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• W2912803467 abstract "This month’s installment of “The AJT Report” looks at the promising potential of chimeric antigen receptor T cell therapy using different types of cellular products to facilitate donor organ tolerance. We also report on the new federal transplantation network contract awarded to the United Network for Organ Sharing. This month’s installment of “The AJT Report” looks at the promising potential of chimeric antigen receptor T cell therapy using different types of cellular products to facilitate donor organ tolerance. We also report on the new federal transplantation network contract awarded to the United Network for Organ Sharing. Following the translational path of CAR T cells in oncology, scientists are preparing immunoregulatory cells and aiming for durable tolerance in transplantation “The potential is to use cell therapy as an adjunctive approach to immunosuppressive therapy…. It may well be a route to facilitate tolerance,” explains Kathryn Wood, DPhil, emeritus professor of immunology at the University of Oxford in the United Kingdom. Dr. Wood describes the parallels between the development of immunoregulatory cells in transplant and the use of chimeric antigen receptor (CAR) T cells clinically to reactivate the immune response and successfully treat some forms of cancer. “I think there is a great deal of enthusiasm and excitement at the moment,” she adds. “Transplantation is part of the cell therapy story.” The field includes many different cell types. Work is underway to demonstrate the safety and efficacy of cell therapy as well as to optimize protocols. “There are a lot of forks in the road that are potentially going to need to be explored,” says Sandy Feng, MD, PhD, professor of surgery at University of California, San Francisco. Products under investigation include donor-specific regulatory T (Treg) cells, polyclonal expanded Tregs, regulatory dendritic cells (DCregs) and mesenchymal stromal cells (MSCs). “I think the field is exploring different forms of cell therapy…because we know that the immune system uses a network of immunoregulatory cells,” explains Dr. Wood, who played a key leadership role in the European Union–funded consortium project known as the ONE Study (http://www.onestudy.org/) that has enabled the initial testing of Treg therapy in clinical organ transplantation. The ONE Study’s intention was to test different cellular products in equivalent patients. Although it was primarily a safety and feasibility study, UK investigators also tracked the incidence of acute rejection. They found no cases of acute rejection in the UK arm of the study. Dr. Wood collaborates with Fadi Issa, MD, PhD, a clinician/scientist in the Transplantation Research Immunology Group in Oxford, UK. He notes that Oxford’s polyclonal CD4+ Treg product, termed TR001, is expanded ex vivo from peripheral human blood under Good Manufacturing Process (GMP) conditions. “It was developed in our group after decades of experimental work,” explains Dr. Issa, who also says that “the field [is now moving]…very quickly.” He says that some groups, such as Dr. Feng’s, have moved on to donor-specific regulatory cells. The team at Oxford, however, has decided to stick with the polyclonal approach. “We have characterized these cells so well and believe in their efficacy…. We therefore now need to assess them clinically,” says Dr. Issa.KEY POINTS•Chimeric antigen receptor (CAR) T cell therapy is being used successfully in the clinic to treat some forms of cancer.•Various cellular products are now under investigation in the field of transplantation, including donor-specific regulatory T (Treg) cells, polyclonal expanded Tregs, regulatory dendritic cells and mesenchymal stromal cells.•Clinical trials, have begun to demonstrate that it is possible to expand and deliver Tregs safely. These early results are attracting multiple groups to the cellular therapy field. •Chimeric antigen receptor (CAR) T cell therapy is being used successfully in the clinic to treat some forms of cancer.•Various cellular products are now under investigation in the field of transplantation, including donor-specific regulatory T (Treg) cells, polyclonal expanded Tregs, regulatory dendritic cells and mesenchymal stromal cells.•Clinical trials, have begun to demonstrate that it is possible to expand and deliver Tregs safely. These early results are attracting multiple groups to the cellular therapy field. While the Oxford group stays aware of what is going on in the field and continues to contribute to the development of new therapies, they also realize that if they change the cell product that they are testing, they could not advance their clinical trials to the next phases and eventually bring the therapy to patients. “There are so many different products and even when the same cell therapy is produced in different GMP labs, the results will probably be different,” says Dr. Issa. Results from the ONE Study and others, however, indicate that infusion of regulatory cells is safe in several different clinical settings, pointing the way to the next step: developing appropriate protocols. Currently the Mario Negri Institute for Pharmacological Research in Italy appears to use the most robust protocol. Their CD105+/CD73+/CD90+ MSCs are derived from bone marrow. Their unique immunomodulatory properties allow the balance between regulatory and memory T cells to be skewed. This immunoregulatory function appears not to be fixed, but rather to result from the microenvironment encountered in vivo.1Casiraghi F Perico N Remuzzi G Mesenchymal stromal cells to promote solid organ transplantation tolerance.Curr Opin Organ Transplant. 2013; 18: 51-58Crossref PubMed Scopus (60) Google Scholar Giuseppe Remuzzi, MD, director of the Institute in Italy, has characterized his cells carefully. He opines, “My product will, in fact, induce tolerance in my patients.” His team designed their protocol with the goal of reducing immunosuppressive medications. To that end, they monitor patients for Treg expansion and suppression of cytotoxic T lymphocytes specifically against donor graft alloantigens. Dr. Remuzzi also highlighted the role of B cells in allograft tolerance and pointed to research indicating that kidney allograft tolerance is associated with elevated naïve and transitional B cells with regulatory properties.2Newell KA Asare A Kirk AD et al.Identification of a B cell signature associated with renal transplant tolerance in humans.J Clin Invest. 2010; 120: 1836-1847Crossref PubMed Scopus (553) Google Scholar When his team sees these signals in the patient, they begin to decrease immunosuppression.2Newell KA Asare A Kirk AD et al.Identification of a B cell signature associated with renal transplant tolerance in humans.J Clin Invest. 2010; 120: 1836-1847Crossref PubMed Scopus (553) Google Scholar “This is complicated stuff—doing cells in human beings,” says Dr. Remuzzi. “The philosophy we have is to do two patients at a time.” In this way, his group incrementally improved their protocol using MSCs in kidney transplant recipients. They began, for example, by giving patients cells post transplant, then changed the protocol for the next set of patients after studies in mice revealed that it is much better to infuse cells pre transplantation. This approach works well. “The histology looks unbelievable…. We have been able to stop the therapy,” reports Dr. Remuzzi. The group now has eight years of follow-up on these patients, including glomerular filtration rate data, which is a first for this cell therapy in transplantation. The team in Italy has been able to safely withdraw maintenance of immunosuppressive drugs in transplant recipients. Dr. Remuzzi cites this as “the first study that shows that, with mesenchymal stem cells, you can modulate the response to allograft.” Despite his impressive results, Dr. Remuzzi does not see the path to commercialization. “We have done it in an academic cell factory…. We have not contacted any companies so far, which is possibly a shame.” Dr. Wood recognizes that, in general, commercialization will require some proprietary element to the isolation or expansion of the cells. This can be challenging with some of the current approaches. “The cost can be considerable,” says Dr. Remuzzi, adding, “At this moment, it has to be considered a research approach.” He hopes that the results will soon be robust enough to justify commercial exploitation. At that point, the cost of cell therapy would likely be relevant but markedly lower than the current cost of CAR T cell therapy for cancer. Angus W. Thomson, PhD, DSc, distinguished professor of surgery and immunology at the University of Pittsburgh Starzl Transplantation Institute, focuses his efforts on Tregs from prospective organ donors. The cells are generated from blood monocytes during seven days of culture in GMP facilities, at which point they are given to the prospective liver recipient. Dr. Thomson envisions that the overall cost may not be as great as that for other cell types (e.g., Tregs), as the culture period is comparatively short and massive cell expansion is not required. The basic research in cell therapy for transplantation has been done, and the evidence suggests that regulatory cells will not only work in transplantation, but possibly even offer up the solution of durable tolerance. Oncologists have found a path to market for CAR T cells, and that same path should work for regulatory cells in transplantation. While there are still many details to iron out, the research is unrolling right now all around the world, and the results will continue to change the direction of the field of transplantation. “We’re excited to have a new contract,” affirms United Network for Organ Sharing (UNOS) chief executive officer Brian Shepard. “It is a privilege for us to do the work that we do.” UNOS has again won the competitive federal contract to serve as the nation’s Organ Procurement and Transplantation Network (OPTN). The new contract will run through 2023 (including option years). With UNOS providing a comprehensive set of services, Mr. Shepard says, “We always felt like we were in a strong position for the rebid.” He also emphasizes the commitment of UNOS to continually improve the nation’s transplant system. In 2018, the number of transplants in the United States is expected to exceed 36,000. All transplant hospitals and organ procurement organizations nationwide are members of the OPTN, and UNOS has held the contract, which is administered by the Health Resources and Services Administration (HRSA), since it was first offered in 1986. The contract is worth approximately $58 million annually, with most of the contract revenue coming from the fees that transplant centers pay when they list a patient. The fee is then rolled into the cost of the transplant. UNOS is familiar with controversy, and the organization spends considerable time and effort integrating input from multiple stakeholders. Mr. Shepard notes that UNOS is proud of its emphasis on inclusivity and is pleased to continue to be part of such an engaged community. The new contract puts even greater emphasis on enhancing professional and public involvement in OPTN policy development. UNOS is a nonprofit, 501(c)3 charitable membership organization based in Richmond, Virginia. In addition to its OPTN responsibilities, the organization receives private funding to help with its other efforts, which include collaborating with members on continuous improvement initiatives to strengthen and enhance their work. Erratum for Chen et al. “Maternal dietary inflammatory potential and quality are associated with offspring asthma risk over 10-year follow-up: the Lifeways Cross-Generation Cohort Study.” Am J Clin Nutr. 2020;111:440–7The American Journal of Clinical NutritionVol. 111Issue 4PreviewErratum for Chen et al. “Maternal dietary inflammatory potential and quality are associated with offspring asthma risk over 10-year follow-up: the Lifeways Cross-Generation Cohort Study.” Am J Clin Nutr. 2020;111:440–7. Full-Text PDF Open ArchiveErratumAmerican Journal of TransplantationVol. 19Issue 3PreviewPullen LC. Immunoregulatory cells: Can they be harnessed for transplant? Am J Transplant. 2019;19(2):309–310. https://doi.org/10.1111/ajt.15247 Full-Text PDF Open Archive" @default.
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