The Society for Immunotherapy of Cancer (SITC) is pleased to present highlights
from the Saturday programs (Nov. 11, 2017) of the 32nd Annual Meeting in National Harbor, Md. (Scroll to the bottom of this blog post to view the Glossary).
Dendritic cell acquisition of MHC I controls CD8+ T cell priming
Brandon MacNabb, BS (University of Chicago) presented data
supporting the concept of MHC I antigen presentation by Batf3-lineage DCs as a
critical component of CD8+-mediated anti-tumor response. Researchers initially
generated H2-KbAB (MHC I+) and Kb-/-(MHC I-) C1498.SIY acute myeloid leukemia
cell lines and subsequently engrafted C57BL/6 mice to determine the
contribution of tumor cell MHC I presentation in CD8+ T cell priming. Initial
assessment revealed reduced tumor growth in C1498.SIY KbAB mice compared to
C1498.SIY Kb-/- mice. CD8+ T cell proliferation was also increased in KbAB mice
compared to Kb-/- mice (p < 0.05). The observed C1498.SIY KbAB-dependent CD8+
proliferation was abolished in Batf3-/- C57BL/6 mice (p < 0.01). IFN-Ï’
secretion was also decreased in Batf3-/- KbAB mice, suggesting that Batf3
initiates CD8+ priming. Transfer of autologous T cells from KbAB tumor-bearing mice
offered complete protection from tumor growth in tumor-free mice. Conversely, autologous
T cells from Kb-/- mice offered no such protection. Interestingly, DCs isolated
from the TME and the tumor-draining lymph node in tumor-positive mice had
increased KbAB MHC I expression (p < 0.001), suggesting DC acquisition of
tumor-derived MHC I. Ex vivo experiments confirmed that migratory KbAB DCs are
capable of CD8+ priming. These data reveal the importance of Batf3-lineage DCs
and tumor-derived MHC I presentation in CD8+ T cell activation of anti-tumor
response, providing insight into potential development of DC-oriented
therapies.
Risk/benefit ratio differs between checkpoint inhibitor monotherapy and combination therapy in the neoadjuvant setting in patients with advanced melanoma.
Sangeetha Reddy, MD (University of Texas MD Anderson Cancer
Center, Houston, TX) discussed preliminary clinical trial results examining the
efficacy of neoadjuvant nivolumab as monotherapy, or in combination with
ipilimumab, in patients with high-risk advanced melanoma. Patients with
resectable stage III or oligometastatic stage IV melanoma received either
nivolumab monotherapy (n=12, 3mg/kg IV Q2W for 4 doses) or combination nivo/ipi
(n=11, 1mg/kg and 3mg/kg, respectively, Q3W for 3 doses) prior to surgical
resection, and then nivolumab (3 mg/kg Q2W) for an additional 6 months. ORR in
the nivolumab and nivo/ipi groups was 25% (3 CR) and 73% (5 CR) respectively
(RECIST 1.1). All patients receiving nivo/ipi were able to undergo surgical
resection; conversely, 2 patients from the nivolumab cohort were not eligible
for resection. Patients with pathological CR had 100% RFS (p = 0.05 versus
non-responders). Incidence of grade 3/4 AEs, however, was higher in the
nivo/ipi than the nivolumab monotherapy cohort (73% vs. 8%). These data
resulted in trial stoppage after DSMB review. Researchers subsequently used IHC
to investigate the TME to determine if specific biomarkers could predict
therapeutic response and resistance. During treatment, responders had increased
CD8+ T cell counts (p = 0.002), PD-L1 expression (p = 0.01) and TIL counts
compared to non-responders. Additionally, T cell clonality was increased in
responders during treatment (p = 0.006 vs. non-responders). RNAseq analyses of
tumor samples are ongoing. These data reveal that both neoadjuvant nivolumab
monotherapy and combination nivo/ipi have activity in patients with advanced,
resectable melanoma, but the risk/benefit ratio differs.
PIVOT-02: Promising early efficacy and safety with CD-122-biased agonist NKTR-214 plus nivolumab in patients with locally advanced/metastatic solid tumors
Adi Diab, MD (MD Anderson Cancer Center, Houston, TX)
presented preliminary results from the phase 1/2 Pivot-02 dose escalation study
of NKTR-214, a novel CD-122-biased agonist, in combination with anti-PD-1 agent
nivolumab, in patients with advanced/metastatic solid tumors (NCT02983045).
NKTR-214 is metabolized to an active cytokine that harnesses the IL-2 pathway
to preferentially activate and expand effector T cells and NK cells in the
tumor microenvironment, resulting in increased proliferation of TILs and
greater T cell PD-1 expression. Based on anticipated synergism between drug
classes, NKTR-214 (0.003 – 0.009mg/kg) and nivolumab (240mg Q2W or 360mg Q3W)
were administered to 38 checkpoint inhibitor-naive patients (mean age 61 yrs,
79% male, 68% no prior treatment for metastatic disease) with BRAF +ve
metastatic melanoma (mM, n=11; 9/18/73% stage M1a/b/c; 46% PD-L1 ≥5%), renal
cell carcinoma (RCC, n=22; 29% first-line PD-L1 ≥ 1%; 63% second-line PD-L1 ≥
1%) or non-small cell lung carcinoma (NSCLC, n=5; 0% PD-L1 ≥1%). At data cutoff
on November 1, 2017, 26/36 (72%) evaluable patients experienced target lesion
tumor shrinkage, the majority of whom (n=19) received NKTR-214 0.006 mg/kg Q3W.
ORR (RECIST v1.1 and iRECIST) was 64% (2 CR, 5 PR) and 46% (1 CR, 5 PR), in
patients with mM and RCC, respectively, treated first-line. ORR in second-line
NSCLC (PD-L1-negative) patients was 75% (1 CR, 2 PR). DCR in the three groups
was 91%, 85% and 75%, respectively, and mTTR approx. 1.8 months across groups.
Treatment is ongoing in all responders. Grade 3 DLTs (hypotension, metabolic
acidosis, diarrhea, hyperglycemia) occurred in 4 patients in the highest dose
cohort. Grade 1/2 TRAEs occurred in ≥50% of patients, most commonly fatigue,
flu-like symptoms, and rash. There were no discontinuations due to TRAEs, no
treatment-related deaths, and NKTR-214 did not increase the risk for irAEs with
nivolumab. The trial established NKTR-214 0.006 mg/kg plus nivolumab 360 mg IV
Q3W as the maximum tolerated dose. Enrollment to 13 expansion cohorts is
underway.
Early FDG-PET serves as a pharmacodynamic biomarker of treatment response in patients with microsatellite stable mCRC treated with carcinoembryonic antigen T-cell bispecific (CEA-TCB) antibody plus atezolizumab
Jose Saro, MD (Roche Innovation Center Zurich, Zurich,
Switzerland) reported preliminary results from a phase 1b trial of CEA-TCB, a
novel T-cell bispecific antibody targeting CEA on tumor cells, and CD3 on T
cells (5-300mg IV, QW), in combination with the anti-PD-L1 antibody
atezolizumab (1200mg IV, Q3W), in patients with microsatellite stable
metastatic colorectal cancer (mCRC) (NCT02650713). mCRC is a disease with high
unmet medical need in which >90% of patients have CEA-high tumors. In the
first trial to employ F-fluorodeoxyglucose-positron emission tomography
(FDG-PET) imaging as a pharmacodynamic biomarker of response, Dr. Saro and
colleagues evaluated change in maximum standardized uptake value (SUVmax ; a
measure of tumor metabolic activity), metabolic tumor volume (MTV), and total
lesion glycolysis (TLG) before, and 3-7 weeks after, treatment in the tumors of
25 patients with locally advanced/metastatic CEA +ve disease and poor response
to standard therapy. FDG uptake 4 weeks after starting treatment was noticeably
reduced compared to baseline, and metabolic response decreased in 17/25 (68%)
patients, mostly those receiving a CEA-TCB dose ≥ 80mg. Changes in on-treatment
metabolic response appeared to be CEA-TCB dose-dependent (p=0.08), and correlated
with tumor shrinkage (p = 0.0002), which was observed in 9/25 (36%) patients,
and with longer PFS [HR 0.08 (95%CI:0.16-0.35); p<0.0001]. These data
suggest that early on-treatment change in FDG-PET may have value as an efficacy
biomarker and to guide dose selection in patients with MSS mCRC. Analyses to
validate FDG-PET are ongoing.
Novel single cell analyses offer unique insight into acquired immunotherapy resistance in patients with Merkel cell carcinoma.
Kelly Paulson, MD, PhD (Fred Hutchinson Cancer Research
Center, Seattle, WA) discussed research using Merkel cell carcinoma (MCC) as a
model to better understand acquired immunotherapy resistance mechanisms. A
59-year old male with widely metastatic, heavily pre-treated MCC received
autologous HLA B*3502-restricted MCPyV-specific CD8+ T cell therapy, which
targets the immunogenic MCPuY MCC-specific oncoprotein, and despite initial
response (90% reduction in tumor burden) experienced metastasis after ~630
days. Using novel single-cell RNA sequencing technologies (scRNAseq) to assess
mixed tumor cell populations across the patient timeline, researchers observed
that CD8+ T cells overexpressed genes related to cell division, activation, and
glycolysis during the initial immune response and tumor regression. Genes
indicating CD8+ activation were most highly expressed at day 370 during patient
response (day 376, p < 0.01 versus pre-treatment), and reduced during early
relapse (day 614, p < 0.01 versus time of response). CD8+ T cells were
observed within the tumor samples at time of relapse (acquired resistance),
eliminating stromal exclusion as a resistance mechanism. Altered tumor cell
gene expression was observed during acquired resistance, resulting in
downregulation of tumor HLA-B and upregulation of HLA-E. Reduced tumor HLA-B
expression mediated therapeutic resistance via loss of HLA-B-restricted T cell
recognition and was reversible in vitro following 5-azacitidine or
IFNγ treatment. HLA-E upregulation suppressed NK cell activity. Only
achievable using scRNAseq, these results elucidate mechanisms that dictate
long-term tumor progression. Additionally, researchers provided a foundation
for using scRNAseq to better understand acquired immunotherapy resistance in
other malignancies.
Unique qualities, but not quantity, of neoantigens predict long-term survival in patients with pancreatic adenocarcinoma
Vinod Balachandran, MD (Memorial Sloan Kettering Cancer Center,
New York, NY) presented a series of studies designed to increase mechanistic
understanding of the relationship between T cell immunity and rare cases of
long-term survival in patients with pancreatic adenocarcinoma (PDAC). A
combined analysis of whole exome sequencing, T cell receptor (TCR) Vβ-chain
sequencing, 9-color multiplexed immunohistochemistry, and transcriptomic
profiling was conducted on tumors collected from stage-matched short (n=68;
median OS, 0.8 yrs) and long-term PDAC survivors (n=82; median OS, 6 yrs). All
patients had surgically resected, non-metastatic PDAC and had not received
neoadjuvant chemotherapy. Antigen immunogenicity was evaluated using a
computational fitness model that integrated clonal genealogy, epitope homology
and TCR affinity, while in vivo reactivity between T cells and neoantigens was
assessed using functional assays in a small (n=7) subgroup of long-term
survivors. Results showed that tumors from long-term survivors had 12-fold
greater density of cytolytic CD3+ CD8+ granzyme-B + cells (p <0.0001 versus
short-term survivors) and >94% unique intratumoral T cell clonality.
Long-term survival was predicted by the combination of high predicted number of
neoantigens and density of CD3+ CD8+ tumor infiltrate (median OS not reached
vs. 0.8 yrs, P=0.004); neither factor alone was sufficient. High-quality
neoantigens independently predicted long-term survival (median OS 8.6 vs. 0.8
yrs; p = 0.002); conversely, quantity of neoantigens did not. This held true in
a cohort of patients not stratified by survival. Interestingly, mutation in
MUC16 was highly correlated with long-term survival (p=0.03) and mutations were
selectively lost during metastasis. T cells from two long-term survivors were
capable of recognizing MUC16 neopeptides to a statistically significant degree.
This study, which indicates that neoantigen quality is a biomarker of
immunogenic tumors in long-term PDAC survivors, may contribute towards rational
application of neoantigen-based therapies in future.
Tumor and T cell metabolic adaptations contribute to acquired checkpoint inhibitor resistance
Ashvin Jaiswal, Dpharm, MS, PhD (UT MD Anderson Cancer
Center, Houston, TX) reported data investigating the role of metabolism in acquired
resistance to checkpoint inhibitors in melanoma. Researchers introduced B16/F10
melanoma cells into BL6 mice and treated animals with combination anti-PD-1,
anti-CTLA-4, anti-PD-L1, and FVAX. Tumor cells from non-responding animals were
subsequently re-introduced into naïve mice, and this process was repeated until
a CPI-resistant tumor cell line (3I-F4) - characterized by increased tumor
growth in naïve mice while receiving CPI therapies - was generated. CPI-resistance
in 3I-F4 tumors was verified to be immune driven. Gene expression analyses of TME
cells from 3I-F4 subjected mice revealed signatures indicating a hypoxic
environment. CPI-resistant tumor cells, however, had gene expression signatures
suggesting hypoxic adaptation and oxidative stress tolerance. 3I-F4 tumors had
increased ECAR and OCR compared to parental B16/F10 tumors, confirming gene
expression analyses. 3I-F4 tumors displayed increased glycolytic activity compared
to parental tumors (p < 0.05). It was hypothesized that these environmental
alterations in resistant tumors would negatively affect TIL survival, but
interestingly TIL counts were similar in parental and resistant tumors both off
and during combination CPI treatment. TILs had reduced glycolytic capacity (p
< 0.01) and effector function (p < 0.05), and gene expression analyses
identified significant alterations in ADH7 and PGAM2 expression. Mice
subsequently challenged with B16/F10 cells overexpressing ADH7 or PGAM2 had
increased resistance to combination CPI therapy compared to control mice (p <
0005 and p < 0.0001, respectively). Biopsy analyses reveal that melanoma patients
resistant to anti-CTLA-4 and anti-PD-1 have similar alterations to glycolytic
activity. These data suggest that tumor and T cell metabolic adaptations can
facilitate CPI resistance in a pre-clinical model, and that CPI-resistant tumors
from melanoma patients have similar metabolic characteristics.
Glossary
AE = adverse event
CI = confidence interval
CPI = checkpoint inhibitor
CPI = checkpoint inhibitor
CR = complete response
DC = dendritic cell
DCR = disease control rate
DLT – dose limiting toxicity
ECAR = extracellular acidification rate
ECAR = extracellular acidification rate
HR = hazard ratio
IHC = immunohistochemistry
irAE – immune-related adverse event
MHC = major histocompatibility complex
mTTR = mean time to response
NK = natural killer
OCR = oxygen consumption rate
OCR = oxygen consumption rate
OS = overall survival
ORR = objective response rate
PFS = progression-free survival
PR = partial response
Q2W = every 2 weeks
Q3W = every 3 weeks
TCR = T cell receptor
TIL = tumor infiltrating lymphocyte
TRAE = treatment-related adverse event
On the quality not quantity of neoantigens, it would be helpful to understand what the immunizing antigen was to begin with and whether the recognition of MUC-1 mutants by long term survivors reflected epitope spreading. Second, there is no guarantee that reformulating the vaccine based on this finding would elicit immunity in individuals that did not have such immunity to begin with.
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