Engineering viral-specific T cells with improved function and persistence

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

Chronic viral infections, including HIV, HCV, HBV remain a major cause of morbidity and mortality. For HIV, antiretroviral therapy (ART) can suppress viral replication allowing many people with HIV to lead a normal life. Nevertheless, even well-controlled HIV is associated with substantial negative effects on overall health. As a result, there has been considerable interest in immune-based approaches for a functional cure in HIV. Several bone marrow (BM) transplant recipients have now been cured of persisting HIV using BM from a person with the ∆32 mutation in CCR5 that prevents HIV infection. Building on these observations, investigators on this P01 have combined this concept with HIV-targeted chimeric antigen receptor (CAR) T cells for HIV cure. CAR T cells have revolutionized cancer treatment. Now, these “living drugs” can be genetically engineered to possess new properties to control disease. Clinical trials conducted by members of this P01 using HIV-specific CAR T cells have, indeed, demonstrated the ability of HIV-specific CAR T cells to delay viral rebound after ART interruption. These data provide tantalizing evidence that adoptive cell therapy (ACT) could be efficacious in HIV. Developing effective CAR T cell therapies for chronic viral infections, however, requires overcoming exhaustion, and enabling appropriate effector biology, tissue access, and durability. The central goal of Project 1 is to identify key genes and pathways can be engineered to prevent T cell exhaustion, improve durability and enhance control of persisting viral infection by antiviral CAR T cells. We will exploit the small animal model of chronic LCMV for rapid iteration of candidate pathways and screen for new discoveries. While chronic LCMV infection is not HIV infection, we will use an understudied low-grade smoldering version of chronic LCMV infection to discover basic T cell biology relevant to HIV cure. Promising leads from this Project will be advanced Projects 2-4 for further testing. We will test the overall hypothesis that molecular circuits that antagonize exhaustion, improve durability and/or augment control of viral reservoirs can be identified and exploited to improve CAR T cell control of persisting infections. Our Aims are: AIM 1. TO TEST WHETHER ENGINEERED IMPROVEMENTS TO VIRUS-SPECIFIC CAR T CELLS TARGETING CYTOKINE RECEPTOR / STAT OR KEY TRANSCRIPTION FACTOR CIRCUITS ENHANCE ACT DURING PERSISTING VIRAL INFECTION. AIM 2. TO APPLY GENOME ENGINEERING APPROACHES TO TEST WHETHER T CELL DIFFERENTIATION STATES CAN BE IMPROVED FOR ACT DURING CHRONIC VIRAL INFECTION. Project 1 will be supported by Core A for administrative efforts and statistical support, Core B for genome engineering and will interface with Core C on moving promising leads to testing in primates or humans. This Project will interact extensively with Project 2 on Tbet and effector biology and testing improved versions of Tbet, with Project 3 for the PD1 studies and optimizing cytokine and STAT biology gaining insights also from the HIV mouse model and with Project 4 for potential translation to primates and humans.