October 22, 2013
Looking to 2014
Over the past decade, the ITN has developed a rich portfolio of trials that have advanced clinical practice and enhanced our understanding of tolerance. As a result of these trials we now know that:
Mechanistic and clinical insights from recent ITN trials have underscored the notion that tolerance will likely require combinations of agents to block or ablate memory effector responses, to boost or stabilize regulation and to re-establish innate immune balance. These mechanistic themes should be clearly articulated and drive the ITN’s portfolio forward, and will require methods for measuring success or failure in reaching these objectives.
To begin thinking about how to accomplish this, the October 2013 NSC meeting in Washington, DC provided an opportunity to sit down with the ITN’s advisors and brainstorm. NSC members and ITN/NIAID staff were divided into three groups to discuss the following topics:
Overall, the NSC is enthusiastic about developing studies with a mechanistically-driven rationale. Although it is challenging to identify one common mechanistic goal amongst multiple distinct diseases, the ITN should facilitate better cross-talk between therapeutic areas to potentially identify universal tolerance themes. The group is supportive of developing smaller, mechanistically-focused pilot studies, but expressed concerns that the use of biomarker-based trial designs (e.g., adaptive designs) may be challenging.
The ITN will work closely with the therapeutic area strategic assessment groups to help crystalize a strategy moving forward.
New Findings
In addition to the strategic planning sessions, the NSC heard about recent data from ITN trials. Mario Ehlers, MD, PhD, presented mechanistic data from the T1DAL study (Inducing Remission in T1DM with Alefacept [Amevive®]) that show patients who received alefacept had reduced effector memory cells (Teff), but maintained their regulatory T cells (Tregs), thereby producing a favorable Treg:Teff ratio. This may have contributed to the positive clinical results, where those in the alefacept group showed better C-peptide responses compared to placebo.
Sandy Feng, MD, PhD presented mechanistic data from the WISP-R study (Withdrawal of Immunosuppression in Pediatric Liver Transplant Recipients) suggesting that markers of senescence and exhaustion may play a role in tolerance. A subset of 5 tolerant subjects (out of the total 12) showed elevated levels of PD1 and CD57, two markers of T-cell exhaustion. The hypothesis is that chronic exposure to antigens may prompt senescence of reactive cells and allow tolerance. Elevated senescence markers were only observed in a subset of tolerant patients, suggesting this is possibly one of multiple mechanisms for achieving tolerance. The ITN will continue to investigate these markers in tolerant patients in other studies in transplantation as well as other diseases.
The NSC also heard clinical updates from the HALT-MS study (High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis) and the ACCESS study (Abatacept and Cyclophosphamide Combination Therapy for Lupus Nephritis). At two-years, approximately 90% of subjects in the HALT-MS study had relapse-free and progression-free survival. In the ACCESS study, although there were no differences in outcomes between the treatment and control arm at one year, the study demonstrated that the Euro-Lupus regimen (lower-dose cyclophosphamide) works well in an ethnically-diverse North American population.
Dendritic Cells for Tolerance: Precarious or Promising?
Three different groups gave presentations about the use of dendritic cell (DC)-based therapies for tolerance. DCs are antigen-presenting cells commonly associated with immune reactivity, but have also been demonstrated to be important regulators and can induce tolerance.
Yong-Jun Liu, MD, PhD (Baylor University) chaired the session, and his colleague SangKon Oh, PhD (Baylor University) presented data demonstrating that targeting antigens to various DC receptors can induce different T cell phenotypes; the challenge lies in restricting plasticity and selectively inducing regulatory T cells.
Charles Nicolette, PhD (Argos Therapeutics) described a molecule in development that blocks a cell surface protein on DCs required for pro-inflammatory signaling (CD83). The molecule has been efficacious in multiple autoimmune preclinical models and in vitro human cells, but further work is needed to bring this molecule to the clinic.
Angus Thomson, MD and Fadi Lakkis, PhD (University of Pittsburgh) described the use of DC cellular therapy for transplant tolerance and presented promising data from primate kidney transplant models demonstrating prolongation of graft survival and regulation of donor-reactive memory T cells. Two Phase I studies have demonstrated the safety of administering regulatory DCs in patients with rheumatoid arthritis and type 1 diabetes, but further work confirming the durability/stability of the regulatory phenotype in vivo is needed before application in an ITN tolerance trial.
The ITN will consider the use of DC-based therapy for tolerance in the future when the stability of DCs in vivo is confirmed.
Vascularized Composite Allotransplantation: Novel Opportunity for Tolerance?
In early 2013, the ITN received a Concept Proposal for a tolerance trial in Vascularized Composite Allotransplantation (VCA), which refers to transplantation of multiple tissue types as a functional unit (e.g., hands, face, abdomens, etc.). This is an extremely new field of research with limited numbers of cases, so the ITN invited world leaders to inform the NSC about the current clinical landscape for VCA and the potential for tolerance trials.
Sandy Feng, MD, PhD (UCSF) chaired the session, and Andy Lee, MD and Gerald Brandacher, MD (Johns Hopkins University), Simon Talbot, MD and Leonardo Riella, MD, PhD (Brigham and Women’s Hospital), Curt Cetrulo, MD (Massachusetts General Hospital), and Brian Pfister, PhD (Clinical and Rehabilitative Medicine Research Program, US Army) gave talks about VCA and tolerance. VCA is a very complex procedure requiring multi-disciplinary teams (plastic surgeons, immunologists, transplant surgeons, etc.) with about 90 total cases of VCA to date (hand, face, arm, abdomen, etc.). Rejection is common shortly after transplantation, but is detected and treated rapidly with very rare graft loss. Because VCA is an elective procedure to enhance quality of life, many patients are unwilling to accept the burden of lifelong immunosuppression; thus, tolerance strategies could greatly increase the application of these procedures.
The NSC agreed that this is an exciting and potentially very informative platform to learn about tolerance (easy access to relevant tissue), but feasibility and appropriateness in the ITN’s portfolio will be further discussed.
The ITN looks forward to working with members of the NSC, strategic assessment groups, NIAID, and Rho to direct and shape the portfolio under the new contract in 2014. Thanks to everyone who participated in the October meeting!
Slides from the October 2013 NSC meeting are available here.
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