Abstract
Background/Aim: Near-infrared photoimmunotherapy (NIR-PIT) is a recently developed cancer treatment modality that selectively kills cancer cells and may induce a therapeutic host immune response. The aim of this study was to determine the feasibility of combining NIR-PIT with immune checkpoint inhibitor (ICI) therapy for unresectable recurrent head and neck cancer. Patients and Methods: Five patients underwent NIR-PIT at Ryukyu University Hospital between January 2022 and April 2024. These patients had unresectable recurrent head and neck squamous cell carcinoma. Among these five patients, four received a combination NIR-PIT and pembrolizumab administration. Results: A total of seven lesions in the oropharynx and oral cavity were targeted. One patient was treated for three different target lesions. The best observed response (BOR) rate was 100%, with three complete responses and four partial responses. The most common treatment-related adverse event was Grade 1 or 2 local pain lasting one to two days postoperatively, which occurred in all patients. Grade 3 adverse events occurred in three cases (42.9%), including pneumonia, pharynx-cutaneous fistula, and trismus. Three patients received ICI therapy following NIR-PIT, achieving a 60% BOR rate. No immune-related adverse events were noted, and the aforementioned Grade 3 adverse events did not worsen during ICI therapy. At a median follow-up of 376 days (range=157-845 days), four target lesions showed no recurrence, while three had recurred. All five patients were alive, including three with no evidence of disease. Conclusion: The combination of NIR-PIT and ICI therapy for unresectable recurrent head and neck cancer was feasible.
Immune checkpoint inhibitor (ICI) therapy with anti-programmed cell death 1 (PD-1) antibodies has been introduced in the treatment of head and neck squamous cell carcinoma (HNSCC) (1, 2) in addition to surgery, radiation, and/or cytotoxic chemotherapy, leading to long-term survival, even in patients with unresectable lesions. As a result, ICIs have become a major focus of research, leading to a paradigm shift in the approach to incurable HNSCC.
Near-infrared photoimmuno-therapy (NIR-PIT) has recently been approved in Japan and the United States for patients with recurrent HNSCC (3-5). NIR-PIT utilizes an antibody photo-absorber conjugate (cetuximab sarotarocan sodium) that is activated after tumor binding by a laser system and rapidly induces necrotic tumor cell death. The conjugate binds with high selectivity to cells expressing epidermal growth factor receptor (EGFR). Cetuximab sarotarocan sodium is activated by irradiation with red light at 690 nm, and only EGFR-expressing tumor cells are killed (3, 6).
NIR-PIT attacks cancer cells not only through direct action but also through subsequent immune activation. The mechanism of immune activation is that cancer cells treated with NIR-PIT release calreticulin, adenosine triphosphate (ATP), and high mobility group box 1 (HMGB1), which activate nearby immature dendritic cells (DCs). The DCs then take up and process cancer-specific antigens released by the ruptured tumor cells. This initiates a localized immune response against the cancer antigens. Notably, multiclonal cancer-specific cytotoxic T cells are primed, which is thought to lead to a high response rate (6, 7).
Although ICI therapy has been shown to prolong survival, the problem is that the response rate is not high (8-10). The reasons for this are thought to be 1) a lack of tumor antigens and defects in the mechanisms of antigen processing and presentation and 2) insufficient infiltration of tumor-specific T lymphocytes. As mentioned above, NIR-PIT is thought to increase the antigenicity of tumors and to enhance its effect by increasing the presentation of multiclonal tumor-specific antigens and the infiltration of tumor-specific T cells, thereby synergistically compensating for the deficiencies of ICIs.
In light of the above, the combination strategy of NIR PIT followed by ICI therapy may improve efficacy (11-14). Several clinical trials have been initiated to investigate the effects of combining NIR-PIT and ICI therapy (15). At the same time, there is a concern that enhanced immune activation due to combination NIR-PIT and ICI therapy could cause more severe immune-related adverse events (16-18) compared with ICI therapy alone (8, 9).
This study aimed to determine the feasibility of combining NIR-PIT with ICI therapy for unresectable recurrent head and neck cancer in a short observation period.
Patients and Methods
This retrospective study was based on a review of hospital charts and clinical records of five consecutive patients with HNSCC who underwent NIR-PIT from January 2022 to April 2024 at Ryukyu University Hospital. The Institutional Review Board of the University of the Ryukyus approved the study protocol (approval no. 1860), and it was conducted in accordance with the principles of the Declaration of Helsinki.
Patients were candidates for NIR-PIT if they had recurrent unresectable HNSCC with a history of prior radiotherapy without distant metastasis. Patients with tumor invasion into bony structures in the skull base, mandible, or maxilla, or into the prevertebral muscle were excluded. Cases with tumors invading or near the carotid artery were also excluded because NIR-PIT induces rapid tumor necrosis, which may lead to fatal post-treatment bleeding in those patients. As the general rule, cases in which the tumor is located within 10 mm of the carotid artery are contraindicated. All treated patients were required to have Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 and adequate organ function confirmed within 21 days of starting treatment initiation. Before starting treatment, head and neck surgeons, radiation oncologists, reconstructive surgeons, and oral and maxillofacial surgeons participated in case evaluations and treatment decision-making.
The pretreatment clinical evaluation included endoscopy, computed tomography (CT), and magnetic resonance imaging (MRI) in the head and neck. Positron emission tomography with CT (PET-CT) was also performed. Case characteristics and clinical features were recorded, including age, sex, target lesion, clinical stage, subsequent treatments, date of disease progression, and oncologic outcomes at the last follow-up examination. Clinical tumor staging was conducted according to the Union for International Cancer Control (UICC) TNM Classification (eighth edition, 2017). Evaluations for disease progression were regularly performed using CT and/or MRI, physical examinations, and endoscopic examinations after completion of the primary treatment protocol. The incidence of adverse events was monitored and graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). The response to treatment was assessed by two radiologists and two head and neck surgeons at our institution according to the Response Evaluation Criteria in Solid Tumors Guideline (version 1.1) (19).
In NIR-PIT, patients received intravenous administration of cetuximab sarotarocan sodium (640 mg/m2) over a 2-h period 20-28 h prior to laser treatment. Because EGFR is also expressed in non-tumor skin and mucosa, patients are photosensitized after cetuximab sarotarocan sodium administration, so they are protected from direct sunlight and kept in rooms with lighting below 120 lx. The type of laser diffuser in the BioBlade® laser system (Rakuten Medical, Inc., Tokyo, Japan) was selected according to the tumor location. Tumors thicker than 10 mm were treated using a cylindrical diffuser, which is to spread the laser light within 15 mm radially. Superficial tumors within 10 mm were treated with a frontal diffuser. Multiple needle catheters were used to deliver the laser beam to the entire tumor, puncturing to a maximum distance of 15 mm to prevent overlapping irradiated areas. The needle was inserted approximately 5 mm from the tumor margin to ensure a 20 mm surgical margin. Different diffusers were used depending on the location, shape, and size of the tumor.
Severe edema has been reported following NIR-PIT due to increased levels of reactive oxygen species generated by the treatment (17). Since laryngeal edema can cause airway obstruction, a temporary tracheostomy was performed before laser exposure in case without laryngectomy. After NIR-PIT, pembrolizumab alone was used for ICI therapy. Pembrolizumab was administered intravenously at a dose of 400 mg at 6-week intervals.
Results
Patient characteristics. Five patients underwent NIR-PIT between January 2022 and December 2023 (Table I). All patients with biopsy-proven SCC had a history of previous curative surgery with free flap reconstruction and prior radiotherapy. Patient 1 had three target lesions (lateral wall of the oropharynx, base of tongue, and tongue) intermittently and each was treated with NIR-PIT. Overall, NIR-PIT treatment was delivered to seven target lesions in 10 cycles overall for five patients (Table II). Of the seven target lesions, five (71.4%) were in the oropharynx and two (28.6%) in oral cavity.
Patients and tumor characteristics.
Treatment, response, and adverse events for tumor lesion.
Patient 2 had undergone high-dose chemotherapy and lower extremity amputation for osteosarcoma of the left lower limb forty years ago and had also undergone definitive surgery and postoperative chemoradiotherapy for tongue cancer 24 years earlier. Therefore, this patient was regarded as a case of secondary cancer.
Laser devices in NIR-PIT. To treat lesion 1, a cylindrical diffuser combined with a frontal diffuser was used because of the mixture of superficial and deep areas in the thickness of the tumor. A cylindrical diffuser alone was used to treat the other six lesions because the tumors were thicker than 10 mm (Figure 1).
Laser treatment for lesion 5. Near-infrared laser illumination of a buccal mucosa carcinoma was performed transorally using cylindrical diffusers for the anterior part of the tumor and percutaneously for the posterior part.
Treatment schedule. Treatment of six of the seven tumors involved a combination of NIR-PIT and ICI therapy (Table II). ICI administration was performed after NIR-PIT for five lesions and before NIR-PIT for one lesion. The main reason for switching from NIR-PIT to ICI therapy was difficulty in continuing NIR-PIT due to complications. Treatment of lesions 3, 5, and 6 resulted in Grade 3 aspiration pneumonia, pharyngo-cutaneous fistula, and trismus, respectively, as adverse events that led to discontinuation of NIR-PIT.
Response rate and adverse events in NIR-PIT. One cycle of NIR-PIT was performed for four of the seven lesions (57.1%) and two cycles were performed for three lesions (42.9%). A complete response (CR) was observed for three lesions and a partial response (PR) for four lesions. The best observed response (BOR) rate was 100% in NIR-PIT. All treatments led to treatment-related adverse events, including Grade 1 or 2 postoperative pain in the treated area. Temporary postoperative fistula was observed for three lesions. Grade 1 or 2 adverse events occurred in six of seven (85.7%) treatments, and the aforementioned Grade 3 adverse events occurred in three (42.9%) treatments.
Response rate and adverse events in ICI therapy. ICI therapy was performed after NIR-PIT for five target lesions in three patients, with a BOR rate of 60%. No immune-related adverse events were observed (Table II). The Grade 3 adverse events that occurred in the treatments of three lesions during NIR-PIT (pneumonia, fistula, and trismus) did not worsen during ICI therapy.
Overall survival outcome. All patients were alive at a median follow-up of 376 days (range=157-845 days), including three patients with no evidence of disease. Four lesions showed no recurrence, and three lesions recurred.
Discussion
This study demonstrated the safety and efficacy of the combination of NIR-PIT and ICI therapy for locally recurrent unresectable HNSCC. The present favorable response rate in NIR-PIT was consistent with previous studies reporting a BOR rate of 43.3%-100% (5, 16, 17). The high response rate in NIR-PIT is mainly attributable to two mechanisms that enhance the local treatment effect: killing of cells directly with laser and subsequently activation of tumor-specific immunity (14).
The response rate to ICI alone has remained modest, with reported BOR rates of 15.7-27.3% (2, 8, 9). In this study, the BOR rate during ICI therapy following NIR-PIT was 60%, which is better than in previous studies of ICI therapy alone. The reason for this was thought to be that NIR-PIT may increase tumor antigenicity and enhance its effect by increasing the presentation of tumor-specific antigens and the infiltration of multiclonal cancer-specific cytotoxic T cells (6). ICI therapy is known to achieve long-tailed survival outcomes (20, 21). Therefore, long-term observation is needed to determine whether better BOR leads to better survival outcomes.
Abscopal effect. Despite local recurrence or progression in NIR-PIT combined with ICI therapy, there were no cases of distant metastasis in this study, suggesting the possibility of an abscopal effect. Antitumor immune activation initially occurs at the targeted cancer site but eventually spreads systemically as immune cells migrate, resulting in a systemic immune response (22). Therefore, the effect of NIR-PIT may extend beyond local therapy, impacting microscopic cancer cells at distant sites. While NIR-PIT is not currently indicated for distant metastases, its efficacy in controlling systemic disease may become apparent, especially in combination with ICI (6).
Timing of ICI therapy in combination with NIR-PIT. The optimal timing of ICI administration in combination with NIR-PIT remains unclear. Previous research and case reports (23) suggest that conducting NIR-PIT before ICI administration leads to favorable outcomes that are consistent with the findings in this study, which demonstrated that ICI administration is feasible either before or after NIR-PIT. Further research is needed to elucidate the optimal timing of ICI therapy in this combination strategy.
NIR-PIT for secondary cancer. In patient 2, NIR-PIT alone resulted in a complete response, and ICI was not administered due to the patient’s long recurrence-free status and history of previous intensive cancer treatments. Secondary cancers are defined as subsequent malignancies (24-26), and there have been no reports on the use of NIR-PIT for such cases. This highlights the potential effectiveness of NIR-PIT even in challenging scenarios such as secondary cancers.
Adverse events in combination therapy. While the combined immunotherapy may offer synergistic effects, immune-related adverse events are a concern (27, 28). For example, combined immunotherapy of nivolumab and ipilimumab improved BOR and survival outcomes in malignant melanoma, compared to either nivolumab or ipilimumab alone. However, the adverse events were more frequent in the combined group (55%) than in the nivolumab (16%) or ipilimumab (27%) monotherapy group (29). In this study, no immune-related adverse events were observed. Moreover, complications associated with NIR-PIT, including Grade 3 adverse events, did not worsen in subsequent ICI therapy. This study suggests that the combination of NIR-PIT and ICI therapy can be performed safely.
Study limitations. Limitations of this study include the small number of cases and the short observation period. Large cohort clinical trials are needed to confirm the efficacy and safety of the combination of NIR-PIT and ICI in HNSCC treatment.
Conclusion
This study demonstrates the efficacy and safety of a combination of NIR-PIT and ICI therapy in the treatment of HNSCC. The results suggest that this combination treatment may represent a promising next-generation strategy for managing locally incurable advanced or recurrent HNSCC. However, further validation through large cohort clinical trials is warranted to confirm these results and establish this treatment modality.
Acknowledgements
This study was supported by and conducted in cooperation with the Ryukyu Society for the Promotion of Oto-Rhino-Laryngology. We thank Narumi Hasegawa, Junko Kawakami, and Masami Gakiya of the Ryukyu Society for the Promotion of Oto-Rhino-Laryngology for helping with data acquisition and administrative work related to this study.
Footnotes
Authors’ Contributions
HH planned the study, collected data, and wrote the manuscript; TI, HK, NK and HY collected data; MS, HM, and AS supervised the study and contributed to writing the manuscript; HH, HK, AS, HM, TH, SK and MT performed clinical treatment, interpreted data, and reviewed the manuscript.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this study.
Funding
This work was supported by a JSPS KAKENHI Grant-in-Aid for Scientific Research (C) (grant no. 24K12721) to HH. The funders had no role in study design, data collection, analysis, decision to publish, or manuscript preparation.
- Received June 10, 2024.
- Revision received June 27, 2024.
- Accepted July 1, 2024.
- Copyright © 2024 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
