Engineering an Effective CAR Treg Combination Therapy to Control VCA Rejection
Abstract
Rationale: Vascularized composite allotransplantation (VCA), including face, limb, and penile transplantation, is used to restore the appearance and function of patients with severe tissue loss. A limitation of current VCA approaches is that immunosuppressive drugs are used to stop the patient s immune system from rejecting the graft. These drugs have side effects, such as increasing the risk of cardiovascular and kidney disease, and globally suppress immunity, putting patients at risk of infection and cancer. Moreover, immunosuppression often fails to prevent rejection: >50% of patients have transient or permanent graft rejection. There is an urgent need to develop more effective and less toxic treatments to control immunity in VCA. Our team is focused on harnessing one of the natural ways that the immune system uses to regulate itself to improve VCA outcomes. Specifically, a special type of white blood cell known as T regulatory cells (or Tregs) has a unique ability to prevent inappropriate immune responses. We know this function of Tregs can be applied in transplantation to promote long-term graft acceptance. We recently made a significant improvement in how Tregs can be used in transplantation by applying a cell engineering strategy involving the creation of a custom- designed protein called a chimeric antigen receptor (CAR). When CAR are expressed on Tregs, they are more potent and specific. However, we also know that CAR-Tregs on their own are not strong enough to control rejection, so we are studying how to use them with other types of immunosuppression that are less toxic than traditional forms. This work revealed the two exciting approaches that are the focus of this proposal: to combine CAR-Tregs with co-stimulation blockade and/or with a microparticle technology to improve their survival. Our combined expertise in CAR-Tregs, VCA immunotherapy, and immunosuppression positions us to make rapid progress in this highly innovative, yet clinically-feasible, approach. Objectives: Our hypothesis is that, in combination with non-toxic immunosuppression, CAR-Treg therapy will be an effective way to minimize VCA rejection. Our objectives are to use mouse models of VCA to test whether CAR-Treg therapy prevents VCA rejection and to optimize combination therapies for a maximal efficacy. Focus Areas: Develop novel approaches for immune tolerance and reduce immunosuppression toxicity. Patient Impact: This work will help make VCA accessible to patients who would benefit from transplant of tissues such as a face, arm, leg, and/or penis. In the past 15 years, ~40% of combat injuries sustained by Service Members involved severe extremity and craniofacial trauma. There are also many civilians who have accidents causing similar injuries. Many of these patients would benefit from VCA. Clinical Applications, Benefits, and Risks: CAR-Treg therapy (with or without a novel immunosuppressive protocol) would be applicable in any patient undergoing VCA. The most likely first application would be in upper extremity (e.g., hand) transplantation since this is the most commonly performed form of this procedure, and hence there is the largest patient population. The benefit would be the opportunity to reduce conventional immunosuppressive therapy and its associated side effects, as well as the overall risk of rejection. The main risk of CAR-Treg therapy is that it may not work as expected and lead to unwanted episodes of rejection. If this were to happen, then conventional immunosuppression could be quickly restored and, if deemed necessary, CAR-Tregs could be eliminated by use of T cell depleting drugs. Time to Patient-Related Outcome: First-in-human trials of CAR Treg therapy are in progress, so by the end of this project (2026), there will be safety and efficacy data from these studies which can be used to support application in VCA. For combination therapy, some of our approaches use clinical-grade d
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310627
Entities
People
- Giorgio Raimondi
Organizations
- Johns Hopkins University
- United States Army