An Immunotherapy Vaccine (PIpepTolDC) for the Treatment of Patients With Type 1 Diabetes

Study Overview
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Brief Summary
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This phase I trial investigates the side effects of PIpepTolDC vaccine in treating patients with type 1 diabetes who use insulin and don't have any other diabetes-related health complications. Type 1 diabetes is an autoimmune disease. This means that the immune system, which usually protects against foreign invaders like bacteria and viruses, attacks the body's insulin-producing betacells in the pancreas (autoimmune response). Overtime, the beta cells are destroyed by the immune system. To stay alive, people with type 1 diabetes must use insulin. PIpepTolDC vaccine is a type of immunotherapy (a treatment that uses a person's own immune system) that works like an allergy shot. The vaccine is made using one's own immune cells (dendritic cells) and a beta cell protein. The vaccine may teach the immune system to stop attacking the beta cells, which may help the beta cells recover and make enough insulin to control blood sugar levels. The vaccine may also help reduce future type 1 diabetes related complications.

Official Title
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A Pilot Study to Evaluate the Safety and Feasibility of Autologous Tolerogenic Dendritic Cells Loaded With Proinsulin Peptide (C19-A3) in Patients With Type 1 Diabetes

Conditions
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Type 1 Diabetes Mellitus

Intervention / Treatment
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* Biological: Tolerogenic Dendritic Cell Vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willingness to undergo leukapheresis Willingness to be followed for about 2 years post-prime dose For participants who have a personal continuous glucose monitoring device (CGMD): Willingness to wear a second CGMD during mandated study CGMD visits Diagnosis of type 1 diabetes based on American Diabetes Association (ADA) criteria Historical presence of at least one type-1 diabetes associated autoantibody GAD specific autoantibodies (glutamic acid decarboxylase autoantibodies [GADA]) Islet cell cytoplasmic autoantibodies (ICA) Islet-antigen 2 specific autoantibody (IA-2A) Zinc transporter 8 specific autoantibody (ZNT8A); and/or Insulin autoantibody (IAA) (must have been obtained within 7 days of initiating exogenous insulin replacement therapy) Time from diagnosis to screening mixed meal tolerance test (MMTT) must be >= 1 year but =< 4 years Stable glycemic control per participant's physician HbA1c =< 7.5% (=< 58 mmol/mol) Non-fasting C-peptide > 0.017 nmol/L Stimulated peak C-peptide levels > 0.2 nmol/L from a 2-hour screening MMTT Positive for *04:01 allele, *04:02 allele and/or *04:04 allele at the human leukocyte antigen (HLA)-DRB1 gene locus Does not possess the protective HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype Adequate self-assessment of blood glucose values and recording of glucose values, and administered insulin doses as deemed sufficient by the participant's physician No diagnosis of type 1 diabetes related microvascular/macrovascular complications (e.g. nephropathy, retinopathy and neuropathy) Deemed acceptable for autologous cell collection (i.e. leukapheresis) Only for those who are naive to CGMD use: Deemed able to correctly use a CGM device following training session with a certified diabetes educator and manufacturer representative Must meet organ function criteria Exclusion Criteria: Other investigational agents, biologics Anti-inflammatory therapy Exception: Over-the-counter (OTC) anti-inflammatory agents (e.g. ibuprofen, Tylenol) are generally allowed. However, those requiring chronic OTC anti-inflammatory agents and unable to stop during mandated CGMD study visits will be excluded Systemic corticosteroids within 28 days prior to leukapheresis Systemic immunosuppressive therapy (e.g. cyclosporine-A, cyclophosphamide) Monoclonal antibody therapy Allergen immunotherapy within 28 days prior to leukapheresis Vaccine(s) within 28 days prior to leukapheresis Prior allogeneic organ transplant Beta-cell stimulants (e.g. sulfonylureas such as glimepiride), glucagon-like peptide-1 agonists, dipeptidyl peptidase-IV inhibitors (exception: Those with acute exposure to these agents during T1D misdiagnosis may be permitted per PI discretion) Insulin sensitizers (e.g. metformin, thiazolidinediones) within 2 months of leukapheresis History of insulin sensitizer use (e.g. metformin, thiazolidinediones) ≥ 2 months Other autoimmune/inflammatory disorders (exceptions: (i) Type 1 diabetes. (ii) Asymptomatic patients with incidental autoantibody titres may be permitted per PI discretion) Other autoimmune/inflammatory disorders (exception type 1 diabetes) Active infection requiring antibiotics and/or anti-virals Known history of HIV, HBV, HCV, HTLV, syphilis History of positive purified protein derivative (PPD) skin test History of atopy requiring systemic treatment and/or history of severe allergic reactions History or current malignancy Unstable cardiac disease History of vascular disease (e.g. deep vein thrombosis, stroke) Clinically significant uncontrolled illness Females only: pregnant or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Autologous Tolerogenic Dendritic Cell with Proinsulin Peptide (PIpepTolDC)<br>After completion of leukapheresis, patients receive a prime dose of PIpepTolDC intradermally (ID) on Day 0, followed by a boost dose of PIpepTolDC ID on Day 28. | Biological: Tolerogenic Dendritic Cell Vaccine<br>* PIpepTolDCs<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Toxicity and adverse events (except hypoglycemia and diabetic ketoacidosis [DKA]) will be recorded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. Hypoglycemia events and DKA will be defined per American Diabetes Association (ADA) grading systems.Observed toxicities will be summarized by type, severity (by CTCAE v 5.0 and nadir or maximum values for lab measures), date of onset, duration, reversibility, and attribution. | Up to 2 years | 
| Apheresis duration | Measured in hours. | up to 2 years | 
| Number of CD14+ monocytes | Number of CD14+ monocytes collected during apheresis | up to 2 years | 
| TolDC recovery after culture | Number of TolDC generated from CD14+ monocytes | up to 2 years | 
| Number of successful manufactured products | Number of manufactured products that meet the required cell dose/day, sterility (e.g. endotoxin and gram staining), and viability compared to the total number of products manufactured. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in stimulated C-peptide area under the curve | Assessed via 2-hr mixed meal tolerance test (MMTT). C-peptide preservation is defined as the maintenance of baseline C-peptide levels. | Baseline up to 2 years of follow up | 
| Change in interferon (IFN)-gamma and IL-10 producing CD4+ T cells | Will be assessed in response to pro-insulin peptide C19-A3, and assessed via cytokine enzyme-linked immunosorbent spot assay. | Baseline up to 2 years of follow up | 
| Change in T cell responsiveness | Will assess for changes in T cell responsiveness to pro-insulin peptide C19-A3 compared to other antigens. Assessed via Lymphocyte Simulation Test. | Baseline up to 2 years of follow up | 
| Change in the number of CD8+ autoreactive T cells | Assessed via quantum dot (Q-DOT) nanotechnology assay. | Baseline up to 2 years of follow up | 
| Change in immune phenotype | Will analyze for changes in immune cell populations via flow cytometry | Baseline up to 2 years of follow up | 
| Change in islet autoantibodies | Will analyze for changes in IAA, GAA, IA-2A, ZnT8A via enzyme-linked immunosorbent assay. | Baseline up to 2 years of follow up | 
| Change in glycosylated hemoglobin A1c (HbA1c) levels | HbA1c levels will be assessed via blood test | Baseline up to 2 years of follow up | 
| Change in exogenous insulin use (units/kg) | Insulin usage will be recorded daily from the insulin pump and/or participant insulin use logs. The mean daily insulin usage over the 10 consecutive days (IU units/kg body weight/day) preceding the clinic visit will be calculated for each participant. | Baseline up to 2 years of follow up | 
| Change in blood glucose levels | Will include clinically important/severe hypoglycemia, hyperglycemia and DKA events as assessed by ADA grading systems. Levels of glucose will be assessed from bloods samples taken during the MMTT and from insulin pump/participant insulin logs | Baseline up to 2 years of follow up |