Journal Thoracic Oncology

Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017
vascularization mechanism such as intussusceptive angiogenesis or vesselcooption.
Reliable biomarkers for the prediction of response to antivascular
drugs are also yet to be identified and clinically validated.
SESSION MTE13: BASIC IMMUNOLOGY FOR THE CLINICIAN
(TICKETED SESSION)
TUESDAY, DECEMBER 6, 2016 - 07:30-08:30
MTE13.02 BASIC IMMUNOLOGY FOR THE CLINICIAN
Edgardo Santos
Florida Atlantic University, Eugene M. and Christine E. Lynn Cancer Institute, Boca
Raton/FL/United States of America
Lung cancer remains the number one cause of cancer-related death worldwide.
Cancer immunotherapy nowadays has become not only a growing field but
also a fascinating area as recent clinical trials have improved both PFS and OS
in first line and second line treatment for patients with advanced NSCLC. The
idea of immunotherapy in cancer is to modify the host immune system, so
cytotoxic T-cells (CTCs) can recognize tumor-associated antigens (TAAs) as
abnormal and be destroyed by an immune response. For many decades, we
have tried unsuccessfully many vaccines against different lung cancer
antigens. It was thought at one point that lung cancer was a non immunogenic
tumor very different from melanoma and kidney cancers. Whole-cell vaccines
(e.g. belagenpumatucel-L) and antigen-specific vaccines (e.g., CIMAvax,
MAGE-A3, L-BPL25) showed just promising results in clinical trials, but failed
to significantly improve clinical outcomes [1-4]. The major reason why vaccines
failed in lung cancer was due to tumor escape mechanisms from host immune
surveillance [5, 6]. One of this mechanisms was recently elucidated,
checkpoint pathway. Lung cancer has been found to have high levels of CTLA-4
expression, programmed death-1 (PD-1), PD ligand 1 (PD-L1), B7-H3 and B7-H4
expression on tumor-infiltrating lymphocytes (TILs), and regulatory CD4+
T-cells (Tregs) suggesting that lung cancer is immunogenic. For many years,
cancer immunology was centered on the adaptive immune system and T-cell
activation. Stimulation of the T-cell response involves antigen presenting cells
(APCs), or dendritic cells (DCs), expressing tumor antigens from the tumor
microenvironment, which then bind to the T-cell receptor (TCR) on CD4+ or
CD8+ T-cells. Meanwhile, B7-1/CD80, or B7-2/CD86 on the APC, bind to CD28 on
the T-cell in a costimulatory fashion to stimulate tumor-antigen specific T-cells
to proliferate. However, cross talk between APCs and T-cells at the
immunological synapse is regulated very closely and can be attenuated. One
of this attenuation signal is mediated by CTLA-4, which is also stimulated by
CD80 and CD86. Although CTLA-4 and CD28 have the same ligands, CTLA-4 has
a much higher affinity for them; hence, T-cell proliferation occurs despite the
effects of CTLA-4 because of the intracellular location, short half-life and
quick degradation of CTLA-4 [7, 8]. Another example of a tumor immune
checkpoint is PD-1 which binds B7-H1/PD-L1 and B7-DC/PD-L2 [9]. By using PD-1
inhibitors, we are able to remove the interaction between PD-1 receptor
located in the T-cells and its ligand expressed in the tumor cells which causes
inhibitory signaling over the T-cells. Hence, an immune response cannot be
mounted. CTLA-4 has been studied in lung cancer in combination with
platinum-based doublet (carboplatin/paclitaxel). Outcomes from that study
were not enough to grant approval from regulatory entities. However,
investigators found better response to CTLA-4 inhibition in patients with
squamous cell histology; this population has higher percentage of TILs than
their non-squamous counterparts. Why the combined therapy (chemotherapy
plus ipilimumab) had limited effect remains unclear. Conversely, studies using
PD-1 inhibitors pembrolizumab and nivolumab have shown OS advantage over
docetaxel in second line therapy, and more recently, OS and PFS advantage in
first line against chemotherapy when tumor cells expressed > 50% of PD-L1
[10]. We also understand that PD-L1 is not the perfect predictive biomarkers
so efforts are directed to discover more specific markers which can help us to
tailor checkpoint inhibitors in lung cancer. The approval of nivolumab in
NSCLC came from two phase III trials CheckMate 017 and CheckMate 057
which studied nivolumab vs docetaxel in second-line for squamous and
non-squamous advanced NSCLC, respectively. The CheckMate 017 reached the
“trifecta” proving that nivolumab was statistically superior to docetaxel for
OS, PFS and response rate (RR). Interestingly, OS benefit was independent of
PD-L1 expression. The CheckMate 057 showed OS and RR in favor of
nivolumab. There was no difference in PFS between nivolumab and docetaxel
in non-squamous NSCLC patients. In this study, PD-L1 expression levels at
different cut-off matter for OS. For those patients who had ≥1%, ≥ 5%, and
10%, the hazard ratio (HR) for OS were 0.59 (p < 0.06), 0.43 (p < 0.001), and 0.40
(p < 0.001), respectively. In both studies, nivolumab was well tolerated and
had better treatment-related adverse event profile. In case of pembrolizumab,
it was KEYNOTE-010 study which proved OS advantage over docetaxel in
second line therapy. Herein, pembrolizumab at a dose of 10 mg/kg and 2 mg/kg
shown an OS of 12.7 months (HR 0.61; p < 0.001) and 10.4 months (HR 0.71; p <
0.001); OS for docetaxel was 8.5 months. Noteworthy, OS was better in
patients whose tumors expressed PD-L1 ≥50%; these patients had an OS of
17.3 and 14.9 months when received pembrolizumab at 10 mg/kg and 2 mg/kg,
respectively. Again, grade 3-5 treatment-related AEs were less common for
both pembrolizumab doses than for docetaxel. Recently, press release on
KEYNOTE-024 phase III study, reported OS in favor of pembrolizumab over
platinum-based doublet in first-line therapy for advanced NSCLC patients
with PD-L1 expression. The clinical results from KEYNOTE-024 may change the
landscape of lung cancer treatment at first-line for advanced NSCLC. Also in
development are the PD-L1 inhibitors which affect the interaction between
PD-L1 and B7.1 and PD-1 receptor and PD-L2; the later interactions are not
affected by PD-1 inhibitors. Atezolizumab and darvulumab have several phase
III trials ongoing in first line for advanced NSCLC. Phase II trials for both
compounds have shown promising results. The role of PD-L1 as predictive
biomarker is still not well defined. PD-L1 expression is a dynamic process and it
also varies as part of an adaptive immune resistance exerted by the tumor.
There are other possible predictive biomarkers such as higher nonsynonymous
mutation burden, molecular smoking signature, higher neo-antigenic burden,
DNA repair pathway mutations, high levels of PD-L1 expression, T-helper type
1 gene expression, and others. There is no question that we must continue
looking for a better predictive biomarker which can help us to determine the
therapeutic benefit of PD-1/PD-L1 inhibitors.References. 1. Nemunaitis J,
Dillman RO, Schwarzenberger PO, et al. Phase II study of belagenpumatucel-L,
a transforming growth factor beta-2 antisense gene-modified allogeneic
tumor cell vaccine in non-small-cell lung cancer. J Clin Oncol. 24, 4721–30
(2006). 2. González G, Crombet T, Neninger E, Viada C, Lage A. Therapeutic
vaccination with epidermal growth factor (EGF) in advanced lung cancer:
analysis of pooled data from three clinical trials. Hum Vaccin. 3(1), 8-13 (2007).
3. Vansteenkiste J, Zielinski H, Linder A, et al. Final results of a multi-center,
double-blind, randomized, placebo-controlled phase II study to assess the
efficacy of MAGE-A3 immunotherapeutic as adjuvant therapy in stage IB/II
non-small cell lung cancer (NSCLC). J Clin Oncol. 25(18S), 7554 (2007). 4. Palmer
M, Parker J, Modi S, et al. Phase I study of the BLP25 (MUC1 peptide) liposomal
vaccine for active specific immunotherapy in stage IIIB/IV non-small-cell lung
cancer. Clin Lung Cancer. 3(1), 49-57 (2001). 5. Gross S, Walden P.
Immunosuppressive mechanisms in human tumors: why we still cannot cure
cancer. Immunology Letters. 116(1), 7–14 (2008). 6. Dunn GP, Bruce AT, Ikeda H,
Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to
tumor escape. Nat Immunol. 3, 991–8 (2002). 7. Egen JG, Kuhns MS, Allison JP.
CTLA-4: new insights into its biological function and use in tumor
immunotherapy. Nat immunol 3(7):611-618, 2002. 8. Zang X, Allison JP. The B7
family and cancer therapy: costimulation and coinhibition. Clin Cancer Res
13(18):5271-5279, 2007. 9. Blank C, Mackensen A. Contribution of the PD-L1/
PD-1 pathway to T-cell exhaustion: an update on implications for chronic
infections and tumor evasion. CancerI Immunol Immunother 56(5):739-745,
2007. 10. http://www.businesswire.com/news/home/20160616005393/en/
Merck%E2%80%99s-KEYTRUDA%C2%AE%C2%A0-pembrolizumab-
Demonstrates-Superior-Progression-Free-Survival. Access online September
20, 2016.
Keywords: lung cancer, checkpoint pathway, Immunotherapy, PD-L1
SESSION MTE15: LYMPH NODE MAPPING IN LUNG CANCER
(TICKETED SESSION)
TUESDAY, DECEMBER 6, 2016 - 07:30-08:30
MTE15.02 LYMPH NODE MAPPING IN LUNG CANCER
David Waller
Thoracic Surgery, Glenfield Hospital, Leicester/United Kingdom
The How and Why? The Aim will be to outline the various methods to map
the extent of lymph node metastasis from a primary NSCLC and to assess
the clinical application and implications of each intervention. The Aim will
also be to highlight the following areas of clinical debate and controversial
issues 1.Preoperative Non-invasive – Lymph node mapping may start with
simple Ultrasound guided cervical node aspiration cytology [1] . Can this be
all that is needed in some advanced cases? c Can computed tomography/
positron emission tomography (CTPET) be relied upon to obviate the need for
invasive nodal mapping ? Can newer techniques including CT lymphography
[2] improve the accuracy of mapping ? Does magnetic resonance imaging (MRI)
have a role in preoperative lymph node mapping. Invasive – We will consider
in detail the debate between endobronchial and endoluminal ultrasound
(EBUS/EUS) and surgical lymph node mapping. What role, if any, does cervical
mediastinoscopy have in addition to EBUS/EUS [3] ? Does the increased
sensitivity of more invasive surgical mediastinal procedures like VAMLA
[4] and TEMLA contribute significantly to preoperative mapping ? We will
discuss why these investigations should influence primary therapy and which
patients should undergo induction therapy and which should have primary
resection. Evidence from the latest TNM revision suggest that mediastinal
nodal disease needs more accurate mapping than previously appreciated. We
will consider how many of these stages of mapping are required before making
S84 Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017