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.