3. Discussion
With recent advances in drug therapies, such as molecular-targeted
therapies and immune checkpoint inhibitors, the role of drug therapy in
the treatment of head and neck cancers is rapidly expanding and its
scope is becoming more complex2. In Japan, the
antiepidermal growth factor receptor antibody cetuximab was approved as
a molecular targeted drug for head and neck cancers in December 2012. On
the other hand, a 2017 subanalysis of the CheckMate 141 trial found that
the antiprogrammed death 1 (PD-1) antibody nivolumab had favorable
effects in the treatment of recurrent and metastatic squamous cell
carcinomas of the head and neck 3. Nivolumab is now
being used as one of the standard treatments for head and neck cancers3.
Nivolumab has been shown to have responses and therapeutic effects
distinct from those of conventional anticancer and molecular targeted
drugs. It has been reported to have long-lasting effects in successful
cases and suppress the exacerbation of tumors for long periods in
unchanged ones4. Studies have suggested that salvage chemotherapy
after the administration of previously approved immune checkpoint
inhibitors is highly effective for the treatment of nonsmall cell lung
cancer 5–7.
In this study, recurrent lymph nodes disappeared after chemotherapy with
cetuximab but increased after the treatment was switched to cetuximab
alone. Nivolumab was subsequently administered; however, as recurrent
lymph nodes continued to increase, chemotherapy with cetuximab was
performed again. The patient has shown a marked reduction of recurrent
lymph nodes and continues to be in a CR at present. These outcomes may
be related to the reactivation of cetuximab and the immunostimulatory
effect of nivolumab.
Regarding the reactivation of cetuximab, Santini et al.8 found tumor
growth after cetuximab was administered and readministered as an
adjuvant therapy in 21 of 39 patients with colorectal cancer, 53.8% of
whom reported a response. Regarding the mechanism by which
readministration of cetuximab is effective, Aparicio and Caldas9 reported that there was a heterogeneous presence of
cells sensitive to cetuximab and low cells in the tumor. They found that
the administration of cetuximab (1) initially led to a reduction in the
number of sensitive cells, an increase in that of insensitive cells, and
tumor growth but (2) subsequently resulted in an increase in the number
of sensitive cells. These findings suggest that readministration of
cetuximab causes tumors to shrink.
Regarding its immunostimulatory effect, nivolumab is a human
immunoglobulin G4 anti–PD-1 antibody 10. PD-1, which
is a receptor from the CD28 family 10, is expressed in
such immune cells as differentiated effector T cells and B cells after
activation. The binding of antigen-presenting cells to PD-L1 and PD-L2
ligands in lymphocytes and that of
PD-L1 expressed in tumor cells and PD-1 expressed in T cells, which
transmits a negative signal to T cells, suppress activation10.
Nivolumab restores the cancer immune response by inhibiting the binding
of PD-1 to PD-L1 and PD-L2 and diminishing inhibitory signals to T cells10. In addition, research has considered that
conventional chemotherapy is brought about by the suppression of cell
growth of cancer cells and cytotoxicity 4. However, in
recent years, it has become clear that immune cells represented by T
cells are involved in long-term clinical effects 4.
Chemotherapeutic agents have been shown to act directly on
immunocompetent and immunosuppressive cells as well as cancer cells,
thereby affecting their antitumor effects 4.
Cisplatin has been reported to increase the expression of tumor-specific
antigens and promote the induction of cytotoxic T cells associated with
them 11. Paclitaxel is known to improve not only
antigenicity by enhancing the expression of major histocompatibility
complex class I molecules in cancer cells but also the ability of
dendritic cells to present antigens to T cells by acting directly on the
dendritic cells12. Fluorouracil has also been shown to selectively
induce apoptosis in myeloid-derived suppressor cells and increase their
antitumor effect 13.
The change in the cancer immune microenvironment caused by the
administration of nivolumab influences the effects of succeeding
chemotherapeutic agents used on immunocompetent and immunosuppressive
cells, with said influence being enhanced by its interaction with the
original cell-killing effect. The limited data on successful cases of
rescue chemotherapy after administration of such immune checkpoint
inhibitors in oral cancer highlight the need for more cases to be
reported.