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TNFR2 Agonist Suppresses GVHD After Stem Cell Transplantation

Samson, Kurt

doi: 10.1097/01.COT.0000502633.07202.d9
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graft versus host disease:
graft versus host disease

Researchers working with laboratory mice have successfully suppressed graft versus host disease (GVHD) in vivo using a novel peptide drug that stimulates new formation of regulatory T cells prior to allogeneic stem cell transplantation. The new approach stops donated immune cells from attacking healthy cells and tissues after a transplant, while still allowing them to target tumors. Until now, the technique has only been possible in vitro. While it was tested in mice, evidence from 16 independent in vitro experiments in humans also suggests a similar benefit (JEM 2016;213:1881-1900).

The team used selective mouse TNF-based agonist of TNF receptor 2, or STAR2, which selectively activates mouse TNFR2 while expanding and activating natural T regulatory (T reg) cells, both in vitro and in vivo. STAR 2 is a highly active mouse TNF-based agonist of TNFR2.

Investigators at the University of Würzburg also reported that a slightly modified version of STAR2 had a similar effect on T reg cells, indicating the approach could also prevent GVHD in leukemia and lymphoma patients.

“This strategy may be beneficial for other pathological settings in which elevated numbers of regulatory T cells are desirable, such as autoimmune diseases and solid organ transplantation,” said Andreas Beilhack, MD, Director of the Interdisciplinary Center for Clinical Research Laboratory for Experimental Stem Cell Transplantation.

STAR2 works by specifically binding to a cell surface protein called TNFR2, activating a signaling pathway that increases the number of T reg cells.

TNF, a cytokine involved in rheumatic and inflammatory disorders, is a protein that mediates intracellular communication by binding to specific cell receptors. While the interaction of TNF with TNFR1 triggers a strong pro-inflammatory response, when TNF interacts with TNFR2 it can promote anti-inflammatory activity, noted co-author Harald Wajant, PhD, Professor of Molecular Internal Medicine at the university.

“Expanding radiation-resistant host T reg cells significantly prolonged survival and reduced GVHD severity in mice. The findings demonstrate the technique's potential to similarly protect patients,” he told Oncology Times.

Donor T regs can suppress GVHD, but until now these could only be grown in the laboratory before being introduced in patients prepared to undergo allogeneic hematopoietic stem cell transplantation. Nonetheless, up to 70 percent of recipients develop acute GVHD, and of those, about 40 percent of patients develop chronic disease.

Human Findings

The positive effects of using donor T reg cells to treat or prevent GVHD in human subjects have been demonstrated in many clinical studies. In this study, the beneficial effects of transplanted T cells against leukemia cells and infectious pathogens remained unaffected while a corresponding human TNFR2-specific agonist expanded human T reg cells in vitro.

“The use of donor T reg cells is challenging with regard to the numbers and purity of the required cells, however, as well as to their stability after infusion into allogeneic stem cell recipients,” noted Wajant.

Although ex vivo expansion of these cells and/or their infusion in high numbers is the only current treatment for certain hematopoietic diseases, including leukemia and lymphoma, GVHD is the primary cause of non-relapse mortality after HCT or allo-HCT transplants.

“The effects of TNF on human T reg cells are less clear, but in our study we showed that a human TNFR2 agonist expands human T reg cells in vitro,” Wajant said. “We are continuing to evaluate STAR2 in other models of auto-immunity and inflammation-driven cancer models.”

Other studies have shown that activation of TNFR2 on human T reg cells inhibits their suppressive functions, although treatment of healthy mice with STAR2 did not cause adverse effects.

“Our therapeutic approach...has advantages over current clinical protocols as it demands neither good manufacturing practice compliance nor ex vivo expansion of donor cells with the potential risk of functional loss. Furthermore, T reg cells are expanded in vivo within GVHD target tissues, as opposed to transplanted cells that would first have to find these targets.

“Because this is preclinical research, long-term perspectives on how human patients might respond is difficult to answer and very speculative. But in principle, every patient suffering from auto-inflammatory diseases or patients with inflammation-driven cancer types might be treatment candidates.”

As with any other anti-inflammatory treatment, activation of regulatory T cells via TNFR2 inherently bears an increased risk of infections. Depending on the tumor type, regulatory T cells can cause pro- or anti-tumor activity. If expansion of T regs by TNFR2 activation is used treating cancer, researchers must first ensure that only appropriate patients are treated, the researchers noted.

T-Cell Research Groundwork

John Levine, MD, Professor at Mount Sinai Icahn School of Medicine's Tisch Cancer Institute, Los Angeles, told Oncology Times that, while the findings are interesting, there remain a number of questions that need to be resolved.

“Reg T cells show promise as a way to control GVHD based on animal experiments and some preliminary human trials, but generating the large numbers of cells needed suggests that even if treatment is effective, infusions will require specialized cell manufacturing facilities and would be costly,” he noted

Even so, Levine said the study “lays the groundwork” for an alternative approach that may be much more feasible.

“The novelty in this study is that the investigators created a synthetic TNFR2 agonist that selectively stimulates the TNFR2 receptor and induces T regs without simultaneously stimulating the TNFR1 receptor that would offset this benefit.”

Although the approach may be most applicable to hematologic malignancies, these are the most common indications for allogeneic BMT; this approach, if it can be translated in humans, could have wide applicability, said Levine.

Further work will be needed to ensure the effectiveness, as well as the preservation, of the anti-leukemia and infection fighting T cell function. In addition, the host, or for humans, the patient needs to be treated with the TNFR2 agonist for 2 weeks prior to transplant, which includes the conditioning regimen, and the resulting regulatory T cells persisted for up to 3 weeks after transplant, he added.

“This may cover the peak time for GVHD to develop, but longer follow-up is needed to assess whether this approach prevents lethal GVHD or simply delays it.”

Also, in the study, only radiation was used to condition the mice and T regs are radiation resistant, so it will be necessary to show that host T regs induced prior to bone marrow transplants are exposed to conditioning regimens that include chemotherapy to maintain GVHD-controlling ability.

The “Neglected” Receptor

TNFR2 has for a long time been a neglected receptor of the TNF superfamily, but it has some marked advantages, noted Denise L Faustman, MD, PhD, Associate Professor of Medicine at Harvard Medical School and Director of Immunobiology at Massachusetts General Hospital, in Charlestown, Mass.

“Unlike other commonly targeted TNF superfamily receptors, TNFR2 has very limited human expression. This suggests that any therapy directed to this receptor would and should have a better profile and greater specificity based on the natural distribution,” she told Oncology Times. “Importantly TNFR2 identifies and is expressed on the most potent T regs. Unlike many other targets for T regs, TNFR2 is not only a marker of the most potent T regs but, more importantly, is the master control switch for human T reg fate.”

When TNFR2 agonism is used on human cells the resulting cells are homogeneously potent TNFR2 T regs, and this contrasts dramatically with many common T reg expansion protocols where many cell populations expand and result in a regulatory problem for developing a novel therapy, she continued.

“Although the findings are based on mouse data, it demonstrates that this select T reg expansion in vivo is potent and changed non-myeloablative hematopoietic stem cell transplantation survival. So this is an important pre-clinical translation study showing the in vivo feasibility in models of TNFR2 T reg agonism,” Faustman noted.

The risks of the therapy should be minimal in humans because TNFR2 has restricted distribution.

“Translation of this to in vitro T reg expansion in humans could be very rapid and very confirmatory, and GVHD in humans without tumors as the underlying first patients would be a smart phase I trial,” she concluded.

Kurt Samson is a contributing writer.

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