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1186P Interim results from exploratory study to determine S-588410-induced

tumor infiltrating lymphocytes and changes in the tumor microenvironment
in esophageal cancer patients

Article  in  Annals of Oncology · October 2018

DOI: 10.1093/annonc/mdy288.059

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Teresa Marafioti Ken Kato

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 Annals of Oncology
1186P Interim results from exploratory study to determine S-588410-
induced tumor infiltrating lymphocytes and changes in the tumor
microenvironment in esophageal cancer patients
T. Kojima1, T. Marafioti2, T. Fujiwara3, Y. Shirakawa3, T. Nakatsura4, K. Kato5, I. Puccio2,
M. Nagira6, N. Ide7, K. Stoeber8, A. Arimura7, H. Daiko9
1 novel biomarkers with prognostic significance in MBC. Thus, successful inclusion of
Department of Gastroenterology and Gastrointestinal Oncology, National Cancer
Center Hospital East, Kashiwa, Chiba, Japan, 2Department of Cellular Pathology,
University College London Hospital, London, UK, 3Gastroenterological Surgery,
Okayama University Hospital, Okayama, Japan, 4Cancer Immunotherapy, Exploratory
Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Japan,
5
Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo,
Japan, 6Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., Osaka,
Japan, 7Project Management Department, Shionogi & Co., Ltd., Osaka, Japan, 8Business
Development, Shionogi & Co., Ltd., Osaka, Japan, 9Esophageal Surgery Division,
National Cancer Center Hospital, Tokyo, Japan
Background: S-588410 is a cancer peptide vaccine composed of 5 HLA-A*24:02-
restricted peptides derived from 5 cancer-testis antigens, DEPDC1, MPHOSPH1,
URLC10, CDCA1 and KOC1, all of which have been found to be upregulated in esoph-
ageal cancer. The aim of this study is to evaluate the effects of S-588410 on the number
of tumor-infiltrating CD8-positive lymphocytes (TIL) and PD-L1 expression in the
tumor tissue before and after the short-term treatment with S-588410 in the pre-surgi-
cal treatment.
Methods: HLA-A*24:02-positive patients (pts) with esophageal cancer who can start
the treatment more than 30 days prior to the surgery were eligible. S-588410 was
injected subcutaneously once weekly, 5 times or more in total. Tumor tissues of pre-
and post-treatment were collected for immunohistochemistry (IHC) analysis for target
antigens, CD8, PD-L1 and HLA class I. Peptide-specific CTLs in PBMC were evaluated
using ELISpot assay.
Results: As Apr 13, 2018, total 15 pts were enrolled and tumor tissues of the first half of
the pts, 8 pts were analyzed. 8 pts received 3 to 6 injections of S-588410. All 5 antigens
and HLA class I on tumor tissues were detected in all pts except for one whose tumor
expressed 4 target antigens. CTL activity circulating in blood markedly increased in all
8 pts at least for 1 of 5 peptides. IHC analysis demonstrated that TIL density and PD-L1
expression on post-treatment tissues clearly increased compared to the baseline; CD8þ
TIL density at baseline was  1% in 5 pts and 1%-10% in 3 pts and that for post-treat-
ment 1%-10% in 2 pts, 10%-50% in 6 pts, and PD-L1 expression at base line was  1%
in 7 pts and 1%-5% in one patient and that for post-treatment was  1% in one patient,
1%-5% in 4 pts and 5%-50% in 3 pts.
Conclusions: The short-term treatment with S-588410 generated peptide-specific CTL
and markedly increased CD8þ TIL density and PD-L1 expression on tumor tissue of
esophageal cancer pts. These interim results suggest that the combination of S-588410
with anti-PD-1/PD-L1 antibody is expected to be more effective than monotherapy,
particularly in pts with low TIL/PD-L1 status.
Clinical trial identification: UMIN000023324.
Legal entity responsible for the study: Shionogi & Co., Ltd.
Funding: Shionogi & Co., Ltd.
Disclosure: T. Kojima: Travel grants: Shionogi & Co., Ltd.; Grants: Ono
Pharmaceutical, MSD, Oncolys BioPharma, Astellas Amgen BioPharama. M. Nagira,
N. Ide, K. Stoeber, A. Arimura: Employee: Shionogi & Co., Ltd. All other authors have
declared no conflicts of interest.
1187P Clinical implication of PDL1 expression and TILs in male breast
cancer: More hype or new hope? Results from the UMBREAC trial
(NCT03240510)
S. Abdeljaoued1, I. Bettaieb1, A. Goucha1, O. Adouni1, H. El Mokh1, H. Bouzaiene2,
J. Ben Hassouna2, H. Boussen3, K. Rahal2, A. Gamoudi1
1 Employee: MedImmune; Stock and/or stock interests or options: AstraZeneca. P.
Immuno-Histo-Cytology, Institut Salah Azaı̈z, Tunis, Tunisia, 2Surgical Oncology,
Institut Salah Azaı̈z, Tunis, Tunisia, 3Department of Medical Oncology, Hopital
Abderrahman Mami, Ariana, Tunisia
Background: Whether PDL1 or TILs have any indication for prognosis in male breast
cancer (MBC) patients remains unknown. In this study, we investigated the relation-
ship between the expression and degree of PDL1 and TILs and evaluated the prognostic
value of these factors in MBC.
Methods: We retrospectively identified 150 MBC patients diagnosed between 2003 and
2013 at Salah Azaı̈z Cancer Institute. PDL1, Stromal (str) CD8þ and CD4þ TILs were
evaluated immunohistochemically. TILs levels were evaluated following 2014
International TILs Working Group guidelines.
Results: Fifty three percent of MBC patients had low str-TILs and 47% had moderate
str-TILs. No lymphocyte predominant breast cancer was identified. Only 12% of MBC
patients had high str-CD8þTILs and 11% had high str-CD4þTILs. TNBC subtype and
HER2 enriched tumors had higher median levels of str-CD8þTILs, str-CD4þ TILs and
str-TILs at diagnosis. On univariate analysis, higher levels of str-CD8þTILs, str-CD4þ
TILs and str-TILs were associated with better OS (p ¼ 0.035, p ¼ 0.043 and p ¼ 0.040
respectively). Multivariate analysis identified str-CD8þ TILs and str-TILs as independ-
ent prognostic factors for OS ([HR ¼ 0.851 (0.706-0.997), p ¼ 0.000] and [HR ¼ 0.69
(0.43-0.96), p ¼ 0.045] respectively). High expression of PD-L1 was observed in 64.5%
Volume 29 | Supplement 8 | October 2018
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abstracts
of MBC samples. Patients with high PD-L1 expression had significantly shorter overall
survival (OS) than patients with low expression (p ¼ 0.002, hazard ratio HR ¼ 5 [2.624
–10.642]). Multivariate analysis identified PD-L1 as independent prognostic factor for
OS (p < 0.001, HR ¼ 0.775 [0.680–0.870]).
Conclusions: PD-L1 expression, Str-CD8þ T cells and str-TILs represents promising
these markers in prognostic clinical models is becoming a realistic hope in MBC.
Clinical trial identification: NCT03240510.
Legal entity responsible for the study: Institut Salah Azaı̈z.
Funding: Has not received any funding.
Disclosure: All authors have declared no conflicts of interest.
Downloaded from https://academic.oup.com/annonc/article-abstract/29/suppl_8/mdy288.059/5142044 by guest on 27 October 2018
1188P Identification of prognostic and predictive factors for durvalumab
efficacy by modeling of tumor response and overall survival (OS) in
patients with non-small cell lung cancer (NSCLC)
Y. Zheng1, R. Narwal2, C. Jin1, P. Baverel3, A. Gupta4, P. Mukhopadhyay5, B.W. Higgs6,
L. Roskos2
1
Clinical Pharmacology & DMPK, MedImmune, South San Francisco, CA, USA, 2Clinical
Pharmacology & DMPK, MedImmune, Gaithersburg, MD, USA, 3Clinical Pharmacology
& DMPK, MedImmune, Cambridge, UK, 4Immuno-Oncology Global Medicines
Development, AstraZeneca, Gaithersburg, MD, USA, 5Biometrics & Information Sciences,
AstraZeneca, Gaithersburg, MD, USA, 6Translational Medicine, MedImmune,
Gaithersburg, MD, USA
Background: Durvalumab, a human anti–PD-L1 mAb, is currently approved for treat-
ment of patients with Stage III unresectable NSCLC. The objectives of this analysis were
to identify prognostic and predictive factors for tumor growth and shrinkage, as well as
for OS in NSCLC patients treated with durvalumab.
Methods: Longitudinal tumor size (TS) and OS data obtained from NSCLC patients in
Study 1108 (all comers) and ATLANTIC (Stage III and above) who received durvalu-
mab were analyzed using a nonlinear mixed effect model that describes the growth and
regression of sensitive and insensitive tumor cells, as well as delay in immune response
leading to tumor killing. A linked OS-dropout model was developed by relating model-
predicted tumor changes to OS and dropout probability over time. Potential prognos-
tic and predictive factors were evaluated in a multivariate covariate analysis using the
models.
Results: The longitudinal TS and OS data from NSCLC patients in both studies are gen-
erally well described by the models. Liver metastasis, neutrophil-to-lymphocyte ratio
(NLR), EGFR mutation, and durvalumab clearance (CL) are identified as prognostic
factors for tumor growth, and tumor cell PD-L1 expression (TC) and baseline tumor
size as predictive factors for tumor killing (p < 0.01). The significant factors for OS after
accounting for the tumor size changes included TC and immune cell PD-L1 expression
(IC), NLR, lactate dehydrogenase, as well as CL (p < 0.01). Among all factors tested,
NLR is the most influential factor on the predicted 1-year survival rates (60% vs. 30%
with NLR below and above the median [4.56]). Positive PD-L1 expression (TC or
IC  25%) is predicted to result in 10-20% increase in one-year survival rates.
Increasing the cutoff value is not predicted to result in substantially greater improve-
ment in the survival rate.
Conclusions: The modeling results provided quantitative assessments of the impact of
various prognostic and predictive factors, as well as biomarker cutoff values on the effi-
cacy of durvalumab in NSCLC patients, and can be used to inform patient selection cri-
teria in future monotherapy or combination studies.
Clinical trial identification: NCT01693562.
Legal entity responsible for the study: MedImmune, LLC.
Funding: MedImmune.
Disclosure: Y. Zheng, R. Narwal, C. Jin, P. Baverel, A. Gupta, B.W. Higgs, L. Roskos:
Mukhopadhyay: Employee, Stock and/or stock interests or options: AstraZeneca.
1189P Intrinsic and extrinsic regulation of PD-L2 expression by transcription
factor STAT3 or c-FOS in oncogene-driven non-small cell lung cancer
D. Shibahara1, K. Tanaka2, E. Iwama2, N. Kubo2, K. Ota3, K. Azuma4, T. Harada2, J. Fujita1,
Y. Nakanishi5, I. Okamoto2
1
Infectious Disease, Respiratory and Digestive Medicine, Ryukyu University Hospital,
Okinawa, Japan, 2Respiratory Medicine, Kyushu University Hospital, Fukuoka, Japan,
3
Respiratory, Kyushu University Hospital, Fukuoka, Japan, 4Respirology, Neurology, and
Rheumatology, Kurume University School of Medicine, Fukuoka, Japan, 5Research
Institute for Diseases of the Chest, Kyushu University Hospital, Fukuoka, Japan
Background: Treatment with antibodies that target programmed cell death 1 (PD-1)
or its ligand programmed death ligand 1 (PD-L1) has demonstrated durable efficacy
for various malignant tumors. Programmed death ligand 2 (PD-L2), which is another
ligand of PD-1, has recently been shown to be implicated in tumor immune escape. The
regulation of PD-L2 expression in tumor cells has remained unclear, however. We here
examined intrinsic and extrinsic regulation of PDL2 expression in NSCLC.
doi:10.1093/annonc/mdy288 | viii423