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DDR2 mutation IMMUNE ACTIVATION AND CHECKPOINT
The DDR2 gene encodes a cell surface RTK that is mutated INHIBITION
to an active form in about 4% of squamous cell carcinomas
of the lung. Dasatinib inhibits DDR2, and one patient Immune recognition is initiated by antigen presenting cells
[22]
treated with the combination of dasatinib and erlotinib had (APCs). When stimulated by antigens on cancer cells, APCs
a tumour response. Clinical trials tomdetermine dasatinib express B7-1 and B7-2 on their cell surface, and migrate to
efficacy are underway. the lymph nodes to present the antigens to resting T cells.
The B7 proteins bind to CD28 on the T cells, initiating a
MEK1 mutation series of downstream signalling events that promotes the
The MAP2K1 gene encodes the MEK1 protein, a central activation, survival and proliferation of the target T cells.
mediator of cell proliferation signals that is downstream These activated T cells then release cytolytic enzymes such
of RAF in the MAPK pathway. MAP2K1 mutations may as perforin and granzyme, as well as cytokines that help
be found in approximately 1% of adenocarcinomas. The recruit other members of the immune system to the cancer
[23]
clinical response of NSCLC with MAP2K1 mutation to cells. The result is tumour destruction and the creation
MEK or ERK inhibitors is currently being investigated. of memory T cells. Several immune checkpoints exist to
dampen the immune response to protect healthy individuals
The accessibility of mutation analysis is limited largely from detrimental inflammation and autoimmunity. Two
due to the high cost, as well as the lack of quality control, well-characterized checkpoint proteins, the cytotoxic
uniformity of techniques and standards among various T-lymphocyte antigen 4 (CTLA-4) and the programmed
laboratories. However, the cost for these tests may decrease death receptor 1 (PD-1), are targets in NSCLC clinical
when the reagents are purchased in bulk. The amount and trials. The purpose of inhibiting these check point proteins
quality of the tumour tissue used for molecular profiling is to prevent their interference with the elimination of
is also an important issue to consider, especially since the cancer cells.
tissue yield for lung cancer samples is limited by small core
biopsies. Judicious use of IHC and conservation of samples Antibodies targeting CTLA-4: ipilimumab
for molecular testing would be helpful. Cell-free circular Ipilimumab is an IgG1 CTLA-4 monoclonal antibody
tumour DNA is also emerging as a useful tool for mutation that prolongs overall survival in patients with metastatic
testing and therapeutic monitoring. melanoma. Currently there is a phase III trial that compares
standard chemotherapy with carboplatin and paclitaxel with
IMMUNOTHERAPY the same regimen combined with concurrent ipilimumab
for patients undergoing chemotherapy for treating naive
More than 80% of lung cancer cases are classified as metastatic squamous cell NSCLC (NCT01285609).
NSCLC. Although there have been significant advances
in the treatment of subsets of patients with molecularly Antibodies targeting PD-1 and PD-L1
defined NSCLC, for instance, NSCLC positive for EGFR Treatment of NSCLC with antibodies against PD-1
mutation and ALK rearrangement, the improvement and programmed death-ligand 1 (PD-L1) has yielded
of prognosis is still modest for the majority of NLCSC encouraging results; early clinical trials showed a prolonged
patients. It is clear that a plateau has been reached with response to the antibody in patients with chemotherapy
traditional chemotherapy, with minimal added benefit when refractory metastatic NSCLC. Randomized phase III
chemotherapy is combined with the angiogenesis inhibitor trials to evaluate anti-PD-1 and anti-PD-L1 antibodies for
bevacizumab. metastatic NSCLC treatment are in progress, and other
studies are investigating various combination strategies.
Immunotherapeutic approaches are based on the premise
that the immune system plays a key role in surveillance Nivolumab is an IgG4 monoclonal antibody against PD-1
and the eradication of malignancy, and tumours evolve in that has been approved for both advanced squamous cell
order to elude the immune system. These approaches differ carcinoma of the lung and unresectable or metastatic
from traditional chemotherapy and targeted therapies that melanoma. Nivolumab received US Food and Drug
primarily target rapidly dividing cells and key molecular Administration approval on March 4, 2015 for the
events that drive tumour growth and invasion. The goal treatment of patients with advanced squamous NSCLC with
of immunotherapy is to help the host’s immune system progression, either in concurrent with or after platinum-
recognize that cancer cells are foreign in order to stimulate based chemotherapy. This approval was based on results
immune response. from the CheckMate 017 and CheckMate 063 trials.

Historically, non-small cell lung cancer (NSCLC was Pembrolizumab, an IgG4 monoclonal antibody also
considered to be non-immunogenic). Two approaches targeting PD-1, is a breakthrough therapeutic agent for
to harness the immune system are of particular interest: treating advanced NLCLC that received FDA approval in
immune checkpoint inhibition and vaccination. late 2014. The approval was based on emerging results

Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ June 15, 2016 ¦ 217