Journal Thoracic Oncology

Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017
microenvironment or could deplete effector cells. Moreover, auto-immune
responses could cause potential side effects. To overcome these problems, we
exploited near infrared photoimmunotherapy (NIR-PIT) at the tumor to deplete
only intratumoral-Tregs. Methods: F(ab’) 2
fragments of an anti-mouse CD25
antibody, PC61.3, were generated and conjugated with a phthalocyanine dye,
IRDye-700DX (αnti-CD25-F(ab’) 2
-IR700). In vitro NIR-PIT effect was examined
against CD25-expressing-T-lymphocytes, HT2-clone-A5E-cells. In vivo
CD25-target-NIR-PIT was performed after an intravenous injection of the
conjugate to mice bearing subcutaneous, luciferase transfected, LL/2 (Lewis
lung carcinoma, LL/2-luc). Tumor-volume, bioluminescence signals (BLI), and
Immune responses following the therapy were examined Results: In vitro
NIR-PIT-induced cytotoxicity was light-dose-dependent. Local CD25-target-NIR-
PIT selectively depleted intratumoral-Tregs; yet, Tregs in any other organs were
not affected. The local CD25-target-NIR-PIT induced a intratumoral rapid
activation and cytotoxic action of CD8-T cells and NK-cells. This led to
significant reductions of tumor-volume (p < 0.0001) and BLI (p < 0.05) and
prolonged survival (p < 0.0001) compared to non-treated controls. Intriguingly,
this local CD25-target-NIR-PIT induced a transient systemic cytokine storm and
antitumor-effects on distant non-irradiated specific tumors. Effects of local
CD25-target-NIR-PIT were significantly (p < 0.0001) inhibited by a CD8-, NK-, or
INFg-depletion, suggesting the anti-tumor roles of CD8 T-cells and NK-cells.
Conclusion: Depletion of intratumoral-Tregs with a local CD25-target-NIR-PIT
rapidly induced CD8 T- and NK-cell activation, thereby restoring local anti-tumor
immunity. Consequently, activated immunity led to regression of not only
NIR-PIT-treated-tumors but also non-NIR-light-exposed-tumors in separate
parts of the body (Fig). These observations suggest that local CD25-target-NIR-
PIT may be a promising new strategy for cancer immunotherapy.
whether variations in these sub-populations might predict objective response
to nivolumab in NSCLC. Methods: Blood samples were collected and stored
from patients receiving nivolumab (3 mg/Kg every 14 days) for advanced NSCLC
within a single-institutional translational research study conducted in the
San Martino Hospital – National Institute for Cancer Research, Genova, Italy
(approved by the local ethical committee). Sample collection was performed
before each administration for 4 consecutive cycles, followed by computed
tomography (CT)-scan. Response assessment was performed with the response
evaluation criteria in solid tumors (RECIST) v. 1.1 and the immune-related
response criteria (irRC); responses were defined as partial response (PR), stable
disease (SD), and progressive disease (PD). Additional CT-scans were performed
at 4 cycles intervals. Peripheral blood mononuclear cells (PBMC) were analyzed
for the frequency of the major adaptive cell subsets, including B cells, natural
killer (NK) cells, and T-cells; the latter were divided into CD8+ T cells, exhausted
CD8+ T cells, CD4+ cells, and regulatory T cells (Tregs); the relative frequencies
and the ratios between the sub-populations at each sample collection were
compared with radiological response. Results: Fifty-four patients were
considered eligible: median age= 70 (44-85); male/female: 70%/30%; current
or former smokers= 87%; non-squamous/squamous histology= 80%/20%.
Patients achieving PR at the first RECIST assessment had a significant
upregulation of Tregs (CD4+ Foxp3+ CD39+ cells; p= 0.021), as well as a decreased
CD8+/Treg ratio (p= 0.033) at the baseline sample. Conversely, patients
experiencing PD at the first RECIST assessment had a significantly upregulated
CD8+/Treg ratio at cycle 2 (p= 0.029). Finally, patients experiencing PD at irRC
had a higher proportion of activated T cells (PD1+ CD56+ CD3+) compared to the
other patients (P= 0.018) at cycle 2. Conclusion: The proportions of Tregs and
activated T cells appear to be correlated with different responses to nivolumab
according to RECIST and irRC. While the immunologic mechanism at the basis of
these findings has to be defined, further studies involving PBMC as predictors
of response to immunotherapy for NSCLC are highly advised.
Keywords: non-small cell lung cancer, Nivolumab, predictive biomarkers,
lymphocytes
POSTER SESSION 3 – P3.02C: ADVANCED NSCLC & CHEMOTHERAPY/TARGETED THERAPY/
IMMUNOTHERAPY
IT BIOMARKERS –
WEDNESDAY, DECEMBER 7, 2016
P3.02C-073 EVIDENCE SUGGESTING A DICHOTOMOUS “PRESENT
VS ABSENT” DETERMINANT OF PDL1 INHIBITOR EFFICACY IN NON-
SMALL CELL LUNG CANCER (NSCLC)
David Stewart, Dominick Bosse, Stephanie Brule
Medicine, University of Ottawa, Ottawa/ON/Canada
Keywords: local cancerimmunotherapy, Lewis lung cancer,
photoimmunotherapy, regulatory T cell
POSTER SESSION 3 – P3.02C: ADVANCED NSCLC & CHEMOTHERAPY/TARGETED THERAPY/
IMMUNOTHERAPY
IT BIOMARKERS –
WEDNESDAY, DECEMBER 7, 2016
Background: NSCLC survival and progression-free survival (PFS) curves often
follow first-order kinetics (Stewart, Lung Cancer 2011;71:217). We
hypothesized that the number of curve decay phases reflects number of
biologically distinct subpopulations with distinct rates of progression or
death that are determined by dichotomous (present vs absent) factors. In
NSCLC, some PDL1-negative patients respond to PDL1 inhibitors, while some
PDL1 strongly-positive patients do not. Methods: We used “arohatgi.info/
WebPlotDigitizer/app/” to digitize published NSCLC PDL1-inhibitor PFS curves
and used GraphPad Prism5 for nonlinear regression analyses (one-phase and
two-phase decay; constraints:Y 0
=100, plateau=0). Results: 26 of 28 curves fit
2-phase decay models with R 2 >0.90, with distinct “fast progression” (FP) and
“slow progression” (SP) subgroups. In studies with PFS curves for different
PDL1-expression groups, patients with higher PDL1 tended to have a larger SP
subgroup, although some with low PDL1 had slow progression and some with
high PDL1 had fast progression (see Table).
P3.02C-072 PREDICTIVE IMMUNOLOGIC MARKERS OF RESPONSE
TO NIVOLUMAB IN NON-SMALL CELL LUNG CANCER
Carlo Genova 1 , Paolo Carrega 2 , Roberta Distefano 1 , Selene Ottonello 3 ,
Gabriella Pietra 3 , Irene Cossu 2 , Erika Rijavec 1 , Federica Biello 1 , Giovanni Rossi 1 ,
Giulia Barletta 1 , Maria Giovanna Dal Bello 1 , Angela Alama 1 , Simona Coco 1 , Irene
Vanni 1 , Claudia Maggioni 1 , Franco Merlo 4 , Maria Cristina Mingari 3 , Francesco
Grossi 1
1 Lung Cancer Unit, San Martino Hospital - National Institute for Cancer Research,
Genova/Italy, 2 Laboratory of Clinical and Experimental Immunology, Giannina
Gaslini Institute, Genova/Italy, 3 Department of Experimental Medicine, San Martino
Hospital - National Institute for Cancer Research, Genova/Italy, 4 Clinical Trials Unit,
San Martino Hospital - National Institute for Cancer Research, Genova/Italy
Background: Nivolumab has become a consolidated therapeutic approach for
previously treated non-small cell lung cancer (NSCLC); however, consistent
prognostic and predictive factors are still lacking. Since these agents act
by enhancing the immune response against tumor cells, it is possible that
distinctive patterns in the circulating T cell sub-populations might be
associated with different responsiveness. The aim of this study is to determine
Copyright © 2016 by the International Association for the Study of Lung Cancer
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