NcXHF

DISIS AND STANTON
TABLE 1. Unique Characteristics of Immune Checkpoint Inhibitor Therapy
Clinical Observation
Slower time to response than observed with standard
cytotoxic agents
Initial increase in tumor size followed by regression
Immune-related adverse events
Prolonged periods of disease stabilization
Mixed responses with some lesions responding while
other metastatic sites progress
Rational
T cells proliferate and divide in response to antigen and immunomodulation. T cells need time
to expand to the numbers required for an influence on tumor growth.
Trafficking T cells can infiltrate the tumor in high enough numbers to cause inflammation and
swelling—known as pseudoprogression.
General immune stimulators, such as checkpoint inhibitors, can induce immunity reactive to
normal tissues that are immunologically active (e.g., skin, gut).
T cells and tumor cells can exist in an immunologic equilibrium in which T cells control tumor
growth but do not eradicate cancer.
This represents the development of immunologic remodeling where some metastatic deposits
have developed mechanisms of immune resistance.
found that PD-1 was expressed on the surface of 50% of TIL,
PD-L1 was present in 45% of breast cancers, and concurrent
expression of both occurred in 29%. 24 TILs expressing PD-1
were more commonly found in the triple-negative subtype
(70%) than in the rest of the subtypes (25% to 44%, p
0.001). PD-L1 was also more commonly expressed in triplenegative
disease than the other subtypes (59 vs. 33%, p
0.017). In this study, PD-1-positive TILs were associated specifıcally
with the presence of p53 mutations in TNBC potentially
representing a neoepitope signature, whereas there was
no correlation of the expression of PD-L1 and mutational
load. An additional study analyzing PD-L1 gene expression
and using data from the Cancer Genome Atlas found that
TNBC showed signifıcant upregulation of PD-L1 as compared
to other subtypes (p 0.001). Evaluation by tissue microarray
demonstrated 19% of 105 patients with TNBC
expressed PD-L1. 25 Data such as these has supported the
study of immune checkpoint inhibitors in TNBC.
One of the fırst completed clinical trials of a PD-1 monoclonal
antibody (pembrolizumab) in TNBC was reported at
the 2014 San Antonio Breast Cancer meeting by Nanda et
al. 26 The phase Ib study enrolled 32 patients with TNBC who
had recurrent or metastatic disease (47% of which had more
than three lines of previous chemotherapy) with PD-L1 expression
in their tumor (58% of all patients screened had PD-
L1-positive tumors). Pembrolizumab was administered 10
mg/kg intravenously every 2 weeks, and treatment could
continue indefınitely as long as patients were stable and their
disease was not clearly progressing as assessed by RECIST
v1.1 every 8 weeks. Treatment with PD-1 blockade was tolerable,
with 56% of patients reporting an adverse event, but
only 16% with grade 3–5 toxicity. There was one treatmentrelated
death caused by disseminated intravascular coagulation.
The overall RR was 19% (27 patients were evaluable for
response) with one (4%) complete response, four (15%) partial
responses, and seven patients (26%) with stable disease.
Of note, the median time to response was 18 weeks (range, 7
to 32) underscoring the unique kinetics of response seen with
immune modulation as compared with conventional cytotoxic
agents. Other unique characteristics of immune checkpoint
inhibitor therapy are shown in Table 1.
Initial data from a phase I study of an anti-PD-L1 monoclonal
antibody, MPDL3280A, in metastatic TNBC was also
reported. 27 To date, Emens et al have treated 12 patients with
PD-L1-positive disease. Grade 3–4 toxicities occurred in 8%
of patients (one renal insuffıciency). Although immune-related
adverse events have been reported with the use of immune
checkpoint inhibitor agents (Table 2), only one patient in this
study demonstrated grade 2 pyrexia that was potentially attributable
to immune activation. In general, immune-related adverse
events occur in a minority of patients. There were no
toxicity related deaths. Despite the fact that over 90% of patients
had been previously treated with more than two prior regimens
and one-third of those enrolled had visceral metastases, the
overall RR was 33% in the nine patients evaluable for effıcacy
(one complete response and two partial responses). All responses
were seen within the fırst 6 weeks of treatment.
CONCLUSION
Population-based studies of TIL in breast cancer have underscored
that the disease is immunologically active, with TNBC
showing the greatest benefıt from an endogenous immune
response. Initial studies of immune modulation clearly indicate
that TNBC is responsive to newly developed immunooncology
agents that have been clinically effective in classic
immunologic tumors such as melanoma. This observation
furthermore may allow immune-based therapies to move
rapidly from clinical development to standard of care in
TNBC. Rational combinations to further enhance immunity
should be tested in all subtypes of breast cancer. Identifying
the components of the tumor immune environment that improve
prognosis in breast cancer may also identify methods
TABLE 2. Immune-Related Adverse Events
Site
Skin
Liver
Endocrine
Gut
Adverse Event
Rash, pruritus, hives, sun sensitivity
Elevated liver function tests, hepatitis
Headache, visual field changes, adrenal insufficiency,
hypopituitarism, hypothyroid, hypophysitis
Diarrhea, colitis
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