Felipe Bedoya
University of Pennsylvania
Network
Latest external collaboration on country level. Dive into details by clicking on the dots.
Publication
Featured researches published by Felipe Bedoya.
Nature Medicine | 2018
Joseph A. Fraietta; Simon F. Lacey; Elena Orlando; Iulian Pruteanu-Malinici; Mercy Gohil; Stefan Lundh; Alina C. Boesteanu; Yan Wang; Roddy S. O’Connor; Wei-Ting Hwang; Edward Pequignot; David E Ambrose; Changfeng Zhang; Nicholas Wilcox; Felipe Bedoya; Corin Dorfmeier; Fang Chen; Lifeng Tian; Harit Parakandi; Minnal Gupta; Regina M. Young; F. Brad Johnson; Irina Kulikovskaya; Li Liu; Jun Xu; Sadik Kassim; Megan M. Davis; Bruce L. Levine; Noelle V. Frey; Don L. Siegel
Tolerance to self-antigens prevents the elimination of cancer by the immune system1,2. We used synthetic chimeric antigen receptors (CARs) to overcome immunological tolerance and mediate tumor rejection in patients with chronic lymphocytic leukemia (CLL). Remission was induced in a subset of subjects, but most did not respond. Comprehensive assessment of patient-derived CAR T cells to identify mechanisms of therapeutic success and failure has not been explored. We performed genomic, phenotypic and functional evaluations to identify determinants of response. Transcriptomic profiling revealed that CAR T cells from complete-responding patients with CLL were enriched in memory-related genes, including IL-6/STAT3 signatures, whereas T cells from nonresponders upregulated programs involved in effector differentiation, glycolysis, exhaustion and apoptosis. Sustained remission was associated with an elevated frequency of CD27+CD45RO–CD8+ T cells before CAR T cell generation, and these lymphocytes possessed memory-like characteristics. Highly functional CAR T cells from patients produced STAT3-related cytokines, and serum IL-6 correlated with CAR T cell expansion. IL-6/STAT3 blockade diminished CAR T cell proliferation. Furthermore, a mechanistically relevant population of CD27+PD-1–CD8+ CAR T cells expressing high levels of the IL-6 receptor predicts therapeutic response and is responsible for tumor control. These findings uncover new features of CAR T cell biology and underscore the potential of using pretreatment biomarkers of response to advance immunotherapies.An IL-6/STAT3 signature and memory CD8 T cell subset in preinfusion chimeric antigen receptor–expressing T cells associate with response in patients with high-risk chronic lymphocytic leukemia.
Molecular Therapy | 2016
Saba Ghassemi; Felipe Bedoya; Selene Nunez-Cruz; Carl H. June; Jos Melenhorst; Michael C. Milone
Adoptive T cell immunotherapy involves the isolation, ex vivo expansion and reinfusion of patient T cells. The efficacy of adoptive immunotherapy is dependent on the ability of T cells to engraft, expand and persist upon adoptive transfer. In this therapy, T cells are cultured ex vivo using natural or artificial antigen presenting cells that deliver signal 1 (TCR/CD3) and signal 2 (e.g. CD28 co-stimulation) along with exogenously added cytokines. IL-2 is the most commonly used cytokine for ex vivo T cell culture; however, there is renewed interest in IL-7 and IL-15 due to their ability to enhance the survival and proliferation of stem cell memory (Tscm) and central memory (Tcm) T cells. We show that primary human T cells freshly isolated from peripheral blood are heterogeneous with substantial numbers of Tscm and Tcm cells in addition to effector differentiated T cells. During ex vivo culture, these cells progressively differentiate into a population of T cells with a predominantly CD45RO+, CD27-, CCR7- effector differentiated phenotype. Exogenous IL-7 and IL-15 delay this transition in T cell phenotype and preserve a greater proportion of Tscm and Tcm cells in the final ex vivo culture product. We hypothesize that limited ex vivo culture of T cells in the presence of IL-7 and IL-15 rather than IL-2 will enhance engraftment and persistence of T cells in vivo contributing to enhanced efficacy in adoptive transfer. We show that T cells can be harvested and viably frozen from ex vivo cultures as early as day 3 following activation. Early activated T cells expressing a chimeric antigen receptor targeting CD19 (CART-19) show potent yet specific cytotoxicity and cytokine production in vitro. We investigated the therapeutic potential of cells harvested at day 3 versus later time points using a Nalm-6 leukemic cell xenograft mouse model. We demonstrate that day 3 CART-19 cells show potent anti-leukemic activity compared to day 5 or day 9 cells. Comparing CART19 cells cultured in either IL-2 or IL-7/15, we show that mice treated at a 10-fold lower dose with day 3 cells cultured in IL-7/15 exhibit the greatest anti-leukemic efficacy compared with day 9 cells where the latter fail to control leukemia. In summary, we show that limiting T cell culture ex vivo to the minimum required for lentiviral transduction in the presence of IL-7 and IL-15 provides the most efficacious T cells for adoptive T cell immunotherapy.
Cancer immunology research | 2018
Saba Ghassemi; Selene Nunez-Cruz; Roddy S. O'Connor; Joseph A. Fraietta; Prachi R. Patel; John Scholler; David M. Barrett; Stefan Lundh; Megan M. Davis; Felipe Bedoya; Changfeng Zhang; John Leferovich; Simon F. Lacey; Bruce L. Levine; Stephan A. Grupp; Carl H. June; J. Joseph Melenhorst; Michael C. Milone
The efficacy of CAR T-cell therapy depends on the engraftment and persistence of T cells following adoptive transfer. Limiting ex vivo culture time of CD19-specific CAR T cells during manufacturing yielded improved persistence and effector function in vivo. The success of chimeric antigen receptor (CAR)–mediated immunotherapy in acute lymphoblastic leukemia (ALL) highlights the potential of T-cell therapies with directed cytotoxicity against specific tumor antigens. The efficacy of CAR T-cell therapy depends on the engraftment and persistence of T cells following adoptive transfer. Most protocols for T-cell engineering routinely expand T cells ex vivo for 9 to 14 days. Because the potential for engraftment and persistence is related to the state of T-cell differentiation, we hypothesized that reducing the duration of ex vivo culture would limit differentiation and enhance the efficacy of CAR T-cell therapy. We demonstrated that T cells with a CAR-targeting CD19 (CART19) exhibited less differentiation and enhanced effector function in vitro when harvested from cultures at earlier (day 3 or 5) compared with later (day 9) timepoints. We then compared the therapeutic potential of early versus late harvested CART19 in a murine xenograft model of ALL and showed that the antileukemic activity inversely correlated with ex vivo culture time: day 3 harvested cells showed robust tumor control despite using a 6-fold lower dose of CART19, whereas day 9 cells failed to control leukemia at limited cell doses. We also demonstrated the feasibility of an abbreviated culture in a large-scale current good manufacturing practice–compliant process. Limiting the interval between T-cell isolation and CAR treatment is critical for patients with rapidly progressing disease. Generating CAR T cells in less time also improves potency, which is central to the effectiveness of these therapies. Cancer Immunol Res; 6(9); 1100–9. ©2018 AACR.
Current Drug Targets | 2017
J. Joseph Melenhorst; Simon F. Lacey; Felipe Bedoya
The chimeric antigen receptor (CAR) technology started out as a tool to understand lymphocyte biology but rapidly developed into a T cell therapeutic agent for the treatment of cancers. Here, we describe the technological advances in the field of CARs and highlight critical components of its success. Additionally, we describe how various laboratories have worked toward developing new, safer, and more potent CARs for cancer.
Blood | 2016
Joseph A. Fraietta; Simon F. Lacey; Nicholas Wilcox; Felipe Bedoya; Fang Chen; Elena Orlando; Jennifer Brogdon; Wei-Ting Hwang; Noelle Frey; Regina M. Young; Edward Pequignot; David E Ambrose; Bruce L. Levine; Hans Bitter; David L. Porter; Jun Xu; Carl H. June; J. Joseph Melenhorst
Blood | 2017
Joseph A. Fraietta; Simon F. Lacey; Elena Orlando; Julian Pruteanu; Mercy Gohil; Yan Wang; Alina C. Boesteanu; Roddy S. O'Connor; David E Ambrose; Wei-Ting Hwang; Nicholas Wilcox; Felipe Bedoya; Corin Dorfmeier; Fang Chen; Harit Parakandi; Minnal Gupta; Edward Pequignot; F. Brad Johnson; Irina Kulikovskaya; Li Liu; Stefan Lundh; Jun Xu; Megan M. Davis; Regina M. Young; Bruce L. Levine; Don L. Siegel; Alexander C. Huang; E. John Wherry; Jing Zhou; Patrick Paczkowski
Blood | 2016
Saba Ghassemi; Patel Prachi; John Scholler; Selene Nunez-Cruz; David M. Barrett; Felipe Bedoya; Joseph A. Fraietta; Simon F. Lacey; Bruce L. Levine; S. Grupp; Carl H. June; Michael C. Milone; J. Joseph Melenhorst
Journal of Clinical Oncology | 2018
Elena Orlando; Rebecca J. Leary; Simon F. Lacey; Joseph A. Fraietta; Felipe Bedoya; David E Ambrose; Nicholas Wilcox; Shannon L. Maude; Noelle V. Frey; Bruce L. Levine; Stephan A. Grupp; David L. Porter; Regina M. Young; Wendy Winckler; Michael Morrissey; Carl H. June; J. Joseph Melenhorst; Jennifer Brogdon; Hans Bitter
Archive | 2017
Z. Zheng; Daniel J. Powell; Michael C. Milone; Jan J. Melenhorst; Bruce L. Levine; Carl H. June; Saba Ghassemi; Felipe Bedoya
Archive | 2017
Z. Zheng; Daniel J. Powell; Michael C. Milone; Jan J. Melenhorst; Omkar U. Kawalekar; Bruce L. Levine; Carl H. June; Saba Ghassemi; Felipe Bedoya