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AM Seminar / Treatment optimization to address acquired resistance and therapeutic failure during immunotherapy

Speaker Name: 
Vanessa Jonsson
Speaker Title: 
Assistant Research Professor,
Speaker Organization: 
Department of Hematology at City of Hope
Start Time: 
Monday, April 20, 2020 - 4:00pm
End Time: 
Monday, April 20, 2020 - 5:00pm
via Zoom presentation
Marcella Gomez


One of the challenges facing immunotherapy as a durable therapeutic approach for cancer is the development of acquired resistance: long term success in patients will depend on understanding the dynamics of host immunity, cancer and immunotherapy.  Chimeric antigen receptor (CAR) T cell therapy is a targeted cellular immunotherapy whereby T cells are genetically engineered to recognize and target tumor antigens. CAR T cell therapies have been effective for the treatment of hematological malignancies; however, in solid tumors, clinical response is transient, and often within months of treatment initiation, resistance emerges.  In this talk, we propose techniques for the combined analysis of patient-derived longitudinal genomic and immunological profiling data to simultaneously 1) identify the dynamics of host immunity during immunotherapy, and 2) uncover cancer immune cell mechanisms driving immunotherapy resistance. To do this, we collected and of longitudinal, single cell RNA sequencing of tumor, peripheral blood and cerebrospinal fluid samples in a patient with recurrent multifocal glioblastoma that received CAR T cells targeting the tumor-associated antigen interleukin-13 receptor alpha 2. This patient’s disease course – a remarkable regression of all tumors for 7.5 months followed by a recurrence – provided the opportunity to characterize the longitudinal dynamics of cancer immunity during response and recurrence in a clinical setting.  The second part of the talk will focus on the observation that CAR T cells targeting a single antigen can drive the emergence of minor, co-existing clonal populations lacking antigen expression—thereby promoting tumor progression. We will discuss the development of a model that describes the dynamics of cancer growth and response to CAR T cell therapy and a receding horizon control formulation to synthesize switching treatment strategies that maximize tumor regression and minimize toxicity. We illustrate the algorithm and show that temporal dosing schedules can control tumors with heterogenous antigen expression. This model sets a framework by which to assess the effectiveness of adaptive CAR T cell treatment strategies, clinical trial design and patient stratification.


Vanessa Jonsson is an Assistant Research Professor in the Department of Hematology at City of Hope, where she leads a research group in computational systems immunology.  Her research program in computational biology focusses on the integration, mathematical modeling and analysis of large-scale, longitudinal genomic, transcriptomic and immunological data from clinical studies to inform and address the mechanisms of immune-resistant cancer progression.  She received a BS and MA in Mathematics from the University of Southern California and a PhD from the California Institute of Technology, where she was advised by Richard Murray (Control and Dynamical Systems) and David Baltimore (Biology). She is a principal investigator on a Parker Institute for Cancer Immunotherapy award to model the evolution of cancer immunity during CAR T cell therapy, and lead investigator on several CAR T cell therapy clinical trials.  She is the recipient of the K12 National Cancer Institute career development award in immuno- oncology.  Prior to her doctoral studies, Vanessa Jonsson was an engineer at NASA’s Jet Propulsion Laboratory, where she designed and implemented flight software for the Aquarius Mission and DARPA’s Urban Challenge.

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