Browsing by Subject "immunotherapy"
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Item Open Access A randomized phase 2 trial of pembrolizumab versus pembrolizumab and acalabrutinib in patients with platinum-resistant metastatic urothelial cancer.(Cancer, 2020-08-05) Zhang, Tian; Harrison, Michael R; O'Donnell, Peter H; Alva, Ajjai S; Hahn, Noah M; Appleman, Leonard J; Cetnar, Jeremy; Burke, John M; Fleming, Mark T; Milowsky, Matthew I; Mortazavi, Amir; Shore, Neal; Sonpavde, Guru P; Schmidt, Emmett V; Bitman, Bojena; Munugalavadla, Veerendra; Izumi, Raquel; Patel, Priti; Staats, Janet; Chan, Cliburn; Weinhold, Kent J; George, Daniel JBACKGROUND:Inhibition of the programmed cell death protein 1 (PD-1) pathway has demonstrated clinical benefit in metastatic urothelial cancer (mUC); however, response rates of 15% to 26% highlight the need for more effective therapies. Bruton tyrosine kinase (BTK) inhibition may suppress myeloid-derived suppressor cells (MDSCs) and improve T-cell activation. METHODS:The Randomized Phase 2 Trial of Acalabrutinib and Pembrolizumab Immunotherapy Dual Checkpoint Inhibition in Platinum-Resistant Metastatic Urothelial Carcinoma (RAPID CHECK; also known as ACE-ST-005) was a randomized phase 2 trial evaluating the PD-1 inhibitor pembrolizumab with or without the BTK inhibitor acalabrutinib for patients with platinum-refractory mUC. The primary objectives were safety and objective response rates (ORRs) according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Immune profiling was performed to analyze circulating monocytic MDSCs and T cells. RESULTS:Seventy-five patients were treated with pembrolizumab (n = 35) or pembrolizumab plus acalabrutinib (n = 40). The ORR was 26% with pembrolizumab (9% with a complete response [CR]) and 20% with pembrolizumab plus acalabrutinib (10% with a CR). The grade 3/4 adverse events (AEs) that occurred in ≥15% of the patients were anemia (20%) with pembrolizumab and fatigue (23%), increased alanine aminotransferase (23%), urinary tract infections (18%), and anemia (18%) with pembrolizumab plus acalabrutinib. One patient treated with pembrolizumab plus acalabrutinib had high MDSCs at the baseline, which significantly decreased at week 7. Overall, MDSCs were not correlated with a clinical response, but some subsets of CD8+ T cells did increase during the combination treatment. CONCLUSIONS:Both treatments were generally well tolerated, although serious AE rates were higher with the combination. Acalabrutinib plus pembrolizumab did not improve the ORR, PFS, or OS in comparison with pembrolizumab alone in mUC. Baseline and on-treatment peripheral monocytic MDSCs were not different in the treatment cohorts. Proliferating CD8+ T-cell subsets increased during treatment, particularly in the combination cohort. Ongoing studies are correlating these peripheral immunome findings with tissue-based immune cell infiltration.Item Open Access Bispecific Antibody Therapy for Effective Cardiac Repair through Redirection of Endogenous Stem Cells(Advanced Therapeutics, 2019-10-01) Huang, K; Li, Z; Su, T; Shen, D; Hu, S; Cheng, KBone marrow stem cells (BMSCs) are a promising strategy for cardiac regenerative therapy for myocardial infarction (MI). However, cell transplantation has to overcome a number of hurdles, such as cell quality control, clinical practicality, low cell retention/engraftment, and immune reactions when allogeneic cells are used. Bispecific antibodies (BsAbs) have been developed as potential agents in cancer immunotherapy but their application is sparse in cardiovascular diseases. In the present study, BsAbs are designed by chemical cycloaddition of F(ab′)2 fragments from monoclonal anti-CD34 and anti- cardiac myosin heavy chain (CMHC) antibodies, which specifically targets circulating CD34-positive cells and injured cardiomyocytes simultaneously. It is hypothesized that intravenous administration of stem cell re-directing (SCRD) BsAbs (anti-CD34-F(ab′)2–anti-CMHC-F(ab′)2) can home endogenous BMSCs to the injured heart for cardiac repair. The in vivo studies in a mouse model with heart ischemia/reperfusion (I/R) injury demonstrate the safety and therapeutic potency of SCRD BsAb, which supports cardiac recovery by reducing scarring, promoting angiomyogenesis, and boosting cardiac function.Item Open Access Development and Characterization of a Luciferase Labeled, Syngeneic Murine Model of Ovarian Cancer.(Cancers, 2022-08) Russell, Shonagh; Lim, Felicia; Peters, Pamela N; Wardell, Suzanne E; Whitaker, Regina; Chang, Ching-Yi; Previs, Rebecca A; McDonnell, Donald PDespite advances in surgery and targeted therapies, the prognosis for women with high-grade serous ovarian cancer remains poor. Moreover, unlike other cancers, immunotherapy has minimally impacted outcomes in patients with ovarian cancer. Progress in this regard has been hindered by the lack of relevant syngeneic ovarian cancer models to study tumor immunity and evaluate immunotherapies. To address this problem, we developed a luciferase labeled murine model of high-grade serous ovarian cancer, STOSE.M1 luc. We defined its growth characteristics, immune cell repertoire, and response to anti PD-L1 immunotherapy. As with human ovarian cancer, we demonstrated that this model is poorly sensitive to immune checkpoint modulators. By developing the STOSE.M1 luc model, it will be possible to probe the mechanisms underlying resistance to immunotherapies and evaluate new therapeutic approaches to treat ovarian cancer.Item Open Access First-line treatment of metastatic melanoma: role of nivolumab.(Immunotargets Ther, 2017) Force, Jeremy; Salama, April KsHistorically, the median overall survival of metastatic melanoma patients was less than 1 year and long-term survivors were rare. Recent advances in therapies have dramatically shifted this landscape with increased survival rates and the real possibility that long-term disease control is achievable. Advances in immune modulators, including cytotoxic T-lymphocyte antigen-4 and programmed death-1 based treatments, have been an integral part of this success. In this article, we review previous and recent therapeutic developments for metastatic melanoma patients. We discuss advances in immunotherapy while focusing on the use of nivolumab alone and in combination with other agents, including ipilimumab in advanced melanoma. One major goal in melanoma research is to optimize combination strategies allowing for more patients to experience benefit while minimizing toxicity. A better understanding of the optimal sequencing, combinations, and mechanisms underlying the development of resistance may provide evidence for rational clinical trial designs of novel immunotherapy strategies in melanoma and other cancer subtypes.Item Open Access Genome-wide prediction of synthetic rescue mediators of resistance to targeted and immunotherapy.(Molecular systems biology, 2019-03-11) Sahu, Avinash Das; S Lee, Joo; Wang, Zhiyong; Zhang, Gao; Iglesias-Bartolome, Ramiro; Tian, Tian; Wei, Zhi; Miao, Benchun; Nair, Nishanth Ulhas; Ponomarova, Olga; Friedman, Adam A; Amzallag, Arnaud; Moll, Tabea; Kasumova, Gyulnara; Greninger, Patricia; Egan, Regina K; Damon, Leah J; Frederick, Dennie T; Jerby-Arnon, Livnat; Wagner, Allon; Cheng, Kuoyuan; Park, Seung Gu; Robinson, Welles; Gardner, Kevin; Boland, Genevieve; Hannenhalli, Sridhar; Herlyn, Meenhard; Benes, Cyril; Flaherty, Keith; Luo, Ji; Gutkind, J Silvio; Ruppin, EytanMost patients with advanced cancer eventually acquire resistance to targeted therapies, spurring extensive efforts to identify molecular events mediating therapy resistance. Many of these events involve synthetic rescue (SR) interactions, where the reduction in cancer cell viability caused by targeted gene inactivation is rescued by an adaptive alteration of another gene (the rescuer). Here, we perform a genome-wide in silico prediction of SR rescuer genes by analyzing tumor transcriptomics and survival data of 10,000 TCGA cancer patients. Predicted SR interactions are validated in new experimental screens. We show that SR interactions can successfully predict cancer patients' response and emerging resistance. Inhibiting predicted rescuer genes sensitizes resistant cancer cells to therapies synergistically, providing initial leads for developing combinatorial approaches to overcome resistance proactively. Finally, we show that the SR analysis of melanoma patients successfully identifies known mediators of resistance to immunotherapy and predicts novel rescuers.Item Open Access Glioblastoma as an age-related neurological disorder in adults.(Neuro-oncology advances, 2021-01) Kim, Miri; Ladomersky, Erik; Mozny, Andreas; Kocherginsky, Masha; O'Shea, Kaitlyn; Reinstein, Zachary Z; Zhai, Lijie; Bell, April; Lauing, Kristen L; Bollu, Lakshmi; Rabin, Erik; Dixit, Karan; Kumthekar, Priya; Platanias, Leonidas C; Hou, Lifang; Zheng, Yinan; Wu, Jennifer; Zhang, Bin; Hrachova, Maya; Merrill, Sarah A; Mrugala, Maciej M; Prabhu, Vikram C; Horbinski, Craig; James, Charles David; Yamini, Bakhtiar; Ostrom, Quinn T; Johnson, Margaret O; Reardon, David A; Lukas, Rimas V; Wainwright, Derek ABackground
Advanced age is a major risk factor for the development of many diseases including those affecting the central nervous system. Wild-type isocitrate dehydrogenase glioblastoma (IDHwt GBM) is the most common primary malignant brain cancer and accounts for ≥90% of all adult GBM diagnoses. Patients with IDHwt GBM have a median age of diagnosis at 68-70 years of age, and increasing age is associated with an increasingly worse prognosis for patients with this type of GBM.Methods
The Surveillance, Epidemiology, and End Results, The Cancer Genome Atlas, and the Chinese Glioma Genome Atlas databases were analyzed for mortality indices. Meta-analysis of 80 clinical trials was evaluated for log hazard ratio for aging to tumor survivorship.Results
Despite significant advances in the understanding of intratumoral genetic alterations, molecular characteristics of tumor microenvironments, and relationships between tumor molecular characteristics and the use of targeted therapeutics, life expectancy for older adults with GBM has yet to improve.Conclusions
Based upon the results of our analysis, we propose that age-dependent factors that are yet to be fully elucidated, contribute to IDHwt GBM patient outcomes.Item Open Access LRP1B mutations are associated with favorable outcomes to immune checkpoint inhibitors across multiple cancer types.(Journal for immunotherapy of cancer, 2021-03) Brown, Landon C; Tucker, Matthew D; Sedhom, Ramy; Schwartz, Eric B; Zhu, Jason; Kao, Chester; Labriola, Matthew K; Gupta, Rajan T; Marin, Daniele; Wu, Yuan; Gupta, Santosh; Zhang, Tian; Harrison, Michael R; George, Daniel J; Alva, Ajjai; Antonarakis, Emmanuel S; Armstrong, Andrew JBackground
Low-density lipoprotein receptor-related protein 1b (encoded by LRP1B) is a putative tumor suppressor, and preliminary evidence suggests LRP1B-mutated cancers may have improved outcomes with immune checkpoint inhibitors (ICI).Methods
We conducted a multicenter, retrospective pan-cancer analysis of patients with LRP1B alterations treated with ICI at Duke University, Johns Hopkins University (JHU) and University of Michigan (UM). The primary objective was to assess the association between overall response rate (ORR) to ICI and pathogenic or likely pathogenic (P/LP) LRP1B alterations compared with LRP1B variants of unknown significance (VUS). Secondary outcomes were the associations with progression-free survival (PFS) and overall survival (OS) by LRP1B status.Results
We identified 101 patients (44 Duke, 35 JHU, 22 UM) with LRP1B alterations who were treated with ICI. The most common tumor types by alteration (P/LP vs VUS%) were lung (36% vs 49%), prostate (9% vs 7%), sarcoma (5% vs 7%), melanoma (9% vs 0%) and breast cancer (3% vs 7%). The ORR for patients with LRP1B P/LP versus VUS alterations was 54% and 13%, respectively (OR 7.5, 95% CI 2.9 to 22.3, p=0.0009). P/LP LRP1B alterations were associated with longer PFS (HR 0.42, 95% CI 0.26 to 0.68, p=0.0003) and OS (HR 0.62, 95% CI 0.39 to 1.01, p=0.053). These results remained consistent when excluding patients harboring microsatellite instability (MSI) and controlling for tumor mutational burden (TMB).Conclusions
This multicenter study shows significantly better outcomes with ICI therapy in patients harboring P/LP versus VUS LRP1B alterations, independently of TMB/MSI status. Further mechanistic and prospective validation studies are warranted.Item Open Access Temozolomide lymphodepletion enhances CAR abundance and correlates with antitumor efficacy against established glioblastoma.(Oncoimmunology, 2018-01) Suryadevara, Carter M; Desai, Rupen; Abel, Melissa L; Riccione, Katherine A; Batich, Kristen A; Shen, Steven H; Chongsathidkiet, Pakawat; Gedeon, Patrick C; Elsamadicy, Aladine A; Snyder, David J; Herndon, James E; Healy, Patrick; Archer, Gary E; Choi, Bryan D; Fecci, Peter E; Sampson, John H; Sanchez-Perez, LuisAdoptive transfer of T cells expressing chimeric antigen receptors (CARs) is an effective immunotherapy for B-cell malignancies but has failed in some solid tumors clinically. Intracerebral tumors may pose challenges that are even more significant. In order to devise a treatment strategy for patients with glioblastoma (GBM), we evaluated CARs as a monotherapy in a murine model of GBM. CARs exhibited poor expansion and survival in circulation and failed to treat syngeneic and orthotopic gliomas. We hypothesized that CAR engraftment would benefit from host lymphodepletion prior to immunotherapy and that this might be achievable by using temozolomide (TMZ), which is standard treatment for these patients and has lymphopenia as its major side effect. We modelled standard of care temozolomide (TMZSD) and dose-intensified TMZ (TMZDI) in our murine model. Both regimens are clinically approved and provide similar efficacy. Only TMZDI pretreatment prompted dramatic CAR proliferation and enhanced persistence in circulation compared to treatment with CARs alone or TMZSD + CARs. Bioluminescent imaging revealed that TMZDI + CARs induced complete regression of 21-day established brain tumors, which correlated with CAR abundance in circulation. Accordingly, TMZDI + CARs significantly prolonged survival and led to long-term survivors. These findings are highly consequential, as it suggests that GBM patients may require TMZDI as first line chemotherapy prior to systemic CAR infusion to promote CAR engraftment and antitumor efficacy. On this basis, we have initiated a phase I trial in patients with newly diagnosed GBM incorporating TMZDI as a preconditioning regimen prior to CAR immunotherapy (NCT02664363).Item Embargo The Role of Akkermansia Species and Subspecies in Human Health(2024) Mueller, Katherine DianneAkkermansia are mucin-degrading bacteria commonly found in the human gastrointestinal (GI) tract. The prevalence and abundance of these bacteria, notably Akkermansia muciniphila, are correlated with immunological and metabolic health in humans and have gained notoriety as a potential next-generation probiotic. Until recently, A. muciniphila was the only species of the phylum Verrucomicrobia identified in the human GI tract. However, it is increasingly clear that Akkermansia in the GI tract are diverse and that there are several human-associated Akkermansia species with significantly larger genomes than A. muciniphila. I hypothesize that this added genetic content may impact how various subgroups of Akkermansia modulate host immunological and metabolic health.To define the breadth of diversity within the genus Akkermansia, I conducted a pangenomic analysis of 234 Akkermansia genomes. My findings based on average nucleotide identity, full-length 16S rRNA gene identity, and conservation among core Akkermansia genes identified a novel group of Akkermansia and indicated that the genus Akkermansia should be split into several species. Further analysis of fatty acid composition and biochemical characterization of representative isolates supported this notion. Additionally, I found that A. muciniphila sensu stricto, the most prevalent Akkermansia species in humans, should be subdivided into two subspecies clades. Having defined species boundaries between strains that were previously all classified as one, I next sought to determine if these distinctions are relevant to the previously established correlations between Akkermansia and human health. To this end, I employed high-resolution species and clade assignments to reanalyze publicly available metagenomic datasets to determine if there are species or clade-specific relationships between Akkermansia and various disease outcomes. I observed species-specific correlations between Akkermansia abundance and obesity in a pediatric cohort. For a set of inflammatory bowel disease cohorts, I identified species-specific and clade-specific decreased abundance of Akkermansia in patients with Crohn’s disease or ulcerative colitis. In patients who had undergone hematopoietic cell transplantation, I found no correlation between Akkermansia species or phylogroups and graph-versus-host-disease development. In patients undergoing immune checkpoint inhibitor therapies for non-small cell lung cancer, I observed a significant association between one A. muciniphila clade and survival outcomes. Additionally, I showed that these species-predictive methods could be applied to additional species of Akkermansia and another mucophilic gastrointestinal bacterium, Ruminococcus gnavus. Finally, I described variability in biofilm production across isolates of the Akkermansia genus. I describe the generation of a library of transposon mutants in one biofilm-producing strain, Akk147, providing a possible link between mucin degradation and biofilm production in modulating the association between Akkermansia and the host. Finally, I tested whether biofilm production enhances the colonization ability of three A. muciniphila isolates of varying biofilm-production and determined that in vitro biofilm production does not enhance colonization of the murine GI tract. Overall, my findings suggest that the prevalence of specific Akkermansia species and clades may be crucial in evaluating their association with host health, and thus their usefulness in promoting health. As these associations differ between disease contexts, making these distinctions should be an important consideration when using Akkermansia as a probiotic or therapeutic supplement.
Item Open Access Videos of Sipuleucel-T Programmed T Cells Lysing Cells That Express Prostate Cancer Target Antigens.(Journal of the National Cancer Institute, 2021-02-25) Kibel, Adam S; Inman, Brant A; Pachynski, Russell K; Vu, Tuyen; Sheikh, Nadeem A; Petrylak, Daniel PSipuleucel-T, an autologous cellular immunotherapy, was approved to treat metastatic castration-resistant prostate cancer in 2010 in the United States. Treatment with sipuleucel-T primes the immune system to target prostate acid phosphatase (PAP), which is expressed by prostate cancer cells, potentially leading to lysis of cancer cell. Expanding upon previously reported indirect evidence of cell killing with sipuleucel-T treatment, we sought to provide direct evidence of cell lysis through visualization. We used advanced video technology and available samples of peripheral blood mononuclear cells from subjects enrolled in the STAMP trial (NCT01487863). Isolated CD8+ T cells were used as effector cells and co-cultured with autologous monocytes pulsed with control or target antigens. Differentially stained effector and target cells were then video-recorded during co-culture. Here, we present video recordings and analyses of T cells from sipuleucel-T-treated subjects showing-for the first time-direct lysis of cells that express prostate cancer target antigens, PAP or prostate-specific antigen.