Study protocol: phase II study to evaluate the effect of cetuximab monotherapy after immunotherapy with PD-1 inhibitors in patients with head and neck squamous cell cancer.

Background: Immunotherapy with programmed death receptor-1 (PD-1) inhibitors, as a single agent or in combination with chemotherapy, is the standard first-line treatment for recurrent or metastatic head and neck squamous cell cancer (R/M HNSCC). Unfortunately, there is no established second-line treatment for the many patients who fail immunotherapy. Cetuximab is the only targeted therapy approved in HNSCC but historically has a low response rate of 13%. Objectives: We hypothesize that cetuximab monotherapy following an immune checkpoint inhibitor (ICI) will lead to increased efficacy due to a potential synergistic effect on the antitumor immune response, as a result of activation effects of both treatments on innate and adaptative immune responses. To the authors' knowledge, this is the only ongoing prospective clinical study that evaluates the combination of cetuximab and ICIs administered sequentially. Methods and analysis: In this non-randomized, open-label, phase II trial, 30 patients with R/M HNSCC who have previously failed or could not tolerate a PD-1 inhibitor as a single agent or in combination with chemotherapy will subsequently be treated with cetuximab monotherapy. Outcomes of interest include overall response rate, duration of response, progression-free survival, overall survival, and treatment toxicity, as well as treatment outcome measured by a patient-reported outcome questionnaire. Saliva and blood will be collected for correlative studies to investigate the immune response status at the end of therapy with an ICI and the effect of cetuximab on the antitumor immune response. The results will be correlated with the response to cetuximab and the time window between the last administration of an ICI and the loading dose of cetuximab. The clinical study is actively recruiting. Ethics: This study was approved by the Wake Forest Comprehensive Cancer Center Institutional Review Board: IRB00065239. Clinical trial registration: This study is registered on ClinicalTrials.gov: NCT04375384.

A Rare Case of Hereditary Hemochromatosis Presenting With Porphyria Cutanea Tarda.

Hereditary hemochromatosis is an autosomal recessive condition with incomplete penetrance that is most commonly caused by a mutation in the HFE gene. Hereditary hemochromatosis can remain asymptomatic in some patients until triggered by certain events. Porphyria cutanea tarda is a condition that can lead to iron overload due to defective synthesis of heme and can cause the onset of adult-onset hereditary hemochromatosis. Herein, we present a case where a 77-year-old man presented with painful blisters on the sun-exposed areas of his hands and was diagnosed with porphyria cutanea tarda. Further testing for mutations in the HFE gene given elevated ferritin was performed and returned positive, which confirmed the diagnosis of adult-onset hereditary hemochromatosis. The patient received serial therapeutic phlebotomy for iron overload and adopted lifestyle modifications such as avoiding sun exposure of upper extremities. The patient's blisters and laboratory iron panel parameters improved with continued phlebotomy. Therapeutic phlebotomy has been demonstrated to be an effective first-line therapy in patients with dual diagnosis. Our case highlights that cutaneous symptoms due to porphyria cutanea tarda may be the first presenting symptom in patients with underlying hemochromatosis.

Exceptional response to cetuximab monotherapy after failure of immunotherapy with a checkpoint inhibitor in a patient with metastatic head and neck squamous cell cancer: case report and review of the literature.

Immunotherapy with PD-1 inhibitors monotherapy or combined with chemotherapy comprises the first-line palliative treatment for patients with recurrent or metastatic head and neck squamous cell cancers (R/M HNSCC). The established survival advantage among responders is overshadowed by the high percentage of patients failing the standard PD-1 inhibitor-based treatments. Salvage therapies are direly needed. However, no current standards are available. We present the case of a 65-year-old patient with heavily pretreated laryngeal squamous cell carcinoma who had an exceptional response to cetuximab monotherapy following the failure of immunotherapy with the PD-1 inhibitor nivolumab. We reviewed the literature for other cases of exceptional response to cetuximab, clinical studies investigating the combined or sequential administration of cetuximab and PD-1 inhibitors, and the mechanistic rationale for consideration of cetuximab as a potential salvage treatment after immunotherapy with PD-1 inhibitors. In addition to the specific epidermal growth factor receptor inhibitory effect, cetuximab, as an immunoglobulin G1 isotype, binds NK cells and elicits antibody-dependent cellular toxicity, triggering a domino of immunostimulatory, and immunoinhibitory effects that actually might decrease the cetuximab anticancer efficacy. However, in a tumor microenvironment exposed to previous treatment with a PD-1 inhibitor, the effects of the PD-1 inhibitor followed by cetuximab on innate and adaptative immune response appear to synergize. Specifically, persistent immune checkpoint inhibitors' consequences may negate downstream immunosuppressive effects of cetuximab caused through PD-1/PD-L1 upregulation, making it a more potent treatment option. Besides the potential synergistic effect on antitumor immune response with previous immune checkpoint inhibitors therapy, cetuximab is the only targeted agent approved for treating R/M HNSCC, making it a most advantageous candidate for further treatment validation studies as salvage treatment post-immunotherapy.

Oculomotor Nerve Palsy as a Manifestation of Immune Thrombocytopenic Purpura: A Case Report.

Immune thrombocytopenic purpura (ITP) is caused by alterations in the immune system resulting in platelet destruction. It often manifests clinically with bleeding or on routine lab work revealing thrombocytopenia in asymptomatic individuals. Neurologic manifestations of this condition are sparsely documented in the literature. Among the symptoms reported were case reports of ischemic strokes, transient ischemic attacks, mononeuropathy multiplex, and polyneuropathy as neurological complications from immune thrombocytopenic purpura. Isolated cranial nerve palsies are uncommon. The following case describes a patient with immune thrombocytopenic purpura who presented with an isolated cranial nerve III palsy. A 55-year-old presented with pain in the right eye that was found in a downward and lateral gaze paralysis. There was no evidence of central or peripheral neurovascular etiology on imaging. However, workup revealed isolated thrombocytopenia with platelets <2000/ml3. Other possible etiologies, such as human immunodeficiency virus (HIV) and infectious etiologies, were evaluated and excluded. Thrombotic thrombocytopenia purpura was excluded with the results from ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity. The patient was appropriately transfused with platelets and was treated with methylprednisolone, which improved his platelets. At the time of discharge, the patient continued to have cranial nerve III palsy and was referred to follow up with hematology on an outpatient basis. In prior case reports where ITP presented as neurological deficits, there was evidence of intraneural microhemorrhage. Our case is unique in that the primary neurologic presentation without central nervous system pathology eventually led to the diagnosis of ITP. The symptoms were attributed to microhemorrhages that were not detected in imaging studies. Further studies are warranted to explore any correlation or causative association between ITP and neurological symptoms. This case report highlights the need to consider uncommon but possible manifestations of conditions that may initially appear seemingly irrelevant to the patient's chief complaint.

Serendipitous synergism - an exceptional response to treatment with pembrolizumab in the course of a natural immunovirotherapy: a case report and review of the literature.

Immune checkpoint inhibitors (ICIs) are the current guideline recommended treatment for many malignancies considered to be terminal. Despite considerable advances, their utility remains limited, and the field requires synergistic partners to further improve outcomes. Oncolytic viruses (OV) are emerging as contenders for the role of the synergistic agent of choice due to their multi-mechanistic effect on activating the tumor 'cold' immune microenvironment. Herpes simplex virus 1, a naturally selective OV, is the most advanced virotherapeutic compound in clinical applications for use in combination with ICI. We here present the case of a 72 year-old patient with a heavily pre-treated, advanced maxillary sinus squamous cell cancer with distant metastases who developed complete response (CR) with only three administrations of a programmed death 1 inhibitor after treatment interference by a severe herpes zoster infection, based on the related alpha-herpesvirus varicella zoster virus (VZV). This exceptional response has been followed and confirmed with imaging studies over more than 5 years. Although the patient had several favorable predictors for response to immunotherapy, we reason that the exceptional response may in part be secondary to the serendipitous VZV infection. Documented cases of cancer patients that achieved CR after few administrations of treatment with ICI are rare, with most reporting follow up of just over 1 year or less. In this case, it is conceivable that the interference of the infection with VZV, soon after the start of immunotherapy with ICI, led to a lasting antitumor immunity and sustained CR. This hypothesis is supported by the concept of 'oncolytic immunotherapy' which is reviewed in this manuscript. In addition, persistence of a TP53 mutation found in a liquid biopsy, despite clinical and radiologic remission, is discussed.