The Society for Immunotherapy of Cancer (SITC) is pleased to present highlights from the first day of the 33rd Annual Meeting in Washington, D.C.
Oxygen Concentration Influences T cell Motility
within Solid and Hematologic Malignancies
Tomasz Zal, PhD (MD Anderson Cancer Center,
Houston, TX, USA) presented research investigating the effect of oxygen
concentrations upon T cell motility within tumors. Previous research suggests
that hyper-oxygenation can improve response to immunotherapy, but its effects
upon T cell motility are unknown. To investigate this question, Dr. Zal
described the development of a novel microscopy method that allows for
measurement of oxygen concentrations using a novel FaST-PLIM method - based
upon PtP-C343 phosphorescence lifetimes - while simultaneously assessing T cell
motility. Initial evaluation of bone marrow samples from patients with acute
lymphoblastic leukemia (ALL) using this approach revealed that T cell motility
is reduced in hypoxic regions, specifically with oxygen pressure less than 5
mmHg. Regions with oxygen pressure greater than 5 mmHg contained T cells with
normal T cell motility. In support, T cell motility in solid lung tumor samples
was also decreased in regions with oxygen pressure less than 5mmHg. Interestingly,
treatment of an ALL mouse model with an inhibitor of oxidative phosphorylation
(IACS-10759) increased oxygen concentrations within the bone marrow, but did
not restore T cell motility. In contrast, supplementation of oxygen to the lung
tissues increased oxygen pressure and recovered T cell motility. Together,
these data suggest that T cell motility is reduced in hypoxic regions of
tumors, and that hyper-oxygenation can restore T cell surveillance that could
potentially enhance immunotherapeutic efficacy.
Meta-Analysis Reveals Correlations Between
Response to Anti-PD-1/PD-L1 Therapy and Biomarker Assessment Methods
Steve Lu, BS (Johns Hopkins University,
Baltimore, MD, USA) presented data from a meta-analysis comparing associations
between response to anti-PD-1/PD-L1 immune checkpoint inhibitors (ICI) and
specific biomarker assessment methods including PD-L1 immunohistochemistry
(IHC), tumor mutational burden (TMB) evaluation, gene expression profiling
(GEP), and multiplex immunofluorescence (IF). In all, data from 8021 patient
samples from greater than 10 tumor types (44 published studies total) were
included in the analysis, with investigators noting the type of biomarker
analysis used in the study as well as the number of patients with complete response,
partial response, and progressive disease. Results indicate that multiplex IF
was more significantly correlated with ICI response (weighted AUC = 0.802) than
PD-L1 IHC, TMB, and GEP (weighted AUC = 0.656, 0.690, 0.652, respectively). A
combined approach using a combination of PD-L1 IHC, TMB, and/or GEP enhanced
association with ICI response compared to the respective individual approaches
(AUC = 0.733), but multiplex IF remained the strongest correlative (AUC =
0.802). This meta-analysis suggests a current hierarchy of biomarker assessment
and association with ICI response. Further studies are necessary to validate
these findings for each individual and combinatorial approach, and identified
ICI response associations will remain in flux as new technologies become
available.
Visualization of Tumors and CD8+ T cell
Distribution in Patients with Advanced Solid Tumors via a Novel Anti-CD8 Minibody
Michael Gordon, MD (HonorHealth Research
Institute, Scottsdale, AZ, USA) presented initial data from a phase 1
first-in-human study investigating a novel method to detect CD8+ T cell
distribution in patients with solid tumors using positron emission tomography
and the anti-CD8 radiolabeled minibody 89Zr-IAB22M2C. In all, 15 patients with
advanced solid tumors (melanoma = 8, non-small cell lung cancer [NSCLC] = 6,
hepatocellular = 1) were provided 89Zr-IAB22M2C (0.5-1.5mg, 3mCi IV) and
subsequently underwent multiple PET scans over a 5-7 day period (scans = 1-2hr,
6-8hr, 24hr, 48hr, 5-7 days). No drug-related adverse reactions during
administration of 89Zr-IAB22M2C were noted, with the exception of transient ADA
in one patient. PET results indicate that 89Zr-IAB22M2C readily accumulates in
CD8-rich tissues including bone marrow and the spleen, and that excess 89Zr-IAB22M2C
was excreted through the hepatobiliary system. Tumor 89Zr-IAB22M2C uptake was
noted in 10/15 patients, and very little signal was observed in background
tissues including muscle, brain, and heart. 89Zr-IAB22M2C signal was observed
over several days (at least day 7), and more clearly identified a secondary
lesion in a patient with hepatocellular carcinoma compared to hepatic phase
CECT. Together, these data indicate that 89zr-IAB22M2C is safe in patients with
advanced solid tumors, and may be able to provide assistance in measuring tumor
size and location, as well as CD8+ T cell distribution.
Early Phase 1 Data Suggest Combination
Anti-TIM-3 and Anti-PD-1 Offers Promising Safety and Efficacy in Patients with
NSCLC Treated with Prior Anti-PD-1/PD-L1 Therapy
Diwakar Davar, MD (University of Pittsburgh,
Pittsburgh, PA, USA) presented data from the phase 1 AMBER trial (NCT02817633) assessing dosage, safety, and efficacy of
TSR-022 – an anti-TIM3 monoclonal antibody – in combination with anti-PD-1
TSR-042 in patients with advanced NSCLC who have relapsed or are refractory to
prior anti-PD-1/PD-L1 therapy. In all, 39 patients (prior pembrolizumab = 14,
prior nivolumab = 23, prior atezolizumab = 5, others = 2; PD-L1 TPS greater
than or equal to one percent = 16, TPS less than one percent = 8, unknown TPS =
15) received TSR-022 (100mg: n=14; 300mg: n=25, Q3W) in combination with TSR-042
(500mg Q3W). Treatment-related adverse events were observed in less than five
percent of patients, with only three grade three events (100mg cohort: one
fatigue, one lipase increase; 300mg cohort: one lipase increase). In all, four
PR and 11 SD were observed in 31 evaluable patients across both cohorts (100mg:
one PR, three SD; 300mg: three PR, eight SD). Interestingly, all four PR were
observed in patients with PD-L1 TPS greater than or equal to one percent.
Together, these data indicate that combination TSR-022 + TSR-042 is safe in
patients with advanced NSCLC who have received prior anti-PD-1/PD-L1 therapy,
and early signs of clinical efficacy support continued investigation of this
treatment regimen. In addition, these data suggest that PD-L1 TPS may serve as
a predictive biomarker of response for this combination strategy.
Phase 1 4280-001 Trial Offers Early Glimpse
into Safety and Efficacy of Treatment of Patients with Advanced Solid Tumors
with Anti–LAG-3 MK-4280 as a Single-Agent or in Combination with Pembrolizumab
Nehal Lakhani, MD, PhD (START-Midwest, Grand
Rapids, MI, USA) presented data from the first-in-human phase 1 4280-001 trial
(NCT02720068) investigating dosage and safety of the anti-LAG-3 antibody
MK-4280 as a single-agent or in combination with anti-PD-1 pembrolizumab for
the treatment of patients with advanced solid tumors. Adult patients with
metastatic solid tumors (sarcoma, appendiceal, billary, colorectal,
adrenocortical, breast, small intestinal, renal cell, among others) received MK-4280
(dose-escalation from 7 - 700mg Q3W) as a single agent (n = 18) or in
combination with pembrolizumab (200mg Q3W, n = 15). No dose-limiting toxicities
were observed in either cohort across all MK-4280 doses. Grade 3 TRAEs were
observed in 50 percent (n=9) and 60 percent (n=9) of the monotherapy and
combination cohorts, respectively. At data cut-off, ORR was six percent (95
percent CI: less than one – 27; one PR, two SD) in the monotherapy cohort, and
27 percent (95 percent CI: 8 – 55; four PR, 2 SD) in the combination cohort.
Disease control rate was 17 percent (95 percent CI: 4 – 41) and 40 percent (95
percent CI: 16 – 68) in patients who received MK-4280 and
MK-4280/pembrolizumab, respectively. These early data suggest that MK-4280 can
be safely provided to patients with advanced solid tumors up to 700mg, and that
administration as a single-agent or in combination with pembrolizumab may
potentially provide clinical benefit.
Updated PIVOT-02 Results Demonstrate Durable
Responses in Advanced Melanoma Patients Treated with NKTR-214 + Nivolumab
Adi Diab, MD (MD Anderson Cancer Center,
Houston, TX, USA) presented updated data from the PIVOT-02 (NCT02983045) trial
assessing efficacy and safety of the IL-2 agonist NKTR-214 in combination with
anti-PD-1 nivolumab for the treatment of patients with advanced melanoma. In
all, 38 patients (PD-L1 greater than or equal to 1 percent = 19, PD-L1 less
than one percent = 14) treated with NKTR-214 (0.006 mg/kg Q3W) and nivolumab
(360 Q3W) displayed an ORR of 53 percent (n = 20, CR = 9, PR = 11). ORR of
PD-L1+ and PD-L1- patients was 68% and 43%, respectively. At median follow-up
of 7.2 months, median duration of response has not yet been reached (95 percent
CI: 2.6 – NR), and 85 percent (17/20) of patients have ongoing responses. Grade
3/4 TRAEs were observed in 8 patients (19.5 percent), most commonly lipase
increase (n = 3) and atrial fibrillation (n = 2). Importantly, incidence of
cytokine-related AEs – a concern with traditional IL-2 treatment – decreased
over continued dosing. Analyses of patient peripheral blood revealed increases
in CD4+ (15x, p less than 0.001), CD8+ (26x, p less than 0.001), and NK cells
(4.5x, p less than 0.001) seven days post-cycle 1. Increased tumor infiltration
of CD8+ T cells was also observed in patients treated with the combination
regimen (baseline = 108 cells/mm2; week 3 = 712 cells/mm2). Gene expression
analyses of treated patient samples also indicate a profile consistent with
CD8+ anti-tumor activity. In all, these data suggest that NKTR-214 + nivolumab
may provide clinical benefit as first-line treatment of patients with advanced
melanoma, and that the combination promotes increased immunity within the tumor
microenvironment.
Inhibition
of MARCO may help Promote Anti-Tumor Activity within the Tumor Microenvironment
Dhifaf Sarhan, PhD
(Karolinska Institutet, Solna, Sweden) described the role of the scavenger
receptor MARCO (macrophage receptor with collagenous structure) towards
modulation of immunity within tumor microenvironment. MARCO is expressed on
suppressive immune cells including myeloid-derived suppressor cells and
tumor-associated macrophages, commonly found in pancreatic cancer samples that
also have low CD8+ T cell infiltration. Pre-clinical studies reveal that
treatment of mice bearing 4T1 mammary carcinoma with an anti-MARCO antibody
reduced tumor growth and metastasis. The mechanism of action, however, remains
unknown. Evaluation of pancreatic cancer samples revealed that low abundance of
MARCO correlated with increased T cell infiltration and survival compared to
MARCO-high samples (p = 0.033 and 0.027, respectively). In addition, treatment
of cytokine-polarized macrophages that display a suppressive phenotype with
anti-MARCO restored IFNgamma production as well as tumor killing function, and
normalized metabolism towards the levels of M1 anti-tumor macrophages.
Together, these data showed that increased MARCO abundance on TAMs and MDSC may
inhibit cytotoxic anti-tumor activity in the tumor microenvironment, and that
treatment of patients with anti-MARCO may be a potential approach towards
restoring immunity in difficult to treat diseases such as pancreatic and breast
cancer.
Personalized NEO-PV-01 Vaccine Promotes
Immunogenic Responses in Patients with Advanced Melanoma and NSCLC
Siwen Hu-Lieskovan (Ronald Reagan UCLA Medical
Center, Los Angeles, CA, USA) presented clinical data from the phase 1b NT-001
trial (NCT02897765) investigating efficacy of NEO-PV-01 – a personalized neoantigen vaccine that
targets up to 20 unique, high quality neoantigens – in combination with
nivolumab for the treatment of patients with metastatic melanoma and NSCLC.
Patients received initial nivolumab for 12 weeks while NEO-PV-01 was
synthesized, and then received the vaccine for an additional 12 weeks. All
patients developed an immune response due to the vaccination, and 56 percent of
epitopes were able to induce a CD4+ and CD8+ immune response that was
detectable two weeks into treatment. 50 percent of melanoma patients achieved
PR prior to NEO-PV-01 vaccination, and an additional 37 percent and 6.3 percent
achieved PR and CR post-vaccination, respectively. In all, 75 percent of
melanoma patients remain on treatment. In addition, 27 percent of patients with
NSCLC achieved PR pre-vaccination, and an additional 25 percent achieved PR
post-vaccination. 64 percent of NSCLC patients remain on treatment. Two
melanoma patients treated with the combination regimen demonstrated durable
responses that were detectable 52- and 70-weeks post treatment initiation, and
one NSCLC patient experienced an immune response detectable 52 weeks
post-initiation of therapy. In summary, data suggest that the NEO-PV-01
vaccination in combination with nivolumab may be effective in treating patients
with melanoma and NSCLC, and that immunity generated by the vaccine is durable
over time.