Multiplexed ion beam imaging visualizes gastric irAEs
Gastric toxicity associated with PD-1 blockade therapy revealed by multiplexed ion beam imaging
Abstract O63
A gastric biopsy taken from a patient with
nivolumab-associated gastroenteritis was analyzed using multiplexed ion beam
imaging (MIBI) by Selena Ferrian, PhD (Stanford University) and colleagues. In order to develop a better
understanding of the pathophysiology of this immune-related adverse event,
twenty-seven labels were analyzed in a single upper gastric biopsy specimen.
The MIBI analysis visualized markers that were consistent
with gastritis and revealed that interferon-gamma was being produced by gastric
epithelial cells, rather than by immune cells. The tissue was characterized by
a mixed inflammation profile, including both granzyme B-diminished/negative CD8
and FoxP3-diminished/negative CD4 T cells, with the majority of the T cells
being CD4+. The investigators defined a set of features found in
PD-1-associated gastritis, which included intense immune infiltrate into the
lamina propria, interferon-gamma production by glandular epithelial cells, and
high Ki67 expression by the epithelial cells as well. This in-depth study of a
common immune-related adverse event may thus provide insight into the mechanisms
of side effects and guide further immune checkpoint inhibitor development,
through elucidating the mechanisms of inflammation and providing future drug
targets.
CD27 T cell stimulation combination shows promise
Phase 1 study of an anti-CD27 agonist as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors
Abstract O83
An anti-CD27 antibody, MK-5890, was tested in solid tumor
patients in a study presented by Ronnie Shapira-Frommer, MD (Oncology Institute, Sheba Medical Center). Patients
received either MK-5890 monotherapy or MK-5890 and pembrolizumab combination
therapy, and monotherapy patients were eligible for cross-over upon disease
progression. Endpoints of this study included safety and tolerability, with a
secondary evaluation of objective response rate.
Forty-four patients were enrolled in the study: 25 received
initial MK-5890 monotherapy at doses from 2-700 mg, while 19 were allotted to
MK-5890 (200 mg) plus pembrolizumab. Dose-limiting toxicities were observed in three
of the monotherapy patients and one patient with the combination, all of which
were related to infusion reactions. Over 90% of patients experienced some level
of treatment-related adverse event, and grade 3-4 events were reported in 22.7%
of the total population. In these initial cohorts, one patient in each group
achieved a partial response. In monotherapy patients that then crossed over to
the combination, adverse events were reported by 85%; at the same time, two of
these patients exhibited a complete response, and another three partial
responses with the median duration of the response not reached. Thus,
costimulation of T cells through an anti-CD27 antibody may help improve anti-tumor
activity of other therapies with further optimization, and the sequencing of
CD27 stimulation appears to play a role in this efficacy.
PD-1-refractory patients may respond to TLR9 agonist
Durable responses in anti-PD-1 refractory melanoma following intratumoral injection of a toll-like receptor 9 (TLR9) agonist, CMP-001, in combination with pembrolizumab
Abstract O85
John M. Kirkwood, MD (University of Pittsburgh Medical
Center) presented the results of a phase 1b study of pembrolizumab in
combination with a TLR9 agonist, CMP-001, in patients with advanced PD-1
refractory melanoma. The majority of patients received combination
pembrolizumab and CMP-001 (N=144), while a few were administered CMP-001 alone
and allowed to cross-over (N=24). CMP-001, which is a CpG-A TLR9 agonist
packaged into a virus-like particle, was intratumorally administered, and
safety and efficacy were assessed.
The therapy was tested using a dose escalation/expansion
strategy, with initial doses ranging from 1-10 mg CMP-001 (N=44), a first
expansion cohort using 5 or 10 mg (N=69), and a second expansion using 10 mg
(N=31). CMP-001 was also administered at two concentrations in the first
expansion cohort. Overall, the treatment was well-tolerated, with the most
common related adverse events being low-grade flu-like symptoms, and six
patients discontinuing treatment due to adverse events. Across all cohorts, the
ORR was 25%, while, among those receiving the diluted CMP-001 formulation, the
ORR was 11%. Responses were noted in non-injected tumors, and, among those
responding to the combination therapy, the median duration of response had not
yet been reached. Response rates were similar whether a patient received
monotherapy or the combination; however, the monotherapy responses were less
durable. This combination therapy therefore holds promise to reverse PD-1
resistance in advanced melanomas, potentially through induction of an
anti-viral immune reaction that is then able to eradicate tumors.
Prognostic B cell biomarkers identified
B-cell activated by checkpoint blockade immunotherapy and radiation improve overall survival in squamous cell carcinomas
Abstract O12
The importance of B cells in responses to immunotherapy and
other cancer therapies was emphasized by Sangwoo Kim, BA (University of
California – San Diego). This study evaluated B cell responses and biomarkers
in HPV-associated head and neck cancer patient samples as well as in
preclinical models. Proteomics arrays and RNA sequencing were employed in human
samples (data from the Cancer Genome Atlas), while murine B cell responses were
analyzed using BCR sequencing, flow cytometry, and single-cell RNA sequencing
after combination treatment with radiotherapy and anti-PD-1 therapy.
The combination therapy in preclinical models was found to
impact many aspects of B cell activity: systemic B cell activation, T1 and
T2-type B cells, memory cells, plasma cells, and antigen specificity were all
altered after the treatments. Specifically, BCR sequencing showed that
combination therapy increased the maximum productive frequency and clonality,
and also modified the CDR3 length. Increases in B cell germinal center
development were also noted through single-cell RNA sequencing, with increasing
density resulting from increasing treatment: more cells with a germinal center
phenotype were observed with combination treatment over each individual
monotherapy. In patient samples, combination therapy was found to increase IgG
levels. Traditionally, HPV+ patients have demonstrated enhanced outcomes over
their HPV- counterparts; however, this significance was abrogated after CD19
(marker for B cells) was taken into account, indicating that B cells play a
major role in responses. For these reasons, the role of B cells in cancer
biology and immunotherapy responsiveness merits further investigation and
consideration, and development of adequate mouse models will be critical to
achieving that goal.
Urinary microbiome linked to BCG response
Variation in the commensal urinary microbiome is associated with response to Bacillus Calmette-Guérin (BCG) immunotherapy in early stage urothelial bladder cancer
Abstract O67
The impact of the urinary microbiome on responses to intravesicular
BCG therapy was investigated by Randy Sweis, MD (University of Chicago) and colleagues. Patients receiving BCG
therapy experience a similar problem as has been observed with other
immunotherapies: up to 50% of patients recur or progress within five years.
Therefore, responsiveness to BCG therapy merits further investigation, as in
this study. Sterile catheterization was employed to collect urine samples, and
these samples were analyzed using 16S rRNA gene sequencing and shotgun
sequencing for their microbial contents. Some samples were also analyzed for
cytokine levels.
Thirty-one patients were enrolled and followed for a median
of 12 months. In that time, 32% of patients recurred after transurethral
resection and BCG instillation. Across all patients, the major phyla included
Actinobacteria, Bacteroidetes, Firmicutes, Proteobacteria, and Tenericutes;
however, distance matrix calculation revealed differences between patients with
and without recurrence. Specifically, a higher abundance of Proteobacteria was
found in recurring patients (P=0.035), with specific taxa showing even larger
differences. At the same time, patients without a recurrence displayed higher
levels of Firmicutes (P=0.049). Cytokine analysis in a subset of 13 patients
revealed no significant differences between recurring and non-recurring
patients. Therefore, the urinary microbiome may indeed have significant impact
on the effectiveness of BCG therapy, just as the gut microbiome has been
implicated with the effectiveness of other treatments.
CD73 antibody demonstrates immunomodulatory capabilities
Immunobiology and clinical activity of CPI-006, an anti-CD73 antibody with immunomodulating properties in a phase 1/1b trial in advanced cancers
Abstract O40
Phase 1 studies of an anti-CD73 antibody, CPI-006, were
presented by Jason Luke, MD, FACP (University of Pittsburgh Medical Center), both as
a single agent and in combination with ciforadenant. CPI-006 was administered
every three weeks to patients with progressive cancer at doses from 1 to 24
mg/kg, with ciforadenant at a fixed 100 mg orally BID. The immunomodulatory
activity of CPI-006 was evaluated through blood analysis of lymphoid subsets,
IgH sequencing, and immunohistochemical analysis of tumor biopsies.
Twenty-four patients received CPI-006 monotherapy, while
sixteen received the combination. All-grade adverse events occurred in 75% of
patients on both regimens, and grade 3-4 events in less than 17% of patients in
both groups. A maximum tolerated dose was not determined. Through tissue
occupancy studies, sustained CD73 occupancy in the periphery was found at doses
at or above 6 mg/kg, and full tumor occupancy at 18 mg/kg or higher doses.
Levels of circulating B and T cells were diminished 30 minutes after infusion,
with B cells partially returning three weeks later, and T cell levels fully
recovering. In alignment with a humoral immune response, the returning cells
had a higher level of memory B cells than before treatment. In patients
receiving at least 6 mg/kg CPI-006, tumor reductions were noted in 4/9 patients
with RCC, NSCLC, or mCRPC, while no responses were noted in cancers without
previous demonstration of sensitivity to these treatments. In addition to its
therapeutic potential, the authors hypothesized that treatment with CPI-006 may
provide opportunities for identification of novel anti-tumor antibodies due to
the induced B cell dynamics.
EGFR-mut NSCLC patients may benefit from neoantigen vaccination
Neoantigen vaccination targeting shared epidermal growth factor receptor (EGFR) mutations induces clinical and immunological responses in non-small cell lung cancer patients
Abstract O18
Gregory A. Lizee, PhD (MD Anderson Cancer Center) presented a phase 1 trial of personalized
neoantigen vaccination in non-small cell lung cancer patients. Peptides for
vaccination were selected from predicted mutation-encoding neoantigens amongst
508 screened cancer-associated genes. Each of the 24 enrolled patients received
at least 12 weekly immunizations in combination with topical imiqimod, and, if
EGFR mutation positive (N=16), also had the option to continue on EGFR
inhibitors.
Clinical responses were observed in seven patients on the
study, all of whom were EGFR mutation-positive. Of these responses, 5/7
displayed T cell responses specific to EGFR neoantigens, and three also had
responses to the L858R driver mutation. The treatment regimen was well
tolerated, and no adverse events of Grade 2-5 were observed. For EGFR
mutation-positive patients, continuing on EGFR inhibitors was strongly
associated with longer overall survival (13.8 vs 7.6 months for continuing vs
stopping therapy, P=0.038), indicating a possible synergy between vaccination
and EGFR inhibition. Therefore, vaccination may be able to overcome resistance
to EGFR inhibitors in NSCLC patients.
Novel CD4+ T cell-DC interactions may lead to increased T cell activity in virally induced cancer
Intratumoral CD163+ DC amplify the type 1 immune response of CD4+CD161+ T cells in HPV16-associated cancers and are associated with better survival
Abstract O44
Several
immune cell subtypes were analyzed in HPV16-associated cancers by Chantal
Duurland, PhD (Leiden University Medical Center)
and colleagues. HPV+ patients have increased survival compared to HPV-
patients, thus the role of the immune response to these cancers should be
better elucidated. High levels of CD4+CD161+ infiltrating T cells have been
found in HPV+ tumors; therefore, the authors used a multi-level approach to
understanding the importance of this unique subset of CD4+ T cells in the HPV+ tumor
microenvironment. The authors also described a population of CD14-CD33-CD163+
cells, which were identified as dendritic cells (DCs). This subset of DCs was
found to associate with strong T cell infiltrates and improved patient survival,
similar to CD4+CD161+ T cells. Thus, there was an effort to understand the
crosstalk of these two immune subsets in HPV+ disease. Further analyses
demonstrated that activated CD163+ DCs generated higher levels of both IL-12
and IL-18 compared to their CD163- counterparts, which in turn induced a type 1
immune response by T cells. Likewise, supplementing patient-derived
HPV16-specific CD4+ T cells with IL-12 and IL-18 enhanced their ability to
produce interferon-gamma, and this was enhanced compared to the CD4+CD161- T
cells. Thus, IL-12 and IL-18 produced by CD163+ DCs can increase stimulation of
CD4+CD161+ T cells within the tumor microenvironment, which could ultimately contribute
to the improved outcomes of patients with virally induced cancers. This study
emphasizes the importance of studying other immune subsets in patient tumors
that may ultimately lead to novel immunotherapeutic combinations.
Seven patients were treated – three with aNK
therapy alone, and another four with aNK and N-803 (an IL-15 superagonist)
combination therapy. The therapy was well-tolerated, without any
treatment-related adverse events over grade 2. Two of the seven patients
experienced objective responses. One patient, refractory to pembrolizumab,
achieved a complete response on aNK monotherapy; however, after six months, the
patient then relapsed. Re-challenge with pembrolizumab after this relapse
resulted in a complete response ongoing at 36 months. These promising initial
findings have led the investigators to begin other trials related to the aNK
therapy as well, without the requirement for on-site processing to aid in the
treatment’s feasibility.
Activated natural killer cell therapy may help Merkel cell patients
Final results from a phase 2 study using off-the-shelf activated natural killer (aNK) cells in combination with N-803, an IL-15 superagonist, in patients with metastatic Merkel cell carcinomaimaging
Abstract O19
Shailender Bhatia, MD (University of Washington) discussed a
study of activated natural killer cells (aNK) in patients with Merkel cell
carcinoma (MCC). The cellular therapy employed in this trial originated from a
rare NK cell lymphoma, and required on-site expansion and activation by
irradiation prior to administration. While MCC often responds to PD-1 blockade,
nearly half of MCC patients display downregulation of MHC-I or other immune
evasion mechanisms, causing them to be refractory to immune checkpoint therapy.
Therefore, this group explored the use of aNK cell therapy in this population,
as this treatment option is effective even in the absence of MHC-I.
Single-cell RNAseq links T follicular helper cells to improved outcomes in HNSCC
Transcriptional dissection reveals antitumor role of T follicular helper cells in head and neck cancer
Abstract O42
A unique T follicular helper (TFH)-like gene
expression signature was observed in CD4+ Tconv cells in TILs from HPV positive
patients whereas a mainly effector-memory signature was detected in TILs from
HPV- patients. Immunofluorescence analysis showed tertiary lymphoid structures
in HPV+ patient samples, further implicating a role for TFH in HNSCC. Analysis
of patient data from the cancer genome atlas revealed that a high TFH signature
was associated with extended progression-free survival, even after an
multivariate analysis controlling for 9 covariates (hazard ratio=0.041,
p=0.02). The increased understanding of the immune microenvironment of HNSCC
from this study may provide guidance for development of future immunotherapies.
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