PD1/PD-L1 inhibition as a potential radiosensitizer in head and neck squamous cell carcinoma: a case report
© The Author(s). 2016
Received: 24 August 2016
Accepted: 1 November 2016
Published: 15 November 2016
Immunotherapy targeting the checkpoint PD1 (programmed cell death protein 1) or PDL1 (programmed death ligand 1) has led to advances in the treatment of melanoma and non-small cell lung cancer (NSCLC). The use of such therapies has also been introduced into the treatment of other malignancies, including head and neck cancer. The combined effects of checkpoint inhibitors and anti-PD1(L1) antibodies and radiation therapy have not yet been sufficiently investigated.
We report a case of locally relapsed non-resectable oral cavity squamous cell carcinoma, with excellent local control after pembrolizumab (MK3475) followed by radiotherapy.
T cell activation induced by checkpoint inhibition may dramatically improve tumor response to radiation. More data are needed to identify the toxicity and efficacy of sequential or concurrent checkpoint inhibitors and radiotherapy.
KeywordsPD1/PDL1 inhibitor Oral cancer Radiation therapy
The development of immunotherapy targeting the PD1/PDL1 checkpoint inhibition pathway represents considerable progress in the treatment of many cancer types. Pembrolizumab is a humanized monoclonal antibody that blocks the interaction of PD-1 with its ligands, PD-L1 and PD-L2. It is FDA approved for the treatment of melanoma and NSCLC and was recently granted accelerated approval for the treatment of recurrent or metastatic head and neck squamous cell carcinoma in patients with disease progression on or after platinum-containing chemotherapy . Little is known regarding the effects of radiation following PD1 inhibition. We report a case of a patient who experienced excellent local control with immunotherapy followed by radiation therapy for relapsed oral cavity cancer.
Pembrolizumab in head and neck cancer
Ongoing trials on PD1 inhibitors in HNSCC
Abbreviated Trial Name/NCT#
Findings/Expected Primary Endpoint
KEYNOTE-012/NCT01848834 Data updated from ASCO 2016
ORR 17.7 % (95 % CI, 12.6–23.9 %; 7 CRs, 27 PRs).
HPV+ 21.9 %, HPV- 15.9 %.
Median OS 8.5 mo (95 % CI, 6.5–10.5).
Grade 3–4; 12 %
No treatment related deaths
KEYNOTE-055/NCT02255097 Presented ASCO 2016
Recurrent/metastatic HNSCC, progressed on platinum and cetuximab
ORR 18 % (95%CI 9–31); HPV+ 22 %, HPV- 16 %
SD 18 %
Grade 3–5; 20 %
Pembrolizumab VS Chemotherapy (methotrexate, docetaxel or cetuximab)
Pembrolizumab VS Pembro + cis/carbo + 5FU VS Cetuximab + cis/carbo + 5FU
First line treatment for recurrent/metastatic HNSCC
CheckMate141/NCT02105636 Presented AACR 2016
Nivolumab VS Chemo (methotrexate, docetaxel or cetuximab)
1 year OS; nivo 36 %, chemo 16.6 %
Median OS; nivo 7.5 mon, chemo 5.1 months
Radiation therapy and immunotherapy
The effects of radiation following PD1 inhibition are unknown. Current data come from the concurrent administration of immune checkpoint inhibitors with radiotherapy. Radiation is thought to enhance antitumor immune responses by causing inflammatory cell death, major histocompatibility complex (MHC) I upregulation, and release of antigens that are taken up by dendritic cells . Mouse models have shown increased PD-L1 expression in tumors following irradiation . The abscopal effect; or the phenomenon in which tumor regression occurs at sites distant from the site of radiation, has been documented in melanoma and NSCLC patients who underwent radiation with ipilimumab, a CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) checkpoint inhibitors [5, 6]. This further supports the concept of synergistic activity between checkpoint inhibitors and radiation.
Identifying the most beneficial timing for combined radiotherapy and immunotherapy remains a challenge. If radiation is given prior to, or concurrently with immunotherapy, immunotherapy may be more effective with tumor specific antigens originally generated by radiotherapy. On the other hand, if immunotherapy is delivered before radiotherapy, the active immune microenvironment may maximize radiation efficacy . In the present case, radiotherapy was given immediately following discontinuation of pembrolizumab in an attempt to control bleeding. The excellent response seen in the present case may be attributed from the synergistic effect of pembrolizumab.
One possible disadvantage of the concurrent administration of checkpoint inhibitors and radiation is the potential for added toxicities. In the present case, it is probable that the risk of adverse events (AE) was mitigated by the sequential delivery of therapy. In an analysis of 29 unresectable/metastatic melanoma patients who underwent radiation while receiving ipilimumab, the authors concluded that concurrent therapy was not associated with higher than expected rates of AEs, nor did it invalidate the palliative effects of radiation or survival benefits from ipilimumab [8, 9].
Ongoing studies on PD1 inhibitors and radiation therapy in HNSCC
Abbreviated Trial Name/NCT#
Expected Primary Endpoint
Cetuximab, ipilimumab and IMRT
Dose limiting toxicities (DLT)
III w/phase I lead in
Nivolumab and cisplatin CRT
stage III-IV, intermediate to high risk HNSCC
DLT for phase I
Concurrent vs sequential pembro, cisplatin and IMRT
1 year PFS
1 year failure rate
Acute toxicity rates
Adjuvant pembro, cisplatin and IMRT
high risk stage III-IV HSNCC
Adjuvant pembro, cisplatin and IMRT
high risk stage III-IV HSNCC
Treatment related adverse events (TRAE)
Disease free survival (DFS)
As we await further data, a trial of radiation following immunotherapy could be considered for disease control in selected patients.
Human papilloma virus
Intensity modulated radiation therapy
Major histocompatibility complex
Non-small cell lung cancer
Objective response rate
Programmed cell death protein 1
Programmed death ligand 1
Squamous cell carcinoma
Treatment-related adverse events
We indicate here that the result of this study was accepted for an oral presentation at the AHNS 9th International Conference on Head and Neck Cancer. The authors have not published or submitted any related papers from the same study. We thank our patients, their families and our colleagues at Karmanos Cancer Institute who supported us in the preparation of this manuscript. All authors read and approved the final manuscript.
The authors did not receive any grants or other financial support for the preparation of this manuscript.
MN and AS contributed to the planning, organization, data collection and writing of the manuscript. AS is also the treating oncologist for this case and is the corresponding author for this manuscript. MZ, HK, SNR, GY and HL all treated the patient, reviewed the manuscript and provided critical edits. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Consent for treatment and publication was obtained from the patient herself. Availability of data and material: Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.
Ethics approval and consent to participate
Need for approval was waived by the Karmanos Protocol Review and Monitoring Committee.
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