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Implementation of Double Immune Checkpoint Blockade Increases Response Rate to Induction Chemotherapy in Head and Neck Cancer.

ABSTRACT: To determine whether a single dose of double immune checkpoint blockade (induction chemoimmunotherapy (ICIT)) adds benefit to induction single-cycle platinum doublet (induction chemotherapy (IC)) in locally advanced head and neck squamous cell carcinoma (HNSCC), patients treated with cisplatin 30 mg/m2 d1-3 and docetaxel 75 mg/m2 d1 combined with durvalumab 1500 mg fixed dose d5 and tremelimumab 75 mg fixed dose d5 (ICIT) within the CheckRad-CD8 trial were compared with a retrospective cohort receiving the same chemotherapy (IC) without immunotherapy. The endpoint of this analysis was the complete response rate (CR). A total of 53 patients were treated with ICIT and 104 patients with IC only. CR rates were 60.3% for ICIT and 40.3% for IC (p = 0.018). In the total population (n = 157), the most important predictor to achieve a CR was treatment type (OR: 2.21 for ICIT vs. IC; p = 0.038, multivariate analysis). The most diverse effects in CR rates between ICIT and IC were observed in younger (age ≤ 60) patients with HPV-positive OPSCCs (82% vs. 33%, p = 0.176), while there was no difference in older patients without HPV-positive OPSCCs (53% vs. 48%). The analysis provides initial evidence that ICIT could result in higher CR rates than IC. Young patients with HPV-positive OPSCCs may have the greatest benefit from additional immune checkpoint inhibitors.

SUBMITTER: Semrau S

PROVIDER: S-EPMC8073509 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Implementation of Double Immune Checkpoint Blockade Increases Response Rate to Induction Chemotherapy in Head and Neck Cancer.

Semrau Sabine S Gostian Antoniu-Oreste AO Traxdorf Maximilian M Eckstein Markus M Rutzner Sandra S von der Grün Jens J Illmer Thomas T Hautmann Matthias M Klautke Gunther G Laban Simon S Brunner Thomas T Tamaskovics Bálint B Frey Benjamin B Zhou Jian-Guo JG Geppert Carol-Immanuel CI Hartmann Arndt A Balermpas Panagiotis P Budach Wilfried W Gaipl Udo U Iro Heinrich H Fietkau Rainer R Hecht Markus M

Cancers 20210419 8

To determine whether a single dose of double immune checkpoint blockade (induction chemoimmunotherapy (ICIT)) adds benefit to induction single-cycle platinum doublet (induction chemotherapy (IC)) in locally advanced head and neck squamous cell carcinoma (HNSCC), patients treated with cisplatin 30 mg/m<sup>2</sup> d1-3 and docetaxel 75 mg/m<sup>2</sup> d1 combined with durvalumab 1500 mg fixed dose d5 and tremelimumab 75 mg fixed dose d5 (ICIT) within the CheckRad-CD8 trial were compared with a r ...[more]

PMID: 33921668

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Project description:The success of immune checkpoint receptor blockade has brought exciting promises for the treatment of head and neck squamous cell carcinoma (HNSCC). While patients who respond to checkpoint inhibitors tend to develop a durable response, <15% of patients with HNSCC respond to immune checkpoint inhibitors, underscoring the critical need to alleviate cancer resistance to immunotherapy. Major advances have been made to elucidate the intrinsic and adaptive resistance mechanisms to immunotherapy. Central genomic events in HNSCC have been found to possess previously unknown roles in suppressing immune sensing. Such inhibitory function affects both the innate and adaptive arms of tumor-specific immunity. While checkpoint blockade effectively reinvigorates adaptive T-cell responses, additional targeting of the oncogenic inhibitors of innate immune sensing likely informs a novel and potent strategy for immune priming. This review discusses the recent advances on the identification of key HNSCC oncogenes that impair antitumor immunity and emerging immune-priming approaches that sensitize poorly immunogenic HNSCCs to checkpoint blockade. These approaches include but are not limited to cancer vaccine systems utilizing novel type I interferon agonists as immune adjuvants, radiation, DNA damage-inducing agents, and metabolic reprogramming. The goal of these multipronged approaches is to expand tumor-specific effector T-cells, break checkpoint receptor-mediated tolerance, and metabolically support sustained T-cell activation. The translation of therapeutics that reverses oncogenic inhibition of immune sensing requires thorough characterization of the HNSCC regulators of innate immune sensors, development of additional immunocompetent HNSCC mouse models, as well as engineering of more robust immune adjuvant delivery systems. Built on the success of checkpoint blockade, validation of novel immune-priming approaches holds key promises to expand the pool of responders to immunotherapy.

Project description:This review focuses on the molecular biology of head and neck squamous cell carcinomas and presents current and emerging biomarkers of the response of patients to induction chemotherapy. The usefulness of genes, proteins, and parameters from diagnostic clinical imaging as well as other clinicopathological parameters is thoroughly discussed. The role of induction chemotherapy before radiotherapy or before chemo-radiotherapy is still debated, as the data on its efficacy are somehow confusing. Despite the constant improvement of treatment protocols and the introduction of new cytostatics, there is still no consensus regarding the use of induction chemotherapy in the treatment of head and neck cancer, with the possible exception of larynx preservation. Such difficulties indicate that potential future treatment strategies should be personalized. Personalized medicine, in which individual tumor genetics drive the selection of targeted therapies and treatment plans for each patient, has recently emerged as the next generation of cancer therapy. Early prediction of treatment outcome or its toxicity may be highly beneficial for those who are at risk of the development of severe toxicities or treatment failure-a different treatment strategy may be applied to these patients, sparing them unnecessary pain. The literature search was carried out in the PubMed and ScienceDirect databases as well as in the selected conference proceedings repositories. Of the 265 articles and abstracts found, only 30 met the following inclusion criteria: human studies, analyzing prediction of induction chemotherapy outcome or toxicity based on the pretreatment (or after the first cycle, if more cycles of induction were administered) data, published after the year 2015. The studies regarding metastatic and recurrent cancers as well as the prognosis of overall survival or the outcome of consecutive treatment were not taken into consideration. As revealed from the systematic inspection of the papers, there are over 100 independent parameters analyzed for their suitability as prognostic markers in HNSCC patients undergoing induction chemotherapy. Some of them are promising, but usually they lack important features such as high specificity and sensitivity, low cost, high positive predictive value, clinical relevance, short turnaround time, etc. Subsequent studies are necessary to confirm the usability of the biomarkers for personal medicine.

Project description:BackgroundThe rate of toxic deaths related to induction chemotherapy in the treatment of locally advanced head and neck cancers is unacceptable and calls into question this therapeutic strategy, which is however highly effective in terms of rate and speed of response. The purpose of the study was to investigate predictive factors of toxicity of induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (TPF) in locally advanced head and neck cancers (LAHNC).MethodsBetween June 2009 and December 2017, 113 patients treated consecutively with TPF were included retrospectively. Patients were receiving induction chemotherapy for either an inoperable cancer or laryngeal preservation. For inoperable cancer, induction chemotherapy was proposed to patients presenting either a large tumor with strong symptoms (dyspnea, dysphagia, pain) or a tumor with rapid progression. Risk factors were chosen among the initial patient and tumour characteristics and chemotherapy modalities.ResultsEighty-nine patients (79%) were male; the median age was 58 years [32-71]. Sixty-nine (61%) patients were treated for inoperable cancer and 44 (39%) for laryngeal preservation. 45% had stage IVa cancer, 28% stage III and 25% stage IVb. Sixty percent of patients had a partial response after TPF, 22% had a complete response, 12% were stable, 5% were progressing, and 1% had a discordant response. Thirty-four patients (30%) received enteral feeding during induction chemotherapy with TPF. The possibility of oral feeding without a tube was predictive of a better response (p = 0.003). Seven (6%) patients died during TPF. There was an increased risk of death with preexisting liver dysfunction (liver dysmorphia on imaging or decrease prothrombin rate) (p = 0.032). There was an increased risk of grade ≥ 3 infection if an enteral feeding occurred during the period of induction chemotherapy (p = 0.03).ConclusionsTPF induction chemotherapy had an 82% objective response rate with 6% toxic deaths. Nutritional status and the presence of hepatic dysfunction are significant risk factors to be taken into account in therapeutic decisions.

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Implementation of Double Immune Checkpoint Blockade Increases Response Rate to Induction Chemotherapy in Head and Neck Cancer.

Publications

Implementation of Double Immune Checkpoint Blockade Increases Response Rate to Induction Chemotherapy in Head and Neck Cancer.

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