The Society for Immunotherapy of Cancer (SITC) is pleased to present scientific highlights from the Nov. 9, 2019, sessions of the 34th Annual Meeting.
In vivo tracking of adoptively transferred T cells enabled
by PET/CT
Flexible copper-64-nanoparticle-based cell labeling system
allows for in vivo tracking of adoptively transferred T-cells by PET/CT
Abstract O1
A flexible system for radiolabeling and tracking adoptive
cellular therapies was presented by Hólmfridur R. Halldórsdóttir, MSc
(Technical University of Denmark). By labeling T cells in vitro using copper-64
([64]Cu) micelles, which are self-assembled lipids, the team was able to
noninvasively monitor the in vivo biodistribution of these radiolabeled cells
over the course of 40 hours using positron emission tomography/computed
tomography (PET/CT), and track their response to various therapeutic
interventions.
Prior to in vivo imaging, the impact of micelles on T cells
was tested. Viability and function of the T cells were not affected by the
micelles. Throughout all in vivo studies, there was correspondence between the
number of T cells in an organ and the measured radioactivity, indicating the
cell tracking technique could provide accurate quantification. Following
whole-body irradiation, elevated activity was noted in the thymus compared to
non-irradiated mice, which is a well-known homing site for T cells after total
body irradiation (4.6±0.1% vs 2.1±0.1% of injected dose, respectively). Tumors
were also treated with a sustained release depot of TLR7 agonist, and,
following this treatment, a higher accumulation of [64]Cu-labeled T cells was
observed in the tumor tissues. This approach may therefore help elucidate the
in vivo behavior of adoptive cellular therapies, without compromising their
efficacy, which has immense implications for future monitoring of cellular
therapies.
HER2-positive cancers may benefit from novel bispecific
treatment
A phase 1 dose escalation study of PRS-343, a HER2/4-1BB
bispecific molecule, in patients with HER2-positive malignancies
Abstract O82
Sarina Piha-Paul, MD (MD Anderson Cancer Center) presented
an investigation of a HER/4-1BB bispecific, known as PRS-343, in patients with
HER2-positive cancers. This dose-escalation study has evaluated cohorts from
0.0005 to 8 mg/kg in order to identify the safety profile of PRS-343 and to
determine the dose for further studies. Measures of response and biomarkers
were among the secondary objectives.
Fifty-three patients with solid tumors have been treated to
date, and the minimal active dose was found to be 2.5 mg/kg. At and above this
threshold, eighteen patients have been treated and are evaluable. In this
patient group, significant expansion of the CD8+ T cell pool was noted after
treatment with PRS-343, especially in the tumor microenvironment, in accordance
with the proposed mechanism of action for PRS-343. This led to a disease control
rate in these patients of 55%, including 2/18 patients confirmed partial
response. Higher expansion of CD8+ T cells was found in responding patients
over non-responders. The treatment was considered safe, with no serious adverse
events or dose-limiting toxicities reported. The investigators are therefore
continuing the further investigation of this first-in-class 4-1BB bispecific.
Front-line atezolizumab improves PD-L1+ NSCLC outcomes
IMpower110: Interim overall survival (OS) analysis of a
phase III study of atezolizumab (atezo) monotherapy vs platinum-based
chemotherapy (chemo) as first-line (1L) treatment in PD-L1-selected NSCLC
Abstract O81
PD-L1-postive NSCLC patients were treated with either
front-line atezolizumab or chemotherapy in the IMpower110 study, presented by Giuseppe Giaccone, MD, PhD (Weill Cornell Medicine). In this study, both squamous and
non-squamous NSCLC patients were enrolled, and randomized 1:1 to atezolizumab
1200 mg Q3W or platinum-based chemotherapy for four or six 21-day cycles. As
the primary endpoint, overall survival was tested hierarchically by PD-L1
status (highest to lowest expression).
Across both arms of the trial, PD-L1 expression was evenly
distributed: 37% of all-comers were TC3/IC3. The majority of patients
experienced treatment-related adverse events: 60.5% of atezolizumab patients
and 85.2% of chemotherapy patients reported any-grade events, with grade 3-4 in
12.9% and 44.1% as well, respectively. In patients with the highest levels of
PD-L1 expression (TC3 or IC3), after a median follow-up of 15.7 months, the
overall survival was significantly improved (by 7.1 months) with atezolizumab
treatment over chemotherapy (HR=0.595, p=0.0106). The statistical endpoints
were not met in the pre-specified next analysis group of TC2/3-IC2/3, however,
so further analysis could not be performed for significance at other PD-L1
levels. Front-line atezolizumab may therefore hold promise for further
exploration in highly-PD-L1-expressing NSCLC patients, who appear to derive the
most benefit in this front-line study.
Microbial colonization linked to colorectal cancer immune
responses
Helicobacter hepaticus remodels the tumor immune
microenvironment and reduces colorectal tumor burden
Abstract O69
Based on the hypothesis that intestinal microbiota may
modulate immune balance, Abigail E. Overacre-Delgoffe, PhD (University of
Pittsburgh) presented a preclinical study of microbiome manipulation in
colorectal cancer (CRC) models. Colitis-associated CRC was established through
AOM-DSS induction, and half of these tumor-bearing mice were colonized with
Helicobacter hepaticus (Hhep) after tumor development. Lymphocytes throughout
the digestive tract and tumor were analyzed using flow cytometry and confocal
microscopy.
Colonization of CRC tumor-bearing mice with Hhep was found
to significantly remodel the tumor microenvironment, leading to increased
dendritic and Tconv cell infiltration, as well as a decreased Treg presence.
This also led to reduction of tumor burden and extension of overall survival
for those mice supplemented with Hhep. Using FISH, Hhep was found to colonize
not only the normal colonic mucosa, but also infiltrated tumors themselves as
well. The authors report that the bacteria also lead to Hhep-specific CD4+ T follicular
helper cell (Tfh) infiltration, which may contribute to more efficient
anti-tumor immunity, particularly due to the increased number of organized
tertiary lymphoid structures in the tumors. Further investigation of the
microbiome may in turn provide insight and potential therapeutic mechanisms for
improving anti-cancer immune responses.
Biomarkers for immunotherapy responsiveness in sarcomas
defined
Immune enrichment and functional T-cell receptor (TCR)
frequencies predict response to immune checkpoint blockade (ICB) in selected
fusion-associated sarcomas
Abstract O33
Biomarkers of response to immunotherapy for sarcomas were
analyzed and presented by Akash Mitra, BS (MD Anderson Cancer Center). Sarcoma
patients (alveolar soft part and synovial) were treated with combination
durvalumab and tremelimumab, and an in-depth analysis of tumor tissues was
performed. Whole-exome, RNA- and TCR-sequencing were conducted to explore
correlates with response.
Unlike some other cancer types, tumor mutational burden was
not correlated with outcomes in this study. Rather, many immune-related
pathways were upregulated in responders, as KEGG pathway analysis indicated
higher activity of T cell and B cell response pathways, as well as increases in
PD-L1. B cell infiltrates were also more frequent in responding tumors in both
pre-treatment and on-treatment biopsies. T cell clonality was inversely correlated
with outcomes, with an increased diversity in responders, and a lower maximum
productive frequency in responders as well. While further immune deconvolution
and BCR sequencing studies are on-going, these genetic and immune signatures
may provide greater insight into the immune responsiveness of sarcomas.
Il-35+ B cells play a role in pancreatic cancer progression
IL-35+ B cells regulates anti-tumor immune response in
pancreatic cancer
Abstract O47
Bhalchandra Mirlekar, PhD (University of North Carolina -
Chapel Hill) presented a study of the immunologic processes that contribute to
pancreatic tumor immunotherapy resistance. This involved the use of both
spontaneous and orthotopic murine pancreatic tumor models, using a model with B
cell-specific genetic loss of IL-35. Combination therapy of IL-35 blockade and
immune checkpoint blockade was explored to further elucidate the role of IL-35.
This study uncovered an important role for regulatory B
cells in the promotion of pancreatic tumorigenesis. Specifically, this cell population
produced IL-35 – a cytokine which has been indicated in the suppression of T
cell responses both in autoimmunity and cancer. The study further indicated
that only B cell-produced IL-35 was essential for this immunosuppression to
occur. When pancreatic tumors from the IL-35 deficient mouse model were treated
with anti-PD-1 therapy, regression of normally immunotherapy-resistant tumors
was observed. These preclinical studies were also corroborated through analysis
of patient pancreatic cancer samples, in which an IL-35+ B cell subset was
found, and correlated with dysfunctional T cells. IL-35-targeted therapy may
therefore be promising for pancreatic cancer, but the model is still slightly
disparate from the actual clinical situation.
Bispecific anti-PD-1 and CTLA-4 antibody demonstrates
promise of lower toxicity
A phase 1 study of AK104, a tetrameric bispecific antibody
that targets PD-1 and CTLA-4 in patients with advanced solid tumors
Abstract O30
A dose escalation and expansion study of a PD-1/CTLA-4
bispecific antibody was presented by Ben Markman, MBBS, FRACP (Monash Medical
Centre). While combination treatments of individual PD-1 and CTLA-4-targeting
antibodies have shown encouraging efficacy, they are also limited by severe
toxicities. Therefore, this group hypothesized that the bispecific tetrameric
form of AK104 may maintain that efficacy while limiting toxicity due to
enhanced tumor specificity. Patients with several solid tumor types were
enrolled and dosed between 0.2 and 10 mg/kg Q2W with AK104 with the goal of
determining the safety, efficacy, and recommended phase two dose of the
treatment.
The bispecific agent was found to have a Kd an order of
magnitude better than that of ipilimumab and nivolumab, supporting its improved
targeting avidity. Fifty-five patients have been treated with a median of four
doses as of data cut-off, with the most at the 6 mg/kg level. Any-grade
treatment-related adverse events were reported in 63% of patients, with 11% of
patients experiencing a grade 3 reaction, both of which compare favorably to
the traditional combination therapy. When patients were treated with doses of
at least 2 mg/kg, the overall response rate was 24%, and the disease control
rate was 44%. Increases in Ki-67, a proliferation marker, were noted in peripheral
CD4+ T cells after treatment with AK104, supporting immune activation. While it
remains early to compare the efficacy of AK104 relative to currently-approved
combination therapies, the initial safety profile of this agent warrants
further investigation.
Immunologic responses noted in vaccine-treated glioblastoma
Phase II trial of therapeutic vaccine consisting of
autologous dendritic cells loaded with autologous tumor cell antigens from
self-renewing cancer cells in patients with newly diagnosed glioblastoma
Abstract O22
A patient-specific vaccine for glioblastoma patients,
AV-GBM-1, was tested in a phase 2 study presented by Daniela Bota, MD, PhD (University of California – Irvine). The technique involved establishment of a
short-term cell line from tumor tissue excised at the time of surgery,
production of dendritic cells from PBMCs, and development of the vaccine
antigens from irradiated tumor cell lysate. Vaccination was performed following
completion of standard optimal therapy (surgical resection, radiotherapy, and
chemotherapy). The study aimed to achieve a 75% survival rate fifteen months
after enrollment, which would represent a 50% increase over survival from
current standard therapies.
Thirty-one of the planned 55 patients have begun treatment,
with success rates of 46/48 for cell line establishment and 41/42 for
development of a successful leukapheresis product. To date, twelve patients
completed all eight doses, and five discontinued early due to progression.
Immunological responses including Th1, Th2, and Th17 responses were noted in
60% of patients for whom this was measured, indicating promising immune
activation with this technique. No notable toxicities have been reported, with
all serious adverse events not attributed to the treatment. The study is still
ongoing, but, given the encouraging immune activation indications and safety
profile so far, the authors are enthusiastic about future results.
Dear JITC Readers,
