Katherine A. Riccione
Duke University
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Featured researches published by Katherine A. Riccione.
Molecular Systems Biology | 2012
Cheemeng Tan; Robert P. Smith; Jaydeep K. Srimani; Katherine A. Riccione; Sameer Prasada; Meta J. Kuehn; Lingchong You
The inoculum effect (IE) refers to the decreasing efficacy of an antibiotic with increasing bacterial density. It represents a unique strategy of antibiotic tolerance and it can complicate design of effective antibiotic treatment of bacterial infections. To gain insight into this phenomenon, we have analyzed responses of a lab strain of Escherichia coli to antibiotics that target the ribosome. We show that the IE can be explained by bistable inhibition of bacterial growth. A critical requirement for this bistability is sufficiently fast degradation of ribosomes, which can result from antibiotic‐induced heat‐shock response. Furthermore, antibiotics that elicit the IE can lead to ‘band‐pass’ response of bacterial growth to periodic antibiotic treatment: the treatment efficacy drastically diminishes at intermediate frequencies of treatment. Our proposed mechanism for the IE may be generally applicable to other bacterial species treated with antibiotics targeting the ribosomes.
Proceedings of the National Academy of Sciences of the United States of America | 2014
Robert P. Smith; Cheemang Tan; Jaydeep K. Srimani; Anand Pai; Katherine A. Riccione; Hao Song; Lingchong You
Significance Understanding how species spread and survive is important in many biological contexts. The ability to disperse has been shown to enhance spread in some species but detract in others. Theoretical studies have predicted that these observations may be due to the Allee effect. To test this theory, we engineered Escherichia coli to have an Allee effect. Using these bacteria, we found that if dispersal is too fast or too slow, a population cannot spread. By manipulating the number of patches, we uncovered tradeoffs that control spread and survival. Finally, we demonstrate that fluctuations in growth may serve to determine if spread occurs. Our results may be useful in controlling invasive species and the spread of infectious diseases. Dispersal is necessary for spread into new habitats, but it has also been shown to inhibit spread. Theoretical studies have suggested that the presence of a strong Allee effect may account for these counterintuitive observations. Experimental demonstration of this notion is lacking due to the difficulty in quantitative analysis of such phenomena in a natural setting. We engineered Escherichia coli to exhibit a strong Allee effect and examined how the Allee effect would affect the spread of the engineered bacteria. We showed that the Allee effect led to a biphasic dependence of bacterial spread on the dispersal rate: spread is promoted for intermediate dispersal rates but inhibited at low or high dispersal rates. The shape of this dependence is contingent upon the initial density of the source population. Moreover, the Allee effect led to a tradeoff between effectiveness of population spread and survival: increasing the number of target patches during dispersal allows more effective spread, but it simultaneously increases the risk of failing to invade or of going extinct. We also observed that total population growth is transiently maximized at an intermediate number of target patches. Finally, we demonstrate that fluctuations in cell growth may contribute to the paradoxical relationship between dispersal and spread. Our results provide direct experimental evidence that the Allee effect can explain the apparently paradoxical effects of dispersal on spread and have implications for guiding the spread of cooperative organisms.
Cancer Research | 2018
Elizabeth A. Reap; Carter M. Suryadevara; Kristen A. Batich; Luis Sanchez-Perez; Gary E. Archer; Robert J. Schmittling; Pamela K. Norberg; James E. Herndon; Patrick Healy; Kendra L. Congdon; Patrick C. Gedeon; Olivia C. Campbell; Adam Swartz; Katherine A. Riccione; John S. Yi; Mohammed K. Hossain-Ibrahim; Anirudh Saraswathula; Smita K. Nair; Anastasie Dunn-Pirio; Taylor M. Broome; Kent J. Weinhold; Annick Desjardins; Gordana Vlahovic; Roger E. McLendon; Allan H. Friedman; Henry S. Friedman; Darell D. Bigner; Peter E. Fecci; Duane A. Mitchell; John H. Sampson
Median survival for glioblastoma (GBM) remains <15 months. Human cytomegalovirus (CMV) antigens have been identified in GBM but not normal brain, providing an unparalleled opportunity to subvert CMV antigens as tumor-specific immunotherapy targets. A recent trial in recurrent GBM patients demonstrated the potential clinical benefit of adoptive T-cell therapy (ATCT) of CMV phosphoprotein 65 (pp65)-specific T cells. However, ex vivo analyses from this study found no change in the capacity of CMV pp65-specific T cells to gain multiple effector functions or polyfunctionality, which has been associated with superior antitumor efficacy. Previous studies have shown that dendritic cells (DC) could further enhance tumor-specific CD8+ T-cell polyfunctionality in vivo when administered as a vaccine. Therefore, we hypothesized that vaccination with CMV pp65 RNA-loaded DCs would enhance the frequency of polyfunctional CMV pp65-specific CD8+ T cells after ATCT. Here, we report prospective results of a pilot trial in which 22 patients with newly diagnosed GBM were initially enrolled, of which 17 patients were randomized to receive CMV pp65-specific T cells with CMV-DC vaccination (CMV-ATCT-DC) or saline (CMV-ATCT-saline). Patients who received CMV-ATCT-DC vaccination experienced a significant increase in the overall frequencies of IFNγ+, TNFα+, and CCL3+ polyfunctional, CMV-specific CD8+ T cells. These increases in polyfunctional CMV-specific CD8+ T cells correlated (R = 0.7371, P = 0.0369) with overall survival, although we cannot conclude this was causally related. Our data implicate polyfunctional T-cell responses as a potential biomarker for effective antitumor immunotherapy and support a formal assessment of this combination approach in a larger randomized study.Significance: A randomized pilot trial in patients with GBM implicates polyfunctional T-cell responses as a biomarker for effective antitumor immunotherapy. Cancer Res; 78(1); 256-64. ©2017 AACR.
Seminars in Oncology | 2014
Patrick C. Gedeon; Katherine A. Riccione; Peter E. Fecci; John H. Sampson
Conventional therapy for malignant glioma (MG) fails to specifically eliminate tumor cells, resulting in toxicity that limits therapeutic efficacy. In contrast, antibody-based immunotherapy uses the immune system to eliminate tumor cells with exquisite specificity. Increased understanding of the pathobiology of MG and the profound immunosuppression present among patients with MG has revealed several biologic targets amenable to antibody-based immunotherapy. Novel antibody engineering techniques allow for the production of fully human antibodies or antibody fragments with vastly reduced antigen-binding dissociation constants, increasing safety when used clinically as therapeutics. In this report, we summarize the use of antibody-based immunotherapy for MG. Approaches currently under investigation include the use of antibodies or antibody fragments to: (1) redirect immune effector cells to target tumor mutations, (2) inhibit immunosuppressive signals and thereby stimulate an immunological response against tumor cells, and (3) provide costimulatory signals to evoke immunologic targeting of tumor cells. These approaches demonstrate highly compelling safety and efficacy for the treatment of MG, providing a viable adjunct to current standard-of-care therapy for MG.
Journal of Visualized Experiments | 2015
Katherine A. Riccione; Carter M. Suryadevara; David Snyder; Xiuyu Cui; John H. Sampson; Luis Sanchez-Perez
Adoptive T cell immunotherapy offers a promising strategy for specifically targeting and eliminating malignant gliomas. T cells can be engineered ex vivo to express chimeric antigen receptors specific for glioma antigens (CAR T cells). The expansion and function of adoptively transferred CAR T cells can be potentiated by the lymphodepletive and tumoricidal effects of standard of care chemotherapy and radiotherapy. We describe a method for generating CAR T cells targeting EGFRvIII, a glioma-specific antigen, and evaluating their efficacy when combined with a murine model of glioblastoma standard of care. T cells are engineered by transduction with a retroviral vector containing the anti-EGFRvIII CAR gene. Tumor-bearing animals are subjected to host conditioning by a course of temozolomide and whole brain irradiation at dose regimens designed to model clinical standard of care. CAR T cells are then delivered intravenously to primed hosts. This method can be used to evaluate the antitumor efficacy of CAR T cells in the context of standard of care.
OncoImmunology | 2018
Carter M. Suryadevara; Rupen Desai; Melissa L. Abel; Katherine A. Riccione; Kristen A. Batich; Steven H. Shen; Pakawat Chongsathidkiet; Patrick C. Gedeon; Aladine A. Elsamadicy; David Snyder; James E. Herndon; Patrick Healy; Gary E. Archer; Bryan D. Choi; Peter E. Fecci; John H. Sampson; Luis Sanchez-Perez
ABSTRACT Adoptive 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).
Clinical Cancer Research | 2016
Carter M. Suryadevara; Katherine A. Riccione; John H. Sampson
Oncolytic viruses, proteasome inhibitors, and natural killer (NK)-cell immunotherapy have all been studied extensively as monotherapies but have never been evaluated in combination. Synergetic treatment of oncolytic virus–infected glioblastomas with a proteasome inhibitor induces necroptotic cell death to enhance NK-cell immunotherapy, prolonging survival against human glioblastoma. Clin Cancer Res; 22(21); 5164–6. ©2016 AACR. See related article by Yoo et al., p. 5265
OncoImmunology | 2018
Katherine A. Riccione; Li-Zhen He; Peter E. Fecci; Pamela K. Norberg; Carter M. Suryadevara; Adam Swartz; Patrick Healy; Elizabeth A. Reap; Tibor Keler; Qi-Jing Li; Kendra L. Congdon; Luis Sanchez-Perez; John H. Sampson
ABSTRACT Despite their promise, tumor-specific peptide vaccines have limited efficacy. CD27 is a costimulatory molecule expressed on CD4+ and CD8+ T cells that is important in immune activation. Here we determine if a novel CD27 agonist antibody (αhCD27) can enhance the antitumor T cell response and efficacy of peptide vaccines. We evaluated the effects of αhCD27 on the immunogenicity and antitumor efficacy of whole protein, class I-restricted, and class II-restricted peptide vaccines using a transgenic mouse expressing human CD27. We found that αhCD27 preferentially enhances the CD8+ T cell response in the setting of vaccines comprised of linked class I and II ovalbumin epitopes (SIINFEKL and TEWTSSNVMEERKIKV, respectively) compared to a peptide vaccine comprised solely of SIINFEKL, resulting in the antitumor efficacy of adjuvant αhCD27 against intracranial B16.OVA tumors when combined with vaccines containing linked class I/II ovalbumin epitopes. Indeed, we demonstrate that this efficacy is both CD8- and CD4-dependent and αhCD27 activity on ovalbumin-specific CD4+ T cells is necessary for its adjuvant effect. Importantly for clinical translation, a linked universal CD4+ helper epitope (tetanus P30) was sufficient to instill the efficacy of SIINFEKL peptide combined with αhCD27, eliminating the need for a tumor-specific class II-restricted peptide. This approach unveiled the efficacy of a class I-restricted peptide vaccine derived from the tumor-associated Trp2 antigen in mice bearing intracranial B16 tumors. CD27 agonist antibodies combined with peptide vaccines containing linked tumor-specific CD8+ epitopes and tumor-specific or universal CD4+ epitopes enhance the efficacy of active cancer immunotherapy.
Translational Immunotherapy of Brain Tumors | 2017
Katherine A. Riccione; Patrick C. Gedeon; Luis Sanchez-Perez; John H. Sampson
Abstract Conventional therapy for glioblastoma (GBM) fails to specifically target and eliminate tumor cells, resulting in nonspecific toxicity that limits therapeutic efficacy. In contrast, immunotherapy utilizes the immune system to eradicate tumor cells with exquisite specificity. Specifically, checkpoint blockade therapy has emerged as a promising strategy for reducing tumor-mediated immunosuppression and promoting endogenous antitumor T cell responses. Recent approvals by the Food and Drug and Administration for the novel immune therapeutics ipilimumab and nivolumab have served to validate this overall treatment modality. In this chapter, we summarize the clinical progress of antibody-based checkpoint blockade and its relevance to GBM immunotherapy. We provide an overview of immune checkpoint biology in cancer, the feasibility of antibody-based immunomodulation as a therapeutic strategy for central nervous system malignancies, preclinical and clinical experiences with checkpoint therapy, and the ongoing progress of checkpoint blockade for GBM treatment.Conventional therapy for glioblastoma (GBM) fails to specifically target and eliminate tumor cells, resulting in nonspecific toxicity that limits therapeutic efficacy. In contrast, immunotherapy utilizes the immune system to eradicate tumor cells with exquisite specificity. Specifically, checkpoint blockade therapy has emerged as a promising strategy for reducing tumor-mediated immunosuppression and promoting endogenous antitumor T cell responses. Recent approvals by the Food and Drug and Administration for the novel immune therapeutics ipilimumab and nivolumab have served to validate this overall treatment modality. In this chapter, we summarize the clinical progress of antibody-based checkpoint blockade and its relevance to GBM immunotherapy. We provide an overview of immune checkpoint biology in cancer, the feasibility of antibody-based immunomodulation as a therapeutic strategy for central nervous system malignancies, preclinical and clinical experiences with checkpoint therapy, and the ongoing progress of checkpoint blockade for GBM treatment.
ACS Synthetic Biology | 2012
Katherine A. Riccione; Robert P. Smith; Anna J. Lee; Lingchong You