Publications by authors named "Ezra E W Cohen"

157 Publications

Pembrolizumab plus cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma: an open-label, multi-arm, non-randomised, multicentre, phase 2 trial.

Lancet Oncol 2021 06 11;22(6):883-892. Epub 2021 May 11.

Moores Comprehensive Cancer Center, University of California, San Diego, La Jolla, CA, USA.

Background: Pembrolizumab (PD-1 inhibitor) and cetuximab (EGFR inhibitor) are active as single agents and in combination with cytotoxic chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Given each drug's single agent activity and unique mechanism of action, we aimed to evaluate the anti-tumour activity of PD-1 blockade with EGFR inhibition in recurrent or metastatic HNSCC.

Methods: This study is an open-label, non-randomised, multi-arm, phase 2 trial done at four academic centres in the USA. Participants were required to have platinum-resistant or platinum-ineligible, recurrent or metastatic HNSCC, be at least 18 years old, have an Eastern Cooperative Oncology Group performance status 0-1, have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and to have received no previous immunotherapy or EGFR inhibition. All participants received pembrolizumab 200 mg intravenously every 3 weeks, combined with an initial loading dose of cetuximab 400 mg/m intravenously followed by 250 mg/m intravenously weekly (21 day cycle). The primary endpoint was overall response rate defined as the proportion of participants with a partial or complete responses (per RECIST version 1.1) by 6 months in the intention-to-treat population. The safety population included all participants who received at least one dose of pembrolizumab. Herein, the final analysis of cohort 1 (no previous PD-1, PD-L1, or EGFR inhibition for recurrent or metastatic HNSCC) is reported. Three additional cohorts (two for participants with a previous response to immunotherapy followed by relapse or progression, with or without previous cetuximab exposure, and one for cutaneous HNSCC) will be reported separately once fully accrued. This study is registered with ClinicalTrials.gov, NCT03082534, and remains open as the three additional cohorts are actively accruing participants.

Findings: Between March 22, 2017, and July 16, 2019, 33 participants were enrolled to cohort 1. All 33 participants received at least one dose of pembrolizumab. Median follow-up duration was 7·3 months (IQR 3·9-10·9). By 6 months, the overall response rate was 45% (95% CI 28-62), with 15 of 33 participants achieving a partial response. The most common grade 3-4 treatment-related adverse event was oral mucositis (three [9%] of 33 participants), and serious treatment-related adverse events occurred in five (15%) participants. No treatment-related deaths occurred.

Interpretation: Pembrolizumab combined with cetuximab shows promising clinical activity for recurrent or metastatic HNSCC, and merits further investigation.

Funding: Merck Sharp & Dohme.
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http://dx.doi.org/10.1016/S1470-2045(21)00136-4DOI Listing
June 2021

Did Everolimus Break the Rules?

Clin Cancer Res 2021 May 13. Epub 2021 May 13.

Moores Cancer Center, University of California, San Diego Health

A phase II study with everolimus (mTORC1 inhibitor) among advanced solid tumors patients with TSC1/TSC2 or MTOR alterations was recently published. Although efficacy was limited, the study provided the future groundwork to advance the targeted therapy approach.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1508DOI Listing
May 2021

Disruption of the HER3-PI3K-mTOR oncogenic signaling axis and PD-1 blockade as a multimodal precision immunotherapy in head and neck cancer.

Nat Commun 2021 04 22;12(1):2383. Epub 2021 Apr 22.

Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.

Immune checkpoint blockade (ICB) therapy has revolutionized head and neck squamous cell carcinoma (HNSCC) treatment, but <20% of patients achieve durable responses. Persistent activation of the PI3K/AKT/mTOR signaling circuitry represents a key oncogenic driver in HNSCC; however, the potential immunosuppressive effects of PI3K/AKT/mTOR inhibitors may limit the benefit of their combination with ICB. Here we employ an unbiased kinome-wide siRNA screen to reveal that HER3, is essential for the proliferation of most HNSCC cells that do not harbor PIK3CA mutations. Indeed, we find that persistent tyrosine phosphorylation of HER3 and PI3K recruitment underlies aberrant PI3K/AKT/mTOR signaling in PIK3CA wild type HNSCCs. Remarkably, antibody-mediated HER3 blockade exerts a potent anti-tumor effect by suppressing HER3-PI3K-AKT-mTOR oncogenic signaling and concomitantly reversing the immune suppressive tumor microenvironment. Ultimately, we show that HER3 inhibition and PD-1 blockade may provide a multimodal precision immunotherapeutic approach for PIK3CA wild type HNSCC, aimed at achieving durable cancer remission.
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http://dx.doi.org/10.1038/s41467-021-22619-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062674PMC
April 2021

Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 107 randomized trials and 19,805 patients, on behalf of MACH-NC Group.

Radiother Oncol 2021 03 27;156:281-293. Epub 2021 Jan 27.

University of Chicago, IL, USA.

Background And Purpose: The Meta-Analysis of Chemotherapy in squamous cell Head and Neck Cancer (MACH-NC) demonstrated that concomitant chemotherapy (CT) improved overall survival (OS) in patients without distant metastasis. We report the updated results.

Materials And Methods: Published or unpublished randomized trials including patients with non-metastatic carcinoma randomized between 1965 and 2016 and comparing curative loco-regional treatment (LRT) to LRT + CT or adding another timing of CT to LRT + CT (main question), or comparing induction CT + radiotherapy to radiotherapy + concomitant (or alternating) CT (secondary question) were eligible. Individual patient data were collected and combined using a fixed-effect model. OS was the main endpoint.

Results: For the main question, 101 trials (18951 patients, median follow-up of 6.5 years) were analyzed. For both questions, there were 16 new (2767 patients) and 11 updated trials. Around 90% of the patients had stage III or IV disease. Interaction between treatment effect on OS and the timing of CT was significant (p < 0.0001), the benefit being limited to concomitant CT (HR: 0.83, 95%CI [0.79; 0.86]; 5(10)-year absolute benefit of 6.5% (3.6%)). Efficacy decreased as patients age increased (p_trend = 0.03). OS was not increased by the addition of induction (HR = 0.96 [0.90; 1.01]) or adjuvant CT (1.02 [0.92; 1.13]). Efficacy of induction CT decreased with poorer performance status (p_trend = 0.03). For the secondary question, eight trials (1214 patients) confirmed the superiority of concomitant CT on OS (HR = 0.84 [0.74; 0.95], p = 0.005).

Conclusion: The update of MACH-NC confirms the benefit and superiority of the addition of concomitant CT for non-metastatic head and neck cancer.
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http://dx.doi.org/10.1016/j.radonc.2021.01.013DOI Listing
March 2021

Comparing programmed death ligand 1 scores for predicting pembrolizumab efficacy in head and neck cancer.

Mod Pathol 2021 03 25;34(3):532-541. Epub 2020 Nov 25.

Late-Stage Immuno-Oncology Research and Development, Merck & Co., Inc., Kenilworth, NJ, USA.

Tumor proportion score (TPS) and combined positive score ([CPS] includes immune cells), 2 methods for scoring programmed death ligand 1 (PD-L1) expression, have been used in clinical trials investigating the immune checkpoint inhibitor pembrolizumab in head and neck squamous cell carcinoma (HNSCC). These trials resulted in regulatory approval for pembrolizumab in the first- and second-line setting outside the United States. We performed a post hoc analysis of the KEYNOTE-040 study (NCT02252042) to determine whether CPS is a practical and suitable alternative scoring method to TPS. In KEYNOTE-040, patients with metastatic HNSCC received pembrolizumab or investigator choice of standard of care (SOC). The relative utility and equivalence of CPS ≥ 50 and TPS ≥ 50% for defining PD-L1 expression status in patients with HNSCC and comparability of scoring methods by tandem receiver operating characteristic (ROC) analysis were analyzed. The cutoff for each method was also evaluated. CPS ≥ 50 appeared equivalent to TPS ≥ 50% for predicting objective response rate (ORR), overall survival, and progression-free survival. ORR for pembrolizumab versus SOC was 26.2 versus 8.5% for TPS ≥ 50%, 28.1 versus 7.7% for CPS ≥ 50, 10.6 versus 11.6% for TPS < 50%, and 10.0 versus 12.0% for CPS < 50. Tandem ROC analysis showed that TPS 50% and CPS 50 maximized delta Youden index and suggested that CPS is more sensitive than TPS at lower cutoffs (i.e., CPS ≥ 1). In conclusion, CPS 50 can be used interchangeably with TPS 50% to determine PD-L1 status in patients with HNSCC. CPS may be more sensitive than TPS at lower cutoffs.
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http://dx.doi.org/10.1038/s41379-020-00710-9DOI Listing
March 2021

The Changing Landscape of Therapeutic Cancer Vaccines-Novel Platforms and Neoantigen Identification.

Clin Cancer Res 2021 Feb 29;27(3):689-703. Epub 2020 Oct 29.

Moores Cancer Center, University of California, San Diego Health, La Jolla, California.

Therapeutic cancer vaccines, an exciting development in cancer immunotherapy, share the goal of creating and amplifying tumor-specific T-cell responses, but significant obstacles still remain to their success. Here, we briefly outline the principles underlying cancer vaccine therapy with a focus on novel vaccine platforms and antigens, underscoring the renewed optimism. Numerous strategies have been investigated to overcome immunosuppressive mechanisms of the tumor microenvironment (TME) and counteract tumor escape, including improving antigen selection, refining delivery platforms, and use of combination therapies. Several new cancer vaccine platforms and antigen targets are under development. In an effort to amplify tumor-specific T-cell responses, a heterologous prime-boost antigen delivery strategy is increasingly used for virus-based vaccines. Viruses have also been engineered to express targeted antigens and immunomodulatory molecules simultaneously, to favorably modify the TME. Nanoparticle systems have shown promise as delivery vectors for cancer vaccines in preclinical research. T-win is another platform targeting both tumor cells and the TME, using peptide-based vaccines that engage and activate T cells to target immunoregulatory molecules expressed on immunosuppressive and malignant cells. With the availability of next-generation sequencing, algorithms for neoantigen selection are emerging, and several bioinformatic platforms are available to select therapeutically relevant neoantigen targets for developing personalized therapies. However, more research is needed before the use of neoepitope prediction and personalized immunotherapy becomes commonplace. Taken together, the field of therapeutic cancer vaccines is fast evolving, with the promise of potential synergy with existing immunotherapies for long-term cancer treatment.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0245DOI Listing
February 2021

Talimogene Laherparepvec and Pembrolizumab in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (MASTERKEY-232): A Multicenter, Phase 1b Study.

Clin Cancer Res 2020 10 15;26(19):5153-5161. Epub 2020 Jul 15.

Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

Purpose: The prognosis for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) is poor, and only a minority of patients benefit from checkpoint immunotherapy. Talimogene laherparepvec (T-VEC), an oncolytic immunotherapy approved for advanced melanoma, in combination with pembrolizumab may yield enhanced antitumor activity over either agent alone.

Patients And Methods: This was a phase Ib/III, multicenter trial testing intratumoral T-VEC combined with intravenous pembrolizumab in R/M HNSCC refractory to platinum-based chemotherapy. For phase Ib, primary endpoint was incidence of dose-limiting toxicity (DLT). Key secondary endpoints included objective response rate and progression-free survival per irRECIST, overall survival, and safety.

Results: Thirty-six patients were enrolled into the phase Ib study. The data cut-off date was August 28, 2018. Median follow-up was 5.8 months (range, 0.3-24.2). One DLT of T-VEC-related fatal arterial hemorrhage was reported. Twenty (55.6%) and 21 (58.3%) patients experienced adverse events (AE) related to T-VEC and pembrolizumab, respectively. Besides the DLT, there were no treatment-related fatal AEs. A confirmed partial response was observed in 5 (13.9%) patients. Ten (27.8%) patients were unevaluable for response due to early death. Median PFS and OS were 3.0 months [95% confidence interval (Cl), 2.0-5.8] and 5.8 months (95% Cl, 2.9-11.4), respectively.

Conclusions: The combination of T-VEC and pembrolizumab demonstrated a tolerable safety profile in R/M HNSCC. The efficacy with the combination was similar to that with pembrolizumab monotherapy in historical HNSCC studies. Phase III part of this study was not further pursued (ClinicalTrials.gov Identifier: NCT02626000).
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1170DOI Listing
October 2020

Tipifarnib in recurrent, metastatic HRAS-mutant salivary gland cancer.

Cancer 2020 09 18;126(17):3972-3981. Epub 2020 Jun 18.

Department of Hematology/Oncology, Memorial Sloan Kettering Cancer Center, New York City, New York.

Background: To the authors' knowledge, there are no approved therapies for recurrent, metastatic (R/M) salivary gland carcinoma (SGC), but molecularly targeted therapies warrant ongoing investigation. In the current study, the authors have reported on the efficacy of tipifarnib in patients with aggressive HRAS-mutant, R/M SGC.

Methods: The current prospective, nonrandomized, multicenter, international cohort study involved 8 centers and was conducted from May 2015 to June 2019. The median follow-up was 22 months (range, 6-55 months). Subjects with HRAS-mutant R/M SGC (any histology) and disease progression within the last 6 months were enrolled. Tipifarnib was dosed orally twice daily. The authors determined the objective response rate using Response Evaluation Criteria in Solid Tumors (version 1.1), duration of response, and molecular predictors of response.

Results: A total of 13 patients with R/M SGC were enrolled; all had received prior systemic therapy (1-3 regimens). One objective response was observed; an additional 7 of 12 evaluable patients (58%) had stable disease as their best response with a median duration of 9 months (range, 3-14 months). Five of 7 patients had >10% tumor regression and 6 of 7 had stable disease lasting >6 months. Q61R was the most frequent activating HRAS mutation noted (7 of 13 patients; 54%), but gene variant and allele frequency did not correlate with outcomes. The median progression-free survival was 7 months (95% confidence interval, 5.9-10.1 months), and the median overall survival was 18 months (95% confidence interval, 9.6-22.4 months) with approximately 58.6% of patients alive at 1 year. Survival was similar regardless of HRAS mutant variant or co-occurring PIK3CA alterations. No participant discontinued treatment because of toxicity.

Conclusions: Tipifarnib resulted in modest clinical activity with a promising disease control rate among patients with HRAS-mutant, R/M SGC who developed disease progression within the last 6 months.
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http://dx.doi.org/10.1002/cncr.33036DOI Listing
September 2020

Safety and Efficacy of Pembrolizumab With Chemoradiotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma: A Phase IB Study.

J Clin Oncol 2020 07 1;38(21):2427-2437. Epub 2020 Jun 1.

Sanford Cancer Center, Sanford Health, Sioux Falls, SD.

Purpose: Pembrolizumab is a humanized monoclonal antibody that blocks interaction between programmed death receptor-1 (PD-1) and its ligands (PD-L1, PD-L2). Although pembrolizumab is approved for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), its role in the management of locally advanced (LA) disease is not defined. We report a phase IB study evaluating the safety and efficacy of adding pembrolizumab to cisplatin-based chemoradiotherapy in patients with LA HNSCC.

Patients And Methods: Eligible patients included those with oral cavity (excluding lip), oropharyngeal, hypopharyngeal, or laryngeal stage III to IVB HNSCC (according to American Joint Committee on Cancer, 7th edition, staging system) eligible for cisplatin-based, standard-dose (70 Gy) chemoradiotherapy. Pembrolizumab was administered concurrently with and after chemoradiotherapy with weekly cisplatin. Safety was the primary end point and was determined by incidence of chemoradiotherapy adverse events (AEs) and immune-related AEs (irAEs). Efficacy was defined as complete response (CR) rate on end-of-treatment (EOT) imaging or with pathologic confirmation at 100 days postradiotherapy completion. Key secondary end points included overall (OS) and progression-free survival (PFS).

Results: The study accrued 59 patients (human papillomavirus [HPV] positive, n = 34; HPV negative, n = 25) from November 2015 to October 2018. Five patients (8.8%) required discontinuation of pembrolizumab because of irAEs, all of which occurred during concurrent chemoradiotherapy; 98.3% of patients completed the full planned treatment dose (70 Gy) of radiotherapy without any delays ≥ 5 days; 88.1% of patients completed the goal cisplatin dose of ≥ 200 mg/m. EOT CR rates were 85.3% and 78.3% for those with HPV-positive and -negative HNSCC, respectively.

Conclusion: Pembrolizumab in combination with weekly cisplatin-based chemoradiotherapy is safe and does not impair delivery of curative radiotherapy or chemotherapy in HNSCC. Early efficacy data support further investigation of this approach.
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http://dx.doi.org/10.1200/JCO.19.03156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365766PMC
July 2020

Quality of Life With Pembrolizumab for Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: KEYNOTE-040.

J Natl Cancer Inst 2021 02;113(2):171-181

Moores Cancer Center at UC San Diego Health, University of California San Diego, La Jolla, CA, USA.

Background: Head and neck squamous cell carcinoma (HNSCC) affects health-related quality of life (HRQoL); few treatments have demonstrated clinically meaningful HRQoL benefit. KEYNOTE-040 evaluated pembrolizumab vs standard of care (SOC) in patients with recurrent and/or metastatic HNSCC whose disease recurred or progressed after platinum-containing regimen.

Methods: Patients received pembrolizumab 200 mg or SOC (methotrexate, docetaxel, or cetuximab). Exploratory HRQoL analyses used European Organisation for Research and Treatment of Cancer (EORTC) 30 quality-of-life, EORTC 35-question quality-of-life head and neck cancer-specific module, and EuroQoL 5-dimensions questionnaires.

Results: The HRQoL population comprised 469 patients (pembrolizumab = 241, SOC = 228). HRQoL compliance for patients in the study at week 15 was 75.3% (116 of 154) for pembrolizumab and 74.6% (85 of 114) for SOC. The median time to deterioration in global health status (GHS) and QoL scores were 4.8 months with pembrolizumab and 2.8 months with SOC (hazard ratio = 0.79, 95% confidence interval [CI] = 0.59 to 1.05). At week 15, GHS / QoL scores were stable for pembrolizumab (least squares mean [LSM] = 0.39, 95% CI = -3.00 to 3.78) but worsened for SOC (LSM = -5.86, 95% CI = -9.68 to -2.04); the LSM between-group difference was 6.25 points (95% CI = 1.32 to 11.18; nominal 2-sided P = .01). A greater difference in the LSM for GHS / QoL score occurred with pembrolizumab vs docetaxel (10.23, 95% CI = 3.15 to 17.30) compared with pembrolizumab vs methotrexate (6.21, 95% CI = -4.57 to 16.99) or pembrolizumab vs cetuximab (-1.44, 95% CI = -11.43 to 8.56). Pembrolizumab-treated patients had stable functioning and symptoms at week 15, with no notable differences from SOC.

Conclusions: GHS / QoL scores were stable with pembrolizumab but declined with SOC in patients at week 15, supporting the clinically meaningful benefit of pembrolizumab in recurrent and/or metastatic HNSCC.
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http://dx.doi.org/10.1093/jnci/djaa063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850527PMC
February 2021

Redirecting extracellular proteases to molecularly guide radiosensitizing drugs to tumors.

Biomaterials 2020 07 11;248:120032. Epub 2020 Apr 11.

Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, 92093, USA; UC San Diego, Moores Cancer Center, La Jolla, CA, 92093, USA. Electronic address:

Patients with advanced cancers are treated with combined radiotherapy and chemotherapy, however curability is poor and treatment side effects severe. Drugs sensitizing tumors to radiotherapy have been developed to improve cell kill, but tumor specificity remains challenging. To achieve tumor selectivity of small molecule radiosensitizers, we tested as a strategy active tumor targeting using peptide-based drug conjugates. We attached an inhibitor of the DNA damage response to antibody or cell penetrating peptides. Antibody drug conjugates honed in on tumor overexpressed cell surface receptors with high specificity but lacked efficacy when conjugated to the DNA damage checkpoint kinase inhibitor AZD7762. As an alternative approach, we synthesized activatable cell penetrating peptide scaffolds that accumulated within tumors based on matrix metalloproteinase cleavage. While matrix metalloproteinases are integral to tumor progression, they have proven therapeutically elusive. We harnessed these pro-tumorigenic extracellular proteases to spatially guide radiosensitizer drug delivery using cleavable activatable cell penetrating peptides. Here, we tested the potential of these two drug delivery platforms targeting distinct tumor compartments in combination with radiotherapy and demonstrate the advantages of protease triggered cell penetrating peptide scaffolds over antibody drug conjugates to deliver small molecule amine radiosensitizers.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285923PMC
July 2020

B Cells Improve Overall Survival in HPV-Associated Squamous Cell Carcinomas and Are Activated by Radiation and PD-1 Blockade.

Clin Cancer Res 2020 07 19;26(13):3345-3359. Epub 2020 Mar 19.

Department of Radiation Medicine and Applied Sciences, Moores Cancer Center, University of California, San Diego, La Jolla, California.

Purpose: To characterize the role of B cells on human papilloma virus (HPV)-associated cancer patient outcomes and determine the effects of radiation and PD-1 blockade on B-cell populations.

Experimental Design: Tumor RNA-sequencing data from over 800 patients with head and neck squamous cell carcinoma (HNSCC) and cervical cancer, including a prospective validation cohort, was analyzed to study the impact of B-cell gene expression on overall survival (OS). A novel murine model of HPV HNSCC was used to study the effects of PD-1 blockade and radiotherapy on B-cell activation, differentiation, and clonality including analysis by single-cell RNA-sequencing and B-cell receptor (BCR)-sequencing. Human protein microarray was then used to quantify B-cell-mediated IgG and IgM antibodies to over 16,000 proteins in the serum of patients treated on a clinical trial with PD-1 blockade.

Results: RNA-sequencing identified and as novel B-cell prognostic biomarkers for 3-year OS (HR, 0.545; < 0.001). PD-1 blockade and radiotherapy enhance development of memory B cells, plasma cells, and antigen-specific B cells. BCR-sequencing found that radiotherapy enhances B-cell clonality, decreases CDR3 length, and induces B-cell somatic hypermutation. Single-cell RNA-sequencing identified dramatic increases in B-cell germinal center formation after PD-1 blockade and radiotherapy. Human proteome array revealed enhanced IgG and IgM antibody responses in patients who derived clinical benefit but not those with progressive disease after treatment with PD-1 blockade.

Conclusions: These findings establish a key role for B cells in patient outcomes and responses to PD-1 blockade in HPV-associated squamous cell carcinomas and demonstrate the need for additional diagnostics and therapeutics targeting B cells.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334097PMC
July 2020

Cost-effectiveness analysis of nivolumab for the treatment of squamous cell carcinoma of the head and neck in the United States.

J Med Econ 2020 May 29;23(5):442-447. Epub 2020 Jan 29.

Royal Marsden NHS Foundation Trust, The Institute of Cancer Research, London, UK.

To assess the cost-effectiveness of nivolumab monotherapy for recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) in the US. We constructed a cohort-based partitioned survival model for three health states (progression-free, progressed disease, and death). Using overall survival and progression-free survival data from the nivolumab and investigator's choice (IC) arms of the CheckMate 141 study, the proportion of patients in each health state was estimated by parametric modeling over a 25-year period. Cost, utility, adverse event, and disease management data inputs were obtained from relevant literature and applied to patients in each health state. A scenario analysis was conducted assuming increased uptake of subsequent immunotherapies. A one-way deterministic sensitivity analysis assessed the impact of variation in multiple parameters. A probabilistic sensitivity analysis in which probabilistic distributions were applied to each input during 1,000 model iterations was also conducted. Total costs incurred were higher with nivolumab ($101,552) than with IC ($38,067). Nivolumab was associated with a higher number of life-years (LY; 1.21) and quality-adjusted life-years (QALYs; 0.89), compared with IC (0.68 and 0.42, respectively). The incremental cost-effectiveness ratio for nivolumab compared with IC was $134,438 per QALY, and this remained qualitatively similar when increased uptake of subsequent immunotherapies was assumed ($129,603 per QALY). Sensitivity analyses supported these findings. These results suggest that, at a willingness-to-pay threshold of $150,000 per QALY, nivolumab is a cost-effective option for therapy of SCCHN in the US.
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http://dx.doi.org/10.1080/13696998.2020.1715414DOI Listing
May 2020

SUPREME-HN: a retrospective biomarker study assessing the prognostic value of PD-L1 expression in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck.

J Transl Med 2019 12 26;17(1):429. Epub 2019 Dec 26.

AstraZeneca, Gaithersburg, MD, USA.

Background: Programmed cell death ligand-1 (PD-L1) expression on tumor cells (TCs) is associated with improved survival in patients with head and neck squamous cell carcinoma (HNSCC) treated with immunotherapy, although its role as a prognostic factor is controversial. This study investigates whether tumoral expression of PD-L1 is a prognostic marker in patients with recurrent and/or metastatic (R/M) HNSCC treated with standard chemotherapy.

Methods: This retrospective, multicenter, noninterventional study assessed PD-L1 expression on archival R/M HNSCC tissue samples using the VENTANA PD-L1 (SP263) Assay. PD-L1 high was defined as PD-L1 staining of ≥ 25% TC, with exploratory scoring at TC ≥ 10% and TC ≥ 50%. The primary objective of this study was to estimate the prognostic value of PD-L1 status in terms of overall survival (OS) in patients with R/M HNSCC.

Results: 412 patients (median age, 62.0 years; 79.9% male; 88.2% Caucasian) were included from 19 sites in seven countries. 132 patients (32.0%) had TC ≥ 25% PD-L1 expression; 199 patients (48.3%) and 85 patients (20.6%) had TC ≥ 10% and ≥ 50%, respectively. OS did not differ significantly across PD-L1 expression (at TC ≥ 25% cutoff median OS: 8.2 months vs TC < 25%, 10.1 months, P = 0.55) or the ≥ 10% and ≥ 50% cutoffs (at TC ≥ 10%, median OS: 9.6 months vs TC < 10%, 9.4 months, P = 0.32, and at TC ≥ 50%, median OS 7.9 vs TC < 50%, 10.0 months, P = 0.39, respectively).

Conclusions: PD-L1 expression, assessed using the VENTANA PD-L1 (SP263) Assay, was not prognostic of OS in patients with R/M HNSCC treated with standard of care chemotherapies. Trial registration ClinicalTrials.gov, NCT02543476. Registered September 4, 2015.
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http://dx.doi.org/10.1186/s12967-019-02182-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933901PMC
December 2019

HPV16 E5 Mediates Resistance to PD-L1 Blockade and Can Be Targeted with Rimantadine in Head and Neck Cancer.

Cancer Res 2020 02 17;80(4):732-746. Epub 2019 Dec 17.

Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, California.

There is a critical need to understand mechanisms of resistance and to develop combinatorial strategies to improve responses to checkpoint blockade immunotherapy (CBI). Here, we uncover a novel mechanism by which the human papillomavirus (HPV) inhibits the activity of CBI in head and neck squamous cell carcinoma (HNSCC). Using orthotopic HNSCC models, we show that radiation combined with anti-PD-L1 immunotherapy significantly enhanced local control, CD8 memory T cells, and induced preferential T-cell homing via modulation of vascular endothelial cells. However, the HPV E5 oncoprotein suppressed immune responses by downregulating expression of major histocompatibility complex and interfering with antigen presentation in murine models and patient tumors. Furthermore, tumors expressing HPV E5 were rendered entirely resistant to anti-PD-L1 immunotherapy, and patients with high expression of HPV16 E5 had worse survival. The antiviral E5 inhibitor rimantadine demonstrated remarkable single-agent antitumor activity. This is the first report that describes HPV E5 as a mediator of resistance to anti-PD-1/PD-L1 immunotherapy and demonstrates the antitumor activity of rimantadine. These results have broad clinical relevance beyond HNSCC to other HPV-associated malignancies and reveal a powerful mechanism of HPV-mediated immunosuppression, which can be exploited to improve response rates to checkpoint blockade. SIGNIFICANCE: This study identifies a novel mechanism of resistance to anti-PD-1/PD-L1 immunotherapy mediated by HPV E5, which can be exploited using the HPV E5 inhibitor rimantadine to improve outcomes for head and neck cancer patients. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/4/732/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-1771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024675PMC
February 2020

Syngeneic animal models of tobacco-associated oral cancer reveal the activity of in situ anti-CTLA-4.

Nat Commun 2019 12 5;10(1):5546. Epub 2019 Dec 5.

Moores Cancer Center, University of California San Diego, 3855 Health Sciences Drive, La Jolla, CA, USA.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Tobacco use is the main risk factor for HNSCC, and tobacco-associated HNSCCs have poor prognosis and response to available treatments. Recently approved anti-PD-1 immune checkpoint inhibitors showed limited activity (≤20%) in HNSCC, highlighting the need to identify new therapeutic options. For this, mouse models that accurately mimic the complexity of the HNSCC mutational landscape and tumor immune environment are urgently needed. Here, we report a mouse HNSCC model system that recapitulates the human tobacco-related HNSCC mutanome, in which tumors grow when implanted in the tongue of immunocompetent mice. These HNSCC lesions have similar immune infiltration and response rates to anti-PD-1 (≤20%) immunotherapy as human HNSCCs. Remarkably, we find that >70% of HNSCC lesions respond to intratumoral anti-CTLA-4. This syngeneic HNSCC mouse model provides a platform to accelerate the development of immunotherapeutic options for HNSCC.
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http://dx.doi.org/10.1038/s41467-019-13471-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895221PMC
December 2019

A phase Ib study of utomilumab (PF-05082566) in combination with mogamulizumab in patients with advanced solid tumors.

J Immunother Cancer 2019 12 4;7(1):342. Epub 2019 Dec 4.

Sanford Research, Sioux Falls, SD, USA.

Background: Expressed on activated T and natural killer cells, 4-1BB/CD137 is a costimulatory receptor that signals a series of events resulting in cytokine secretion and enhanced effector function. Targeting 4-1BB/CD137 with agonist antibodies has been associated with tumor reduction and antitumor immunity. C-C chemokine receptor 4 (CCR4) is highly expressed in various solid tumor indications and associated with poor prognosis. This phase Ib, open-label study in patients with advanced solid tumors assessed the safety, efficacy, pharmacokinetics, and pharmacodynamics of utomilumab (PF-05082566), a human monoclonal antibody (mAb) agonist of the T-cell costimulatory receptor 4-1BB/CD137, in combination with mogamulizumab, a humanized mAb targeting CCR4 reported to deplete subsets of regulatory T cells (Tregs).

Methods: Utomilumab 1.2-5 mg/kg or 100 mg flat dose every 4 weeks plus mogamulizumab 1 mg/kg (weekly in Cycle 1 followed by biweekly in Cycles ≥2) was administered intravenously to 24 adults with solid tumors. Blood was collected pre- and post-dose for assessment of drug pharmacokinetics, immunogenicity, and pharmacodynamic markers. Baseline tumor biopsies from a subset of patients were also analyzed for the presence of programmed cell death-ligand 1 (PD-L1), CD8, FoxP3, and 4-1BB/CD137. Radiologic tumor assessments were conducted at baseline and on treatment every 8 weeks.

Results: No dose-limiting toxicities occurred and the maximum tolerated dose was determined to be at least 2.4 mg/kg per the time-to-event continual reassessment method. No serious adverse events related to either treatment were observed; anemia was the only grade 3 non-serious adverse event related to both treatments. Utomilumab systemic exposure appeared to increase with dose. One patient with PD-L1-refractory squamous lung cancer achieved a best overall response of partial response and 9 patients had a best overall response of stable disease. No patients achieved complete response. Objective response rate was 4.2% (95% confidence interval: 0.1-21.1%) per RECIST 1.1. Depletion of Tregs in peripheral blood was accompanied by evidence of T-cell expansion as assessed by T-cell receptor sequence analysis.

Conclusions: The combination of utomilumab/mogamulizumab was safe and tolerable, and may be suitable for evaluation in settings where CCR4-expressing Tregs are suppressing anticancer immunity.

Trial Registration: ClinicalTrials.gov identifier: NCT02444793.
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http://dx.doi.org/10.1186/s40425-019-0815-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894203PMC
December 2019

p16 status and choice of chemotherapy in the KEYNOTE-040 study - Authors' reply.

Lancet 2019 10;394(10206):1323

The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, National Institute of Health Research Biomedical Research Centre, London, UK.

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http://dx.doi.org/10.1016/S0140-6736(19)31264-4DOI Listing
October 2019

Precision Chemoradiotherapy for HER2 Tumors Using Antibody Conjugates of an Auristatin Derivative with Reduced Cell Permeability.

Mol Cancer Ther 2020 01 9;19(1):157-167. Epub 2019 Oct 9.

Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California.

The most successful therapeutic strategies for locally advanced cancers continue to combine decades-old classical radiosensitizing chemotherapies with radiotherapy. Molecular targeted radiosensitizers offer the potential to improve the therapeutic ratio by increasing tumor-specific kill while minimizing drug delivery and toxicity to surrounding normal tissue. Auristatins are a potent class of anti-tubulins that sensitize cells to ionizing radiation damage and are chemically amenable to antibody conjugation. To achieve tumor-selective radiosensitization, we synthesized and tested anti-HER2 antibody-drug conjugates of two auristatin derivatives with ionizing radiation. Monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF) were attached to the anti-HER2 antibodies trastuzumab and pertuzumab through a cleavable linker. While MMAE is cell permeable, MMAF has limited cell permeability as free drug resulting in diminished cytotoxicity and radiosensitization. However, when attached to trastuzumab or pertuzumab, MMAF was as efficacious as MMAE in blocking HER2-expressing tumor cells in G-M. Moreover, MMAF anti-HER2 conjugates selectively killed and radiosensitized HER2-rich tumor cells. Importantly, when conjugated to targeting antibody, MMAF had the advantage of decreased bystander and off-target effects compared with MMAE. In murine xenograft models, MMAF anti-HER2 antibody conjugates had less drug accumulated in the normal tissue surrounding tumors compared with MMAE. Therapeutically, systemically injected MMAF anti-HER2 conjugates combined with focal ionizing radiation increased tumor control and improved survival of mice with HER2-rich tumor xenografts. In summary, our results demonstrate the potential of cell-impermeable radiosensitizing warheads to improve the therapeutic ratio of radiotherapy by leveraging antibody-drug conjugate technology.
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http://dx.doi.org/10.1158/1535-7163.MCT-18-1302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946877PMC
January 2020

Selection of Head and Neck Cancer Patients for Intensive Therapy.

Int J Radiat Oncol Biol Phys 2020 01 30;106(1):157-166. Epub 2019 Sep 30.

Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California; Center for Precision Radiation Medicine, La Jolla, California. Electronic address:

Purpose: Previous studies have found that patients with head and neck cancer (HNC) with a higher relative hazard for recurrence versus competing mortality (ω ratio) are more likely to benefit from intensive therapy. Nomograms to predict this ratio (ω scores) can be useful to guide clinical management; however, comorbidity and other risk factors are frequently lacking from trial samples.

Methods And Materials: In this study of 7117 US veterans, we evaluated the ability of a ω score nomogram developed from clinical trial data to stratify patients with HNC treated with radiation therapy by their relative risk of cancer progression versus competing mortality. We then fit generalized competing event models to determine the effect of comorbidity and other covariates on the ω ratio.

Results: The ω score was effective in stratifying patients with HNC according to their risk for cancer recurrence relative to competing mortality, especially among patients aged >70 years. Patients with ω score ≥0.80 were more likely to receive intensive therapy compared with patients with a ω score <0.80 (66 vs. 54%; P < .001). On multivariable generalized competing event regression, T2-4 category (relative hazard ratio [RHR], 1.08; 95% confidence interval [CI], 1.01-1.16), N2-3 category (RHR, 1.07; 95% CI, 1.01-1.15), and being employed (RHR, 1.11; 95% CI, 1.03-1.20) were associated with increased ω ratio, and increasing age (RHR, 0.83; 95% CI, 0.78-0.89), Charlson comorbidity index ≥2 (RHR, 0.85; 95% CI, 0.79-0.91), being a current smoker (RHR, 0.90; 95% CI, 0.84-0.96), and lower body mass index (RHR, 0.89; 95% CI, 0.84-0.95) were associated with a decreased ω ratio.

Conclusions: The ω scores are effective in stratifying patients with HNC and are correlated with the intensity of treatment given. The ω scores incorporating comorbidity and other risk factors could help identify patients with HNC most likely to benefit from intensive therapy.
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http://dx.doi.org/10.1016/j.ijrobp.2019.09.011DOI Listing
January 2020

Afatinib as second-line treatment in patients with recurrent/metastatic squamous cell carcinoma of the head and neck: Subgroup analyses of treatment adherence, safety and mode of afatinib administration in the LUX-Head and Neck 1 trial.

Oral Oncol 2019 10 23;97:82-91. Epub 2019 Aug 23.

Department of Medicine, West German Cancer Center, University Hospital Essen of the University Duisburg-Essen, Essen, Germany.

Objectives: Patients with head and neck squamous cell carcinoma (HNSCC) can experience severe symptom burden and/or difficulty swallowing, leading to problems with treatment adherence/administration. In LUX-Head and Neck 1 (LH&N1; NCT01345682), second-line afatinib improved progression-free survival (PFS) versus methotrexate in patients with recurrent/metastatic HNSCC. We report adherence and safety across pre-specified and additional subgroups potentially linked to afatinib PFS benefit in LH&N1 (p16 status, smoking history), and afatinib adherence, safety and efficacy by administration (oral versus feeding tube; post-hoc analysis).

Methods: Patients were randomized (2:1) to afatinib (40 mg/day) or intravenous methotrexate (40 mg/m/week).

Results: Among 320 afatinib-treated and 160 methotrexate-treated patients, 83-92% and 76-92% (of patients with data available) across all subgroups took ≥80% of treatment. Across p16 status and smoking history subgroups, the most common treatment-related adverse events (AEs) were diarrhea (70-91%), rash/acne (72-84%), stomatitis (34-73%) with afatinib; and included stomatitis (39-100%), fatigue (22-50%), nausea (19-36%) with methotrexate. Dose reduction decreased AE incidence/severity. Baseline characteristics were generally similar between oral/feeding tube (n = 276/n = 46) groups. 89%/89% (of patients with data available) took ≥80% of assigned afatinib. Median PFS was 2.6 versus 2.7 months (hazard ratio: 0.997; 95% confidence interval: 0.72-1.38). The most common afatinib-related AEs were: rash/acne (74% versus 74%), diarrhea (73% versus 65%), stomatitis (40% versus 30%).

Conclusion: Subgroup analyses of LH&N1 demonstrate that afatinib has predictable and manageable safety across patient subgroups, with high treatment adherence, and is effective via oral and feeding tube administration.
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http://dx.doi.org/10.1016/j.oraloncology.2019.08.004DOI Listing
October 2019

The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC).

J Immunother Cancer 2019 07 15;7(1):184. Epub 2019 Jul 15.

UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

Head and neck cancers, including those of the lip and oral cavity, nasal cavity, paranasal sinuses, oropharynx, larynx and nasopharynx represent nearly 700,000 new cases and 380,000 deaths worldwide per annum, and account for over 10,000 annual deaths in the United States alone. Improvement in outcomes are needed for patients with recurrent and or metastatic squamous cell carcinoma of the head and neck (HNSCC). In 2016, the US Food and Drug Administration (FDA) granted the first immunotherapeutic approvals - the anti-PD-1 immune checkpoint inhibitors nivolumab and pembrolizumab - for the treatment of patients with recurrent squamous cell carcinoma of the head and neck (HNSCC) that is refractory to platinum-based regimens. The European Commission followed in 2017 with approval of nivolumab for treatment of the same patient population, and shortly thereafter with approval of pembrolizumab monotherapy for the treatment of recurrent or metastatic HNSCC in adults whose tumors express PD-L1 with a ≥ 50% tumor proportion score and have progressed on or after platinum-containing chemotherapy. Then in 2019, the FDA granted approval for PD-1 inhibition as first-line treatment for patients with metastatic or unresectable, recurrent HNSCC, approving pembrolizumab in combination with platinum and fluorouracil for all patients with HNSCC and pembrolizumab as a single agent for patients with HNSCC whose tumors express a PD-L1 combined positive score ≥ 1. These approvals marked the first new therapies for these patients since 2006, as well as the first immunotherapeutic approvals in this disease. In light of the introduction of these novel therapies for the treatment of patients with head and neck cancer, The Society for Immunotherapy of Cancer (SITC) formed an expert committee tasked with generating consensus recommendations for emerging immunotherapies, including appropriate patient selection, therapy sequence, response monitoring, adverse event management, and biomarker testing. These consensus guidelines serve as a foundation to assist clinicians' understanding of the role of immunotherapies in this disease setting, and to standardize utilization across the field for patient benefit. Due to country-specific variances in approvals, availability and regulations regarding the discussed agents, this panel focused solely on FDA-approved drugs for the treatment of patients in the U.S.
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http://dx.doi.org/10.1186/s40425-019-0662-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6632213PMC
July 2019

Afatinib vs Placebo as Adjuvant Therapy After Chemoradiotherapy in Squamous Cell Carcinoma of the Head and Neck: A Randomized Clinical Trial.

JAMA Oncol 2019 Aug;5(8):1170-1180

Department of Translational Science, Moores Cancer Centre, University of California at San Diego, La Jolla.

Importance: Locoregionally advanced head and neck squamous cell cancer (HNSCC) is treated curatively; however, risk of recurrence remains high among some patients. The ERBB family blocker afatinib has shown efficacy in recurrent or metastatic HNSCC.

Objective: To assess whether afatinib therapy after definitive chemoradiotherapy (CRT) improves disease-free survival (DFS) in patients with HNSCC.

Design, Setting, And Participants: This multicenter, phase 3, double-blind randomized clinical trial (LUX-Head & Neck 2) studied 617 patients from November 2, 2011, to July 4, 2016. Patients who had complete response after CRT, comprising radiotherapy with cisplatin or carboplatin, with or without resection of residual disease, for locoregionally advanced high- or intermediate-risk HNSCC of the oral cavity, hypopharynx, larynx, or oropharynx were included in the study. Data analysis was of the intention-to-treat population.

Interventions: Patients were randomized (2:1) to treatment with afatinib (40 mg/d) or placebo, stratified by nodal status (N0-2a or N2b-3) and Eastern Cooperative Oncology Group performance status (0 or 1). Treatment continued for 18 months or until disease recurrence, unacceptable adverse events, or patient withdrawal.

Main Outcomes And Measures: The primary end point was DFS, defined as time from the date of randomization to the date of tumor recurrence or secondary primary tumor or death from any cause. Secondary end points were DFS at 2 years, overall survival (defined as time from the date of randomization to death), and health-related quality of life.

Results: A total of 617 patients were studied (mean [SD] age, 58 [8.4] years; 528 male [85.6%]). Recruitment was stopped after a preplanned interim futility analysis on July 4, 2016, on recommendation from an independent data monitoring committee. Treatment was discontinued. Median DFS was 43.4 months (95% CI, 37.4 months to not estimable) in the afatinib group and not estimable (95% CI, 40.1 months to not estimable) in the placebo group (hazard ratio, 1.13; 95% CI, 0.81-1.57; stratified log-rank test P = .48). The most common grade 3 and 4 drug-related adverse effects were acneiform rash (61 [14.8%] of 411 patients in the afatinib group vs 1 [0.5%] of 206 patients in the placebo group), stomatitis (55 [13.4%] in the afatinib group vs 1 [0.5%] in the placebo group), and diarrhea (32 [7.8%] in the afatinib group vs 1 [0.5%] in the placebo group).

Conclusions And Relevance: This study's findings indicate that treatment with afatinib after CRT did not improve DFS and was associated with more adverse events than placebo in patients with primary, unresected, clinically high- to intermediate-risk HNSCC. The use of adjuvant afatinib after CRT is not recommended.

Trial Registration: ClinicalTrials.gov identifier: NCT01345669.
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http://dx.doi.org/10.1001/jamaoncol.2019.1146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567846PMC
August 2019

A Threshold Model for T-Cell Activation in the Era of Checkpoint Blockade Immunotherapy.

Front Immunol 2019 18;10:491. Epub 2019 Mar 18.

Department of Radiation Medicine and Applied Sciences, San Diego Moores Cancer Center, University of California, San Diego, San Diego, CA, United States.

Continued discoveries of negative regulators of inflammatory signaling provide detailed molecular insights into peripheral tolerance and anti-tumor immunity. Accumulating evidence indicates that peripheral tolerance is maintained at multiple levels of immune responses by negative regulators of proinflammatory signaling, soluble anti-inflammatory factors, inhibitory surface receptors & ligands, and regulatory cell subsets. This review provides a global overview of these regulatory machineries that work in concert to maintain peripheral tolerance at cellular and host levels, focusing on the direct and indirect regulation of T cells. The recent success of checkpoint blockade immunotherapy (CBI) has initiated a dramatic shift in the paradigm of cancer treatment. Unprecedented responses to CBI have highlighted the central role of T cells in both anti-tumor immunity and peripheral tolerance and underscored the importance of T cell exhaustion in cancer. We discuss the therapeutic implications of modulating the negative regulators of T cell function for tumor immunotherapy with an emphasis on inhibitory surface receptors & ligands-central players in T cell exhaustion and targets of checkpoint blockade immunotherapies. We then introduce a Threshold Model for Immune Activation-the concept that these regulatory mechanisms contribute to defining a set threshold of immunogenic (proinflammatory) signaling required to elicit an anti-tumor or autoimmune response. We demonstrate the value of the Threshold Model in understanding clinical responses and immune related adverse events in the context of peripheral tolerance, tumor immunity, and the era of Checkpoint Blockade Immunotherapy.
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http://dx.doi.org/10.3389/fimmu.2019.00491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6431643PMC
September 2020

Immune Modulation of Head and Neck Squamous Cell Carcinoma and the Tumor Microenvironment by Conventional Therapeutics.

Clin Cancer Res 2019 07 27;25(14):4211-4223. Epub 2019 Feb 27.

Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, California.

Head and neck squamous cell carcinoma (HNSCC) accounts for more than 600,000 cases and 380,000 deaths annually worldwide. Although human papillomavirus (HPV)-associated HNSCCs have better overall survival compared with HPV-negative HNSCC, loco-regional recurrence remains a significant cause of mortality and additional combinatorial strategies are needed to improve outcomes. The primary conventional therapies to treat HNSCC are surgery, radiation, and chemotherapies; however, multiple other targeted systemic options are used and being tested including cetuximab, bevacizumab, mTOR inhibitors, and metformin. In 2016, the first checkpoint blockade immunotherapy was approved for recurrent or metastatic HNSCC refractory to platinum-based chemotherapy. This immunotherapy approval confirmed the critical importance of the immune system and immunomodulation in HNSCC pathogenesis, response to treatment, and disease control. However, although immuno-oncology agents are rapidly expanding, the role that the immune system plays in the mechanism of action and clinical efficacy of standard conventional therapies is likely underappreciated. In this article, we focus on how conventional and targeted therapies may directly modulate the immune system and the tumor microenvironment to better understand the effects and combinatorial potential of these therapies in the context and era of immunotherapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635035PMC
July 2019

Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study.

Lancet 2019 01 30;393(10167):156-167. Epub 2018 Nov 30.

The Institute of Cancer Research, London, UK; The Royal Marsden NHS Foundation Trust, National Institute of Health Research Biomedical Research Centre, London, UK.

Background: There are few effective treatment options for patients with recurrent or metastatic head-and-neck squamous cell carcinoma. Pembrolizumab showed antitumour activity and manageable toxicity in early-phase trials. We aimed to compare the efficacy and safety of pembrolizumab versus standard-of-care therapy for the treatment of head-and-neck squamous cell carcinoma.

Methods: We did a randomised, open-label, phase 3 study at 97 medical centres in 20 countries. Patients with head-and-neck squamous cell carcinoma that progressed during or after platinum-containing treatment for recurrent or metastatic disease (or both), or whose disease recurred or progressed within 3-6 months of previous multimodal therapy containing platinum for locally advanced disease, were randomly assigned (1:1) in blocks of four per stratum with an interactive voice-response and integrated web-response system to receive pembrolizumab 200 mg every 3 weeks intravenously or investigator's choice of standard doses of methotrexate, docetaxel, or cetuximab intravenously (standard-of-care group). The primary endpoint was overall survival in the intention-to-treat population. Safety was analysed in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT02252042, and is no longer enrolling patients.

Findings: Between Dec 24, 2014, and May 13, 2016, 247 patients were randomly allocated to pembrolizumab and 248 were randomly allocated to standard of care. As of May 15, 2017, 181 (73%) of 247 patients in the pembrolizumab group and 207 (83%) of 248 patients in the standard-of-care group had died. Median overall survival in the intention-to-treat population was 8·4 months (95% CI 6·4-9·4) with pembrolizumab and 6·9 months (5·9-8·0) with standard of care (hazard ratio 0·80, 0·65-0·98; nominal p=0·0161). Fewer patients treated with pembrolizumab than with standard of care had grade 3 or worse treatment-related adverse events (33 [13%] of 246 vs 85 [36%] of 234). The most common treatment-related adverse event was hypothyroidism with pembrolizumab (in 33 [13%] patients) and fatigue with standard of care (in 43 [18%]). Treatment-related death occurred in four patients treated with pembrolizumab (unspecified cause, large intestine perforation, malignant neoplasm progression, and Stevens-Johnson syndrome) and two patients treated with standard of care (malignant neoplasm progression and pneumonia).

Interpretation: The clinically meaningful prolongation of overall survival and favourable safety profile of pembrolizumab in patients with recurrent or metastatic head and neck squamous cell carcinoma support the further evaluation of pembrolizumab as a monotherapy and as part of combination therapy in earlier stages of disease.

Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co.
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http://dx.doi.org/10.1016/S0140-6736(18)31999-8DOI Listing
January 2019

Leveraging TCR Affinity in Adoptive Immunotherapy against Shared Tumor/Self-Antigens.

Cancer Immunol Res 2019 01 27;7(1):40-49. Epub 2018 Nov 27.

Laboratory of Cellular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, California.

Adoptive cellular therapy (ACT) using T-cell receptor (TCR)-engineered lymphocytes holds promise for eradication of disseminated tumors but also an inherent risk of pathologic autoimmunity if targeted antigens or antigenic mimics are expressed by normal tissues. We evaluated whether modulating TCR affinity could allow CD8 T cells to control tumor outgrowth without inducing concomitant autoimmunity in a preclinical murine model of ACT. RIP-mOVA mice express a membrane-bound form of chicken ovalbumin (mOVA) as a self-antigen in kidney and pancreas. Such mice were implanted with OVA-expressing ID8 ovarian carcinoma cells and subsequently treated with CD8 T lymphocytes (CTL) expressing either a high-affinity (OT-I) or low-affinity (OT-3) OVA-specific TCR. The effects on tumor growth versus organ-specific autoimmunity were subsequently monitored. High-affinity OT-I CTLs underwent activation and proliferation in both tumor-draining and pancreatic lymph nodes, leading to both rapid eradication of ID8-OVA tumors and autoimmune diabetes in all treated mice. Remarkably, the low-affinity OT-3 T cells were activated only by tumor-derived antigen and mediated transient regression of ID8-OVA tumors without concomitant autoimmunity. The OT-3 cells eventually upregulated inhibitory receptors PD-1, TIM-3, and LAG-3 and became functionally unresponsive, however, allowing the tumors in treated mice to reestablish progressive growth. Antibody-mediated blockade of the inhibitory receptors prevented exhaustion and allowed tumor clearance, but these mice also developed autoimmune diabetes. The findings reveal that low-affinity TCRs can mediate tumor regression and that functional avidity can discriminate between tumor-derived and endogenous antigen, while highlighting the risks involved in immune-checkpoint blockade on endogenous self-reactive T cells.
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http://dx.doi.org/10.1158/2326-6066.CIR-18-0371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793606PMC
January 2019

A pharmacodynamic study of sirolimus and metformin in patients with advanced solid tumors.

Cancer Chemother Pharmacol 2018 08 9;82(2):309-317. Epub 2018 Jun 9.

Section of Hematology Oncology, Department of Medicine, University of Chicago, 5841 S. Maryland Avenue, MC 2115, Chicago, IL, 60637, USA.

Background: Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor. Metformin may potentiate mTOR inhibition by sirolimus while mitigating its adverse effects. We conducted a pilot study to test this hypothesis.

Methods: Patients with advanced solid tumor were treated with sirolimus for 7 days followed by randomization to either sirolimus with metformin (Arm A) or sirolimus (Arm B) until day 21. From day 22 onwards, all patients received sirolimus and metformin. The primary aim was to compare the change in phospho-p70S6K (pp70S6K) in peripheral blood mononuclear cells (PBMC) from day 8 to day 22 using a two-sample t test. Secondary aims were objective response rate, toxicity, and other serum pharmacodynamic biomarkers (e.g., fasting glucose, triglycerides, insulin, C-peptide, IGF-1, IGF-1R, IGF-BP, and leptin).

Results: 24 patients were enrolled, with 18 evaluable for the primary endpoint. There was no significant difference in mean change in pp70S6K in arm A vs. arm B (- 0.12 vs. - 0.16; P = 0.64). Similarly, there were no significant differences in other serum pharmacodynamic biomarkers. There were no partial responses. There were no dose-limiting or unexpected toxicities.

Conclusions: Adding metformin to sirolimus, although well tolerated, was not associated with significant changes in pp70S6K in PBMC or other serum pharmacodynamic biomarkers.

Impact: Combining metformin with sirolimus did not improve mTOR inhibition.
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http://dx.doi.org/10.1007/s00280-018-3619-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739841PMC
August 2018

Effect of Adding Motolimod to Standard Combination Chemotherapy and Cetuximab Treatment of Patients With Squamous Cell Carcinoma of the Head and Neck: The Active8 Randomized Clinical Trial.

JAMA Oncol 2018 11;4(11):1583-1588

Moores Cancer Center, University of California San Diego, La Jolla.

Importance: Immunotherapy for recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) is promising. The toll-like receptor 8 (TLR8) agonist motolimod may stimulate innate and adaptive immunity.

Objective: To determine whether motolimod improves outcomes for R/M SCCHN when combined with standard therapy.

Design, Setting, And Participants: The Active8 study was a multicenter, randomized, double-blind, placebo-controlled clinical trial enrolling adult patients (age ≥18 years) with histologically confirmed R/M SCCHN of the oral cavity, oropharynx, hypopharynx, or larynx between October 2013 and August 2015. Follow-up ended September 2016. Analysis for the present report was conducted between June 2016 and December 2017.

Interventions: Combination treatment with platinum (carboplatin or cisplatin), fluorouracil, cetuximab (the EXTREME regimen), and either placebo or motolimod, each administered intravenously every 3 weeks. Patients received a maximum of 6 chemotherapy cycles, after which patients received weekly cetuximab with either placebo or motolimod every 4 weeks.

Main Outcomes And Measures: Progression-free survival (PFS) as determined by independent central review using immune-related RECIST (Response Evaluation Criteria in Solid Tumors). Key secondary end points included overall survival (OS) and safety.

Results: Of 195 patients enrolled, 85% were men (n = 166); 82% were white (n = 159); median age was 58 years (range 23-81 years). Median PFS was 6.1 vs 5.9 months (hazard ratio [HR], 0.99; 1-sided 90% CI, 0.00-1.22; P = .47), and median OS was 13.5 vs 11.3 months (HR, 0.95; 1-sided 90% CI, 0.00-1.22; P = .40) for motolimod vs placebo. Increased incidence of injection site reactions, pyrexia, chills, anemia, and acneiform rash were noted with motolimod. Of 83 cases oropharyngeal cancer, 52 (63%) were human papillomavirus (HPV) positive. In a prespecified subgroup analysis of HPV-positive participants, motolimod vs placebo resulted in significantly longer PFS (7.8 vs 5.9 months; HR, 0.58; 1-sided 90% CI, 0.00-0.90; P = .046) and OS (15.2 vs 12.6 months; HR, 0.41; 1-sided 90% CI, 0.00-0.77; P = .03). In an exploratory analysis, patients with injection site reactions had longer PFS and OS (median PFS, 7.1 vs 5.9 months; HR, 0.69; 1-sided 90% CI, 0.00-0.93; P = .06; and median OS, 18.7 vs 12.6; HR, 0.56; 1-sided 90% CI, 0.00-0.81; P = .02).

Conclusions And Relevance: Adding motolimod to the EXTREME regimen was well tolerated but did not improve PFS or OS in the intent-to-treat population. Significant benefit was observed in HPV-positive patients and those with injection site reactions, suggesting that TLR8 stimulation may benefit subset- and biomarker-selected patients.

Trial Registration: ClinicalTrials.gov identifier: NCT01836029.
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http://dx.doi.org/10.1001/jamaoncol.2018.1888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6248084PMC
November 2018

Randomized phase II trial of cixutumumab alone or with cetuximab for refractory recurrent/metastatic head and neck squamous cell carcinoma.

Oral Oncol 2018 07 19;82:83-90. Epub 2018 May 19.

University of Texas M. D. Anderson Cancer Center, Houston, TX, United States. Electronic address:

Objectives: Cixutumumab (CIX) and cetuximab (CET) monoclonal antibodies block ligand-binding to insulin-like growth factor-1 receptor (IGF-1R) and epidermal growth factor receptor (EGFR) respectively. The objective of this study was to assess the efficacy of CIX alone or combined with CET in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients.

Methods: In this open-label phase II trial, 91 R/M HNSCC patients who progressed within 90 days of platinum-based chemotherapy, were randomized to CIX 10 mg/kg alone or with CET 500 mg/m every 2 weeks. Patients were stratified by prior CET use. The primary endpoint was median progression-free survival (PFS). Exploratory biomarker assessments included relevant markers on archival tumor and serial cytokine/angiogenic-factor profiles in blood.

Results: Forty-seven patients were treated with CIX monotherapy and 44 with combination. The median PFS was 1.9 and 2.0 months and clinical benefit rate (complete or partial responses and stable disease) was 5.9% and 15.3%, respectively. There was no exacerbation of CET toxicity by concurrent CIX exposure. Higher tumor expression of IGF-1 was associated with improved PFS in the CIX + CET arm while increased p-EGFR expression correlated with shorter PFS in patients receiving single agent CIX. Higher serum baseline levels of IGF-1 and IGFBP-3 correlated with improved PFS and overall survival (OS) in the CIX arm. Neither regimen resulted in improved PFS or OS compared to historical data with CET alone.

Conclusion: The results of this study do not support the use of cixutumumab alone or with cetuximab in unselected patients with R/M HNSCC.
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http://dx.doi.org/10.1016/j.oraloncology.2018.05.014DOI Listing
July 2018