A Vaccine (PIpepTolDC) for the Treatment of Patients with Type 1 Diabetes

Inclusion Criteria

• Documented informed consent of the participant
• 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
• Age: 18-45 years
• Diagnosis of type 1 diabetes based on American Diabetes Association (ADA) criteria: * Hyperglycemia (glycosylated hemoglobin [HbA1c]) >= 6.5% (>= 48 mmol/mol); OR * Fasting plasma glucose >= 126 mg/dl (7.0 mmol/L); OR * 2-hour plasma glucose >= 200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test; OR * In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose >= 200 mg/dl (11.1 mmol/L) ** This includes latent autoimmune diabetes in adults
• 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)
• Pre-screening: Non-fasting C-peptide > 0.017 nmol/L and/or C-peptide reading current within 1 year from source document(s) > 0.017 nmol/L
• Stimulated peak C-peptide levels > 0.2 nmol/L from a 2-hour screening MMTT
• Pre-screening: Positive for *04:01 allele, *04:02 allele and/or *04:04 allele at the human leukocyte antigen (HLA)-DRB1 gene locus
• Pre-screening: 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. vein assessment for 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
• Absolute neutrophil counts (ANC) >= 1,000/mm^3 (within 7 days prior to leukapheresis)
• Platelets >= 100,000/mm^3 (within 7 days prior to leukapheresis)
• Total bilirubin =< 1.5 X upper limit of normal (ULN) (within 7 days prior to leukapheresis)
• Aspartate aminotransferase (AST) =< 1.5 x ULN (within 7 days prior to leukapheresis)
• Alanine aminotransferase (ALT) =< 1.5 x ULN (within 7 days prior to leukapheresis)
• Creatinine clearance of >= 60 mL/min per 24 hour urine test or the Cockcroft-Gault formula (within 7 days prior to leukapheresis)
• Negative for human immunodeficiency virus antigen (HIV Ag), HIV 1+2 antibody (Ab), human T-cell leukemia virus (HTLV) I/II Ab, hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb) (immunoglobulin M [IgM] and immunoglobulin G [IgG]), hepatitis C virus antibody (HCV Ab), and syphilis, and negative result from COVID-19 polymerase chain reaction (PCR) (within 72 hours [hrs]) (within 7 days prior to leukapheresis)
• Women of childbearing potential (WOCBP): negative urine and/or serum pregnancy test * NOTE: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required (within 7 days prior to leukapheresis)
• Agreement by WOCBP and males of childbearing potential (MOCBP) to two effective methods of birth control or practice complete abstinence during screening MMTT through to 2 years of PIpepTolDCs follow-up for WOCBP only OR from Day 0 to Day +90 for MOCBP * Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only) ** Effective birth control defined as hormonal contraception/barrier contraception/ surgical procedures to prevent pregnancy

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 principal investigator [PI] discretion)
• Insulin sensitizers (e.g. metformin, thiazolidinediones) within 2 months of leukapheresis
• History of insulin sensitizer use (e.g. metformin, thiazolidinediones) >= 2 months (exception: history of ‘off-label’ uses of these agents for non-diabetes indications may be permitted per PI discretion)
• Other autoimmune/inflammatory disorders (exceptions: (i) Type 1 diabetes. (ii) Asymptomatic patients with incidental autoantibody titres may be permitted per PI discretion)
• 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 as defined by one of the following: * Cardiac events such as myocardial infarction (MI) within the past 6 months * NYHA (New York Heart Association) heart failure class III-IV * Uncontrolled atrial fibrillation or hypertension
• History of vascular disease (e.g. deep vein thrombosis, stroke)
• Clinically significant uncontrolled illness
• Females only: pregnant or breastfeeding
• Any other condition (including psychosocial condition) that would, in the investigator’s judgment, contraindicate the patient’s participation in the clinical study due to safety concerns with clinical study procedures
• Any other condition that would confound study results
• Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)