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2019 May See New Approach to Refractory Crohn’s

When anti-inflammatory drugs fail and surgery is not an option, stem cell transplantation, long used in hematologic cancer treatment, may be a way to correct the faulty immune responses of Crohn’s disease (CD) patients.

In 2018, a randomized multicenter British trial got underway using the regenerative power of autologous hematopoietic stem cell transplantation (HSCT) to reboot the faulty immune systems of refractory CD patients. Coordinated by the University of Sheffield, the ASTIClite (Autologous Stem cell Transplantation In refractory Crohn’s disease – Low Intensity Therapy Evaluation) trial will assess the efficacy of low-dose treatment versus standard care for inducing regression of ileocolonic ulceration in refractory CD at week 48.

“We’re hoping that by completely resetting the patient’s immune system through a stem cell transplant, we might be able to radically alter the course of the disease,” the trial’s lead investigator, James Lindsay, MD, of Queen Mary University London, told MedPage Today. Re-injected after chemoablation, the stem cells will populate the gut and bone marrow to form a naive immune system with no memory of the bacteria to which the old immune system reacted with inflammation, he explained.

As a secondary outcome, the study will evaluate whether low-dose cyclophosphamide plus granulocyte colony-stimulating factor is a safe and effective mobilization regimen in refractory CD patients. Other endpoints are the impact of the protocol on disease activity, quality of life, and adverse events compared with standard care. Finally, the trial will assess the safety and efficacy of tumor necrosis factor inhibition in patients with endoscopic disease recurrence at week 24 after HSCTlite. Results should be available in 2022, Lindsay said.

The current clinical trial is a follow-up to the 2015 ASTIC trial of stem cell therapy, which used higher doses of ablative and hematopoietic drugs. In this study, HSCT did not achieve the primary endpoint of sustained clinical disease remission at 12 months compared with standard therapy, and drug-related toxicity was considerable.

Stateside, another new HSCT trial known as Maintenance in Autologous Stem Cell Transplant for Crohn’s Disease (MASCT-CD) is launching at the Icahn School of Medicine at Mount Sinai in New York City. To improve the success of HSCT, Amir Steinberg, MD, and colleagues will incorporate the antibody vedolizumab (Entyvio) after transplantation with the expectation the α4β7 integrin antagonist will increase and maintain remission in a cohort of 50 patients.

Drug-refractory CD patients with imaging-documented active mucosal disease will be tapered off their current medications and undergo stem cell mobilization with low-dose chemotherapy, growth factors, and 1 to 2 weeks’ hospitalization. The next stage will be HSCT with high-dose chemotherapy and 2 to 4 weeks’ hospitalization.

After restoration of the immune system, patients will receive vedolizumab at standard dosing for a total of eight doses. Patients will be followed up each month and undergo colonoscopy and MR/CT scan at 6 months. The study is expected to be completed in 2020.

Autologous stem cells have also proven effective for tissue healing in CD patients, but allogeneic stem cells may also have a role to play. For example, an initiative begun at the Mayo Clinic in Rochester, Minnesota, and is recruiting healthy donors to provide allogeneic stem cells to treat anal fistulas in CD patients. “With allogeneic cells you have the advantage of an off-the-shelf product to offer patients when they walk in,” Amy L. Lightner, MD, told MedPage Today. In the allogeneic study, the cells will be delivered arterially.

In another innovation, Lightner and colleagues will alter the therapeutic target from the intestinal cells themselves to the extra-cellular vesicles, functional nanoparticles secreted by cells and containing RNA, proteins, carbohydrates, and lipids involved in cell signaling. “We can culture mesenchymal cells and engineer them as immunosuppressives to target the vesicles with less risk and much lower cost per dose – maybe $100 as opposed to $10,000,” she explained.

Lightner said she plans to continue stem cell investigations, including a phase I trial targeting the extracellular vesicles, at the Cleveland Clinic, where she takes up a new position in early 2019.