Immunotherapy targeting T-cell regulatory molecules is highly effective in multiple
cancers refractory to standard chemotherapies. However, blocking inhibitory molecules
on activated T cells not only increases tumor cell destruction but also can breach
tolerance, enabling pathological T cells to react with self-antigens. Indeed, autoimmune
endocrinopathies, including hypophysitis, hypopituitarism, and thyroiditis, have been
reported in trials involving anti-CTLA-4 and anti-PD-1 monoclonal antibodies (1–3).
But autoimmune diabetes has not been definitively linked to these agents.
We describe the development of new-onset insulin-dependent diabetes in five patients
after receiving anti-PD-1 antibodies, either as single agent or in combination with
other cancer drugs. Clinical history and key laboratory findings are summarized in
Table 1. Notably, while the patients presented with diverse cancer types, and some
had been treated with other immunological agents, their histories were common for
anti-PD-1 antibody exposure prior to developing autoimmune diabetes. Time from drug
administration to diabetes onset spanned 1 week to 5 months, when patients presented
with severe hyperglycemia or diabetic ketoacidosis (DKA) with elevated HbA1c. Diabetes
was a new diagnosis for all but one patient who had preexisting type 2 diabetes controlled
with metformin. Most patients exhibited inappropriately low or undetectable C-peptide
(Table 1). All were initiated on insulin therapy upon presentation and remained insulin-dependent
for glucose control.
Table 1
Clinical history and key laboratory findings
Patient
Age/sex
Primary diagnosis
Pertinent history
Anti-PD-1 drug
Other chemotoxins
Diabetes presentation
Random C-peptide* and glucose
Time after anti-PD-1
Antibody positivity/titers^
HLA
Diabetes antigen-specific T cells†
1
55/F
Melanoma
Autoimmune thyroid disease
Nivolumab
Ipilimumab, prednisone
DKA, glucose 532 mg/dL, HbA1c 6.9% (52 mmol/mol)
<0.1 ng/mL and 52 mg/dL
5 months
None
A2.1+, DR4+
0.35%
2
83/F
Non–small-cell lung cancer
Remote smoker
Nivolumab
None
DKA, glucose 350 mg/dL, HbA1c 7.7% (61 mmol/mol)
<0.1 ng/mL and 336 mg/dL
<1 month
GAD65/1.2
A2.1+, DR4+
0.28%
3
63/M
Renal cell carcinoma
Hypertension
Nivolumab
Proleukin, bevacizumab, interferon
Random glucose 247, 340 mg/dL; HbA1c 8.2% (66 mmol/mol)
1.3 ng/mL and 79 mg/dL
4 months
GAD65/1.1, ICA512/1.2, Insulin (IAA)/47
A2.1+, DR4+
2.01%
4
58/M
Small-cell lung cancer
Type 2 diabetes
Nivolumab
Carboplatin/ etoposide, paclitaxel
DKA, glucose 749 mg/dL, HbA1c 9.7% (83 mmol/mol) (from 8.5% [69 mmol/mol] prior)
<0.1 ng/mL and 284 mg/dL0.6 ng/mL and 523 mg/dL
1 week
GAD65/13819
A2.1+
0.89%
5
64/F
Melanoma
Autoimmune thyroid disease, psoriasis
Pembrolizumab
None
Ketonuria, glucose 703 mg/dL, HbA1c 7.4% (57 mmol/mol)
0.5 ng/mL and 268 mg/dL
<1 month
None
DR4+
N/A
*
C-peptide reference range: 1.1–4.4 ng/mL.
†
Patients 1, 2, 3, and 4 were positive for HLA-A2.1 from screening by flow cytometry
using monoclonal antibody BB7.1 (Abcam, Cambridge, MA). HLA-A2.1 tetramers were obtained
from the National Institutes of Health Tetramer Core Facility (Atlanta, GA) and loaded
with peptides from five diabetes antigens: insulin A chain (GIVEQCCTSI), insulin B
chain (HLVEALYLV), preproinsulin (ALWMRLLPL), GAD65 (VMNILLQYVV), and IGRP (LNIDLLWSV)
(5). Peripheral blood mononuclear cells (PBMCs) were incubated with the five class
I diabetes antigen-containing tetramers. The data shown represent positive staining
after subtracting staining with a negative tetramer. PBMCs from HLA-A2.1+ donors without
diabetes served as negative control and showed staining (mean ± 2 SD) of 0.5%. PBMCs
were also stained with monoclonal antibodies to CD45RO, CCR7, and CD45RA to identify
cellular phenotypes. Flow data were analyzed using FlowJo software version 9.6.1 (Tree
Star, Ashland, OR).
^
Diabetic autoantibodies to GAD65, ICA512, and insulin were performed at LabCorp, Burlington,
NC. Normal GAD65 titers <0.5 U/mL, ICA512 <1.0 U/mL, and IAA <5.0 U/mL.
Three of the five patients had positive autoantibodies to diabetes autoantigens, with
markedly elevated anti-GAD65 titer in patient 4. Among four HLA-A2+ patients, two
had increased diabetes antigen-specific CD8+ T cells, consistent with prior findings
of such cells in new-onset type 1 diabetes (4,5). The majority of these cells were
CCR7− or + or CD45RO+ effector or memory cells (66%) (data not shown). Interestingly,
two patients also developed autoimmune thyroiditis as manifested by thyroid autoantibodies
and abnormal thyroid function tests, consistent with heightened autoimmunity from
the immune-enhancing monoclonal antibodies.
We highlight the fact that our patients exhibited both cellular and humoral diabetes-associated
autoimmunity, an otherwise rare finding in this age-group (>55 years). Not only do
our cases demonstrate temporal correlation between anti-PD-1 treatment and diabetes
onset, they also provide the first mechanistic support for cancer immunotherapies
targeting T-cell regulatory pathways to precipitate autoimmune diabetes. Other factors
that may influence predisposition for hyperglycemia and autoimmunity in our patients
included combined use with other immune modulators (patient 1), pancreatic metastases
(patient 3), and preexisting type 2 diabetes (patient 4). Nonetheless, the fact that
they all developed acute severe hyperglycemia with ketoacidosis or low/undetectable
C-peptide levels is strong evidence for a new and insulin-deficient type of diabetes.
Diabetes had previously been reported as an adverse event to anti-PD-L1 (2) and one
case was reported in 206 subjects treated with nivolumab (3), but there lacked evidence
for an autoimmune mechanism. Our report demonstrates humoral and cellular autoimmunity
in multiple patients with anti-PD-1–induced diabetes. While it is difficult to estimate
the true incidence of this phenomenon, the five patients in our series represent less
than 3% of total subjects who have participated in PD-1/PD-L1 trials at our institution.
These cases illustrate the importance of recognizing this potential precipitant of
autoimmune diabetes in older individuals receiving immunotherapy.