The Growing Burden of Type 1 Diabetes and the Quest for Immune Therapies

Type 1 diabetes (T1D), an autoimmune condition where the body's immune system mistakenly attacks insulin-producing beta cells in the pancreas, affects millions worldwide. In the United States alone, over 1.6 million people live with T1D, with approximately 64,750 new cases diagnosed annually, including more than 18,000 among youth under 20 years old. Globally, the prevalence is estimated at around 8.4 million individuals, a figure projected to rise significantly due to improved diagnostics and changing environmental factors. This chronic disease requires lifelong insulin therapy, rigorous blood glucose monitoring, and carries risks of severe complications such as hypoglycemia, ketoacidosis, cardiovascular disease, and neuropathy.

Traditional management focuses on symptom control rather than addressing the root cause—the dysregulated immune response. Recent advances in immunotherapy offer hope for disease modification, particularly in the 'honeymoon phase' shortly after diagnosis when residual beta cell function persists. This window, typically lasting months, is critical for interventions aiming to halt autoimmunity and preserve endogenous insulin production, potentially reducing insulin dependence and complication risks.

Unraveling Immune Dysregulation in Type 1 Diabetes

At the heart of T1D lies a breakdown in immune tolerance. Autoreactive T cells, particularly effector CD8+ and CD4+ T cells, infiltrate the pancreatic islets, leading to beta cell destruction. Genetic susceptibility, involving HLA genes and others like INS and PTPN22, interacts with environmental triggers such as viral infections or early diet to initiate this process. Key inflammatory cytokines like IFN-gamma and IL-17 amplify the attack.

Regulatory T cells (Tregs), a subset of CD4+ T cells expressing FoxP3, normally suppress these autoreactive responses. In T1D, Treg numbers and function are impaired, failing to maintain balance. Interleukin-2 (IL-2), a cytokine essential for Treg survival and proliferation, holds promise but standard IL-2 also activates pro-inflammatory effector T cells and natural killer cells due to ubiquitous low-affinity IL-2 receptors. This dual action limits its therapeutic potential.

The Emergence of Selective Treg Stimulation

Academic researchers have pioneered engineered IL-2 variants to preferentially target the high-affinity IL-2 receptor (IL-2Rαβγ) on Tregs. Low-dose IL-2 trials in T1D demonstrated modest C-peptide preservation, but dose optimization remains challenging. Next-generation molecules like rezpegaldesleukin represent a leap forward, incorporating polyethylene glycol (PEG) conjugation and mutations to enhance Treg selectivity, prolong half-life, and minimize effector activation.

• PEGylation reduces renal clearance, enabling sustained exposure.
• Mutations in IL-2 mutein diminish binding to IL-2Rβγ on effectors.
• Results in 10-20 fold preferential Treg expansion in preclinical models.

Rezpegaldesleukin: Engineering Precision for Immune Balance

Rezpegaldesleukin (REZPEG, NKTR-358), developed by Nektar Therapeutics in collaboration with academic partners, is a novel pegylated IL-2 receptor agonist. By hyper-activating the Treg compartment, it dampens islet autoimmunity while promoting tissue repair signals. Preclinical studies in non-obese diabetic (NOD) mice showed delayed diabetes onset and preserved beta cell mass, with pharmacodynamic data confirming robust Treg increases without effector overactivation.

Building on successes in atopic dermatitis (REZOLVE-AD Phase 2b) where it achieved significant EASI score improvements and durable responses, the molecule now enters T1D evaluation. Its self-administered subcutaneous injection format enhances patient feasibility.

The RESET T1D Trial: A Landmark University-Led Effort

Sponsored by TrialNet, an NIH-funded network of over 200 sites led by top academic institutions, the Phase 2 RESET T1D study evaluates rezpegaldesleukin in approximately 70 patients with new-onset stage 3 T1D. Chaired by Kevan C. Herold, MD, C.N.H. Long Professor at Yale University, the trial underscores higher education's pivotal role in translational research.

Primary endpoint: Change in stimulated C-peptide area under the curve (AUC) via mixed-meal tolerance test (MMTT) at 12 months (6-month treatment + 6-month follow-up). Secondary measures include HbA1c, insulin use, pharmacokinetics, and safety. Patients receive biweekly injections, randomized 2:1 to drug or placebo.

Academic Powerhouses Spearheading the Research

TrialNet's international clinical centers, predominantly university-affiliated, drive recruitment and execution. Key sites include:

• Benaroya Research Institute at Virginia Mason (Seattle), focusing on immunology.
• Stanford University, renowned for diabetes innovation.
• Vanderbilt University Medical Center, with expertise in beta cell preservation.
• University of Texas Southwestern, advancing immunotherapy.
• Barbara Davis Center at University of Colorado Anschutz Medical Campus.
• Columbia University and Medical College of Wisconsin, among others.

These institutions provide multidisciplinary teams of endocrinologists, immunologists, and statisticians, ensuring rigorous data collection. Herold notes, "Therapies targeting Tregs could fundamentally alter T1D progression if they preserve beta cell function beyond the honeymoon phase."

Who Qualifies? Eligibility and Study Participation

Initial cohorts target adults aged 18-45 diagnosed within 3 months, with detectable C-peptide on MMTT, confirming residual beta cells. Exclusion criteria include prior immunotherapy or significant comorbidities. Screening involves medical history, labs, and OGTT/MMTT.

Participation spans 1 year: 15 visits during treatment (q2 weeks injections, monitoring), then quarterly follow-ups. Sites cover travel, meals, and compensation for time. Phased enrollment allows safety reviews before pediatric expansion (12+ years).

Endpoints and Expected Outcomes: Gauging Beta Cell Preservation

C-peptide, a byproduct of insulin synthesis, quantifies endogenous production. MMTT stimulates physiological insulin response, providing sensitive readouts. Historical benchmarks: Teplizumab delayed stage 3 T1D by 2-3 years in at-risk patients; abatacept preserved C-peptide ~50% at year 2.

Rezpegaldesleukin's Treg focus may yield superior durability. Safety profile from AD trials shows mild injection reactions, no serious infections, supporting advancement. Full data anticipated 2027.

Contextualizing with Prior Immunotherapies

FDA-approved teplizumab (Tzield) delays onset in stage 2 T1D via CD3 modulation but offers limited post-diagnosis benefit. Anti-CD3 (otelixizumab), rituximab (B-cell depletion), and IL-1 blockers showed transient effects. Treg therapies like low-dose IL-2 (5-10% C-peptide gain) set the stage, but rezpegaldesleukin's selectivity addresses prior limitations.

Challenges, Risks, and Mitigation Strategies

Potential risks include over-immunosuppression, autoantibody fluctuations, or waning effects post-treatment. Long-term monitoring addresses malignancy concerns from chronic IL-2. University biostatisticians employ adaptive designs for efficiency.

• Robust PK/PD modeling from prior trials.
• Biomarkers like Treg:Teff ratio guide dosing.
• Diverse cohorts ensure generalizability.

Broader Implications for T1D Management and Research

Success could shift paradigms toward combination regimens (e.g., antigen-specific + Treg), beta cell regeneration adjuncts, or precision medicine via immune phenotyping. Economic burden—$16.9 billion annually in US—underscores value. For patients, reduced hypoglycemia fear and HbA1c variability promise better quality of life.

Academic Jobs platform connects researchers to roles in this field; explore opportunities at leading centers. For more on TrialNet studies, visit their official site. Nektar's announcement details the collaboration in their press release.

Photo by Belinda Fewings on Unsplash

Looking Ahead: University Innovations Shaping T1D's Future

Beyond RESET T1D, universities pioneer CAR-Tregs, nanoparticle-delivered autoantigens, and AI-optimized trials. Yale, Stanford, and others integrate single-cell RNA-seq to stratify responders. If rezpegaldesleukin succeeds, Phase 3 could follow by 2028, potentially approving a second disease-modifying agent. This trial exemplifies higher education's commitment to collaborative, impactful science, offering hope for the next generation of T1D patients.