CD38 antibody daratumumab improves the anti-myeloma effect of newly emerging multi-drug therapies

The therapeutic human CD38 antibody daratumumab improves the anti-myeloma effect of newly emerging multi-drug therapies

Combination Therapy for Chronic Hepatitis B: Current Indications.

Hepatitis B infection remains a major public health problem globally and in the United States, with significant use of healthcare resources. Several therapeutic agents active against viral and host targets are currently available for its treatment. The success of combination therapy in HIV infection, which has similarities to hepatitis B in both therapeutic targets and treatment options, stimulated studies on the efficacy and safety of various combinations of available drugs in the treatment of hepatitis B infection. In this review, we analyze the current role of combination therapy in chronic hepatitis B infection.

Safety of small molecules in combination with interferon-based therapy for hepatitis C virus

Importance of the field: HCV is a leading cause of liver disease in the US, where ∼ 3.4 million people are chronically infected. The standard of care (SOC) of pegylated IFN and ribavirin combination therapy has limited efficacy with ∼ 50% sustained viral response, and is associated with a considerable adverse event profile in many patients. New drugs that directly target the virus are in development, and promise more effective therapies for chronic HCV infection.Areas covered in this review: Patient sub-classes with poor prognosis with SOC are identified, as are their associated adverse event profiles. Novel drugs, known as specifically targeted antiviral therapy for HCV (STAT-C), are currently being evaluated in clinical trials in multidrug combinations. Emerging safety signals and strategies to identify and prevent viral resistance to STAT-C drugs are also addressed.What the reader will gain: How the multidrug combinations are being developed and tested, what their relative strengths and weakness are, and which patient groups will benefit the most.Take home message: The central questions to successful multidrug combination therapies including novel small molecules will be their composite safety and efficacy profiles. Carefully conducted clinical trials and timely updates will be needed for ongoing improvements in patient care.