Head and Neck Squamous Cell Carcinoma (HNSCC) Clinical Trial
Official title:
Induction Therapy With Docetaxel, Cisplatin, 5-Fluoro Uracil and Pembrolizumab in Untreated Locally-advanced Unresectable Squamous Cell Head and Neck Carcinoma (Pembrolizumab and Induction Chemotherapy in Head and Neck Squamous Cell Carcinoma. PICH Study)
Non-randomized phase I/II, open-labeled clinical study, 1-arm, multicenter, of docetaxel (T),
cisplatin (P), 5-fluorouracil (F) and pembrolizumab every 21 days for 3 cycles followed by
radiotherapy (RT) combined with carboplatin in untreated unresectable locally-advanced Head
and Neck Squamous Cell Carcinoma (HNSCC).
The TPF and pembrolizumab combination will be called TP²F.
The importance of intact immune surveillance in controlling outgrowth of neoplastic
transformation has been known for decades. Accumulating evidence shows a correlation between
tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various
malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector
T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term
survival in many solid tumors.
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune
control. The normal function of PD-1, expressed on the cell surface of activated T-cells
under healthy conditions, is to down-modulate unwanted or excessive immune responses,
including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member
related to CD28 and CTLA-4, which has been shown to negatively regulate antigen receptor
signaling upon engagement of its ligands (PD-L1 and/or PD L2). The structure of murine PD-1
has been resolved. PD-1 and family members are type I transmembrane glycoproteins containing
an Ig Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail,
which is responsible for the binding of signaling molecules. The cytoplasmic tail of PD-1
contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif
(ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM). Following T-cell
stimulation, PD 1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within
its cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ,
PKCθ and ZAP70 which are involved in the CD3 T-cell signaling cascade. The mechanism by which
PD-1 down modulates T-cell responses is similar to, but distinct from, that of CTLA-4 as both
molecules regulate an overlapping set of signaling proteins. PD-1 was shown to be expressed
on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and
Natural Killer cells. Expression has also been shown during thymic development on CD4-CD8-
(double negative) T-cells as well as subsets of macrophages and dendritic cells. The ligands
for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of
cell types, including non-hematopoietic cells (various tumor cells and stromal cells) as well
as hematopoetic myeloid cells (dendritic cells and macrophages…). Both ligands are type I
transmembrane receptors containing both IgV- and IgC-like domains in the extracellular region
and contain short cytoplasmic regions with no known signaling motifs. Binding of either PD-1
ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor. PD-L1 is
expressed at low levels on various non-hematopoietic tissues, most notably on vascular
endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting cells
found in lymphoid tissue or chronic inflammatory environments. PD-L2 is thought to control
immune T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted
T-cell function in peripheral tissues. Although healthy organs express little (if any) PD-L1,
a variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor.
PD-1 has been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma
(MEL). This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune
evasion and should be considered as an attractive target for therapeutic intervention.
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands,
PD-L1 and PD-L2. KeytrudaTM (pembrolizumab) has recently been approved in the United Stated
for the treatment of patients with unresectable or metastatic melanoma and disease
progression following ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor.
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