Clinical Transplant Tolerance Induction by the Use of Ex Vivo Expanded Antigen Specific Regulatory T Cells

Organ and tissue transplantation currently relies on nonspecific immunosuppressive agents (IS) given life-long to prevent graft rejection. These drugs have significant and cumulative toxicities, such as nephrotoxicity and increased rate of infections, malignancy, diabetes, and hypertension. Also they are very costly. The elusive goal since organs were first transplanted in humans is to establish donor-specific immunologic tolerance, a state where a donated organ is accepted as “self,” eliminating the need for IS. Regulatory CD4+CD25+FOXP3+ T cells (Tregs) have been shown to induce tolerance in transplantation models (1, 2) and to be elevated in tolerant human recipients (3-10). However, there have been limited efforts to harness their therapeutic potential in the clinic (11, 12). We have perfected large scale isolation and POLYCLONAL expansion of GMP grade Tregs, obtained an IND from the FDA (#15898), and successfully completed a PHASE 1 safety trial in living donor kidney transplant patients (11). No study- related adverse events or signs of rejection were noted upon infusion of polyclonally expanded Tregs. Additionally, these patients developed increased numbers of circulating Tregs post-infusion. Based upon the success of this phase 1 trial, a phase II efficacy trial is currently being developed to start in 2016. Antigen specific Tregs have the potential advantage over polyclonally expanded Tregs of being more targeted and potent in controlling immune responses (15). Therefore, we have developed a unique culture system and obtained preliminary data demonstrating 1) the feasibility of expanding alloantigen-specific Treg ex vivo, and 2) the ability of these cells to down-regulate immune responses in an antigen specific manner in vitro (16). Next, we have to demonstrate our ability to expand donor-specific Tregs in large scale in the “cGMP” Facility (as similar to the polyclonal expansion) and to test the in vivo safety and efficacy of the expanded antigen-specific Tregs using an animal model so as to obtain an IND. Towards this end, we are applying to the Falk Foundation “Catalyst Award” (Figure 1). Subsequently, during the “transformational award” period, we propose to perform a phase I clinical trial to assess the safety of infusions of donor-specifically expanded (in cGMP facility) autologous Tregs from HLA-disparate kidney transplant recipients (Figure 1). Escalating doses of expanded Tregs will be infused with the primary objective of determining the safety, i.e., having no increased rates of infection and sensitization or even clinical rejection in protocol biopsies when compared to institutional historical controls. Secondary objectives will include evidence for signatures of tolerance in the form of increased post-infusion Tregs and donor-specific immune unresponsiveness. Tolerance is the “holy grail” of transplantation, and therefore, if our high reward approach is successful, it will transform the clinical practice of transplantation. Transplant tolerance will have multiple benefits including (i) improved quality and length of life for the transplant recipient, (ii) greater healthcare dollar savings by eliminating costly life-long immunosuppressive drugs, (iii) the resulting “one transplant for life” spares the limited number of available organs so that for more recipients can be transplanted. This fits well with the mission of the Falk Medical Research Trust to support “medical research to improve treatments … find cures for diseases for which no definite cure is known.” Additionally, as a recipient of previous fu