827-P

2022 Update on the BCG Clinical Trial Programs in Advanced Type 1 Diabetes
W.M. Kühtreiber, H.F. Dias, E. Hostetter, A.H. Lee, N. Ng, G. Wolfe, A. Aristarkhova, J. Bradley, H. Zheng, & D.L Faustman
MASSACHUSETTS GENERAL HOSPITAL & HARVARD MEDICAL SCHOOL, BOSTON, MA, USA– BCG-treated lymphocytes become a major
consumer and regulator of blood sugars invivo– WBC with accelerated glycolysis stop sugartransport when blood sugar is < 50 mg/dl– BCG restores the underlying sugartransport defects in the WBCs of those with
T1D to levels closer to normal– Gradually (over 3 years) BCG induces
potent regulatory T cells (Tregs) tosuppress autoimmunity•••

At our institution, multiple clinicalprotocols are underway testing BCG’s
ability to lower HbA1c, reduce insulin
requirements and change day-to-day
fluctuations in blood sugars
Here we provide an update on the BCG
clinical trial program at Massachusetts
General Hospital (MGH): Enrollment
numbers, study timelines and interim
outcomes for key T1D biomarkers
We also report on an observational studyinvestigating BCG bladder cancer
treatment and HbA1c52

Radiology Study
Phase II Study

6150

6100

Total No.
SubjectsControl/
Placebo (n)Double Blinded/
Open-Label

43

Randomized,
Double-Blinded

050

Open-Label
Randomized,
Double-Blinded
Open-Label~3 y/5 y~3-4 y/5 yRandomized,
Double-Blinded
Randomized,
Double-Blinded

2y/5 yTransition Study

29290

Phase II
Crossover
COVID-BCG
Study*

6NANA

143

95481507575

Phase II PediatricStudy*

Time
Followed/
Duration
5 or 10 y/10 y

Randomized,
Double-Blinded

2 y/5 y• We investigated whether BCG therapy for bladder cancer via intravesical instillation improves blood sugar levels inpatients with comorbid T1D or type 2 diabetes (T2D) by analyzing three large US patient databases: UnitedHealthcare (UHC, N=45 million), Massachusetts General Brigham (MGB, N=6.5 million) and Management
Sciences Associates/Quest Diagnostics (MSA, N=263 million adults), identifying subjects with documented T1D(N=19) or T2D (N=106) undergoing BCG therapy for bladder cancer, and retrospectively assessing BCG’ssubsequent year-by-year impact on blood sugar trends% Change HbA1c after BCG Instillation for Bladder Cancer

18 mo/18 moT2D• An 8-year, randomized clinical trial in adults with longstanding T1D showed
BCG vaccinations induced long-term improvements in glycemic control-10-2001201234567

30

12T2D

20
100-10-20

320
100-10-2001201234567

3YearsMSA (Quest)

T1D
10.0
9.0

8.0

T2D

7.0

1110
987601 2 30 1 2Years• A randomized, double-blinded, placebo-controlled clinical trial with a 5-year
follow up in adults with T1D will read out in about 1.5 years

Multi-center trial with sites at MGH and NYU-Langone
Age 11 to <18 years, ≥ 2 years of T1D, stratified by C-peptide (+/-) at enrollment
Trial will evaluate the impact of BCG on restoring aerobic glycolysis, improving
blood sugars and inducing Tregs to stop pancreas-driven disease
In those with significant C-peptide, it will also evaluate pancreas preservation

Combined20*10 *0-10-2001234567*01234567
Years

Average Change HbA1c after BCG Instillation for Bladder Cancer– In adults with longstanding disease (no pancreas C-peptide), the mechanism ofblood sugar lowering is correction of aerobic glycolysis defects in WBC, which
restores regulated sugar metabolism• A double-blind, placebo-controlled clinical trial in older children (n=150) has
started:T1D

20
100Years

Current Clinical Trial Updates•

United Healthcare

Years--To date, 144 patients with longstanding T1D have received at least two doses of the BCG vaccine. Studygroups include: 1) Long-term follow up of a Phase I study in adults to study the durability of lowered HbA1cvalues after BCG treatment; 2) Randomized, double-blind Phase II clinical trial in adults with longstanding T1Dto demonstrate the reproducibility of Phase I findings; 3) Radiologic study to quantify and identify through FDGCAT scans the organs/organ systems utilizing more sugar after BCG treatment; 4) Adult study comparing 2 vs6 doses of BCG over 5 years of observation; and 5) Multi-center clinical trial of adolescents with ≥ 2 years T1D.
* Currently enrolling.

•••Data Source
MGBMSA (Quest)

T1D%Δ in A1c– BCG corrects underlying aerobicglycolysis defects in the white blood cells(WBC) of subjects with T1D

Phase I +Crossover

BCGTreated(n)9%Δ in A1c

The BCG vaccine has two key beneficial
effects as it relates to T1D1-3:

Retrospective Study: Effects of BCG Bladder Cancer
Treatment on HbA1c

T1D Patient Enrollment & Follow-Up Timelines for BCG Studies

Average A1c•The bacillus Calmette-Guérin (BCG)
vaccine, introduced a century ago fortuberculosis prevention, is being tested
in clinical trials as a treatment for type 1
diabetes (T1D) and other autoimmune
diseases

Average A1cIntroduction•3

Data Source
MGB
7.5
7.0
6.5
6.0
5.5

7.2
7.0
6.8
6.6
6.4
6.2

01234567

01234567

Years

United Healthcare
7.8
7.6
7.4
7.2
7.0

T1DCombined
*
8.5
7.5
6.5

0 1 2 3
Years

5.5
T2D

7.2
7.0
6.8
6.6
6.4
6.2

01234567*01 234 567

Fig 1. Lower HbA1c in T1D, but
not T2D, post-BCG treatment for
bladder cancer. For T1D, all threedatasets show a reduction in HbA1cvalues (% change in HbA1c postBCG instillation) and a near 10%
decrease in A1cs at differing timepoints. The combined T1D datashows a statistically significant
decrease in HbA1C year 1 and year
5 post-BCG (p = 0.0304, 0.0136). In
contrast, MSA data for T2D shows
no change and MGB data shows anincrease in HbA1c values post-BCG
instillation. The combined T2D data
indicates a significant increase inyear 4 after BCG instillation (p =0.0223). (N for each dataset: MGB =4, MSA = 9 and UHC = 6 for T1D;
MGB = 97, MSA = 9 for T2D.)
Fig 2. Decreasing trends inaverage HbA1c for T1D, but not
T2D. In T1D, lower A1cs are seen
for all three databases for subjects
treated with BCG for bladdercancer. When all three T1D
datasets were combined, aStudent’s paired t-test showedsignificance when comparing year
0 to year 5 (p = 0.0133). In T2D,
the trend is in an upwards direction
post BCG instillation, a significant
increase when comparing year 0 toyear 4 (p = 0.0460). (N for eachdataset: MGB=4, MSA=9 and UHC= 6 for T1D; MGB = 97, MSA = 9for T2D.)

YearsConclusions•

BCG vaccine therapy may provide a safe and affordable medical intervention inlongstanding autoimmune diabetes; several clinical trials are underway•

In longstanding T1D, the primary mechanism for BCG vaccine efficacy is correction ofunderlying aerobic glycolysis defects in WBCs, thereby restoring regulated glucose
transport for lowered and improved HbA1c values; BCG also gradually induces Tregs•

Elderly patients with very longstanding T1D who received BCG bladder cancer treatment
show a similar gradual lowering of HbA1c, but this is not seen in those with T2DRefs: 1. Kühtreiber WM, NPJ Vaccines (2018); 2. Shpilsky GF, iScience (2021); 3. Dias HF, Vaccine (2022).
www.postersession.com
Funding Acknowledgement: The Iacocca Foundation. No conflicts of interest to declare. Contact: dfaustman@mgh.harvard.edu