The incidence of HPV-related oropharyngeal cancers has increased in recent decades. While cure rates exceed those of HPV-negative head and neck cancers, both acute and long-term sequelae of ...chemotherapy, radiation and surgery have led to clinical investigation into de-escalation of treatment. De-escalation trials have sought to reduce long-term treatment-related morbidity by altering or omitting chemotherapy, reducing radiation, or incorporating less invasive surgical resection through transoral surgery. More recent approaches include the use of novel agents such as immunotherapy in place of cisplatin. With the advent of tumor-tissue-modified HPV DNA detection and monitoring in blood, new strategies incorporating this biomarker are being developed.
Immunotherapy approaches for head and neck squamous cell carcinoma (HNSCC) are rapidly advancing. Human papillomavirus (HPV) has been identified as a causative agent in a subset of oropharyngeal ...cancers (OPC). HPV-positive OPC comprises a distinct clinical and pathologic disease entity and has a unique immunophenotype. Immunotherapy with anti-PD1 checkpoint inhibitors has exhibited improved outcomes for patients with advanced HNSCC, irrespective of HPV status. To date, the clinical management of HPV-positive HNSCC and HPV-negative HNSCC has been identical, despite differences in the tumor antigens, immune microenvironment, and immune signatures of these two biologically distinct tumor types. Numerous clinical trials are underway to further refine the application of immunotherapy and develop new immunotherapy approaches. The aim of this review is to highlight the developing role of immunotherapy in HPV-positive HNSCC along with the clinical evidence and preclinical scientific rationale behind emerging therapeutic approaches, with emphasis on promising HPV-specific immune activators that exploit the universal presence of foreign, non-self tumor antigens.
To evaluate the role of social and geographic factors on the likelihood of receiving transoral robotic surgery (TORS) or non-robotic transoral endoscopic surgery treatment in early stage ...oropharyngeal squamous cell carcinoma (OPSCC).
The National Cancer Database was queried to form a cohort of patients with T1-T2 N0-N1 M0 OPSCC (AJCC v.7) who underwent treatment from 2010 to 2016. Demographics, tumor characteristics, treatment type, social, and geographic factors were all collected. Univariate analysis and multivariate logistic regression were then performed.
Among 9267 identified patients, 1774 (19.1%) received transoral robotic surgery (TORS), 1191 (12.9%) received transoral endoscopic surgery, and 6302 (68%) received radiation therapy. We found that lower cancer stage, lower comorbidity burden and HPV- positive status predicted a statistically significant increased likelihood of receiving surgery. Patients who reside in suburban or small urban areas (>1 million population), were low-to- middle income, or rely on Medicaid were less likely to receive surgery. Patients that reside in Medicaid-expansion states were more likely to receive TORS (p > .0001). Patients that reside in states that expanded Medicaid January 2014 and after were more likely to receive non-robotic transoral endoscopic surgery (p > .0001).
Poorer baseline health, lower socioeconomic status and residence in small urban areas may act as barriers to accessing minimally invasive transoral surgery while residence in a Medicaid-expansion state may improve access. Barriers to accessing robotic surgery may be greater than accessing non-robotic surgery.
In phase I development, CDX-3379, an anti-ErbB3 monoclonal antibody, showed promising molecular and antitumor activity in head and neck squamous cell carcinoma (HNSCC), alone or in combination with ...cetuximab. Preliminary biomarker data raised the hypothesis of enhanced response in tumors harboring
mutations. This phase II, multicenter trial used a Simon 2-stage design to investigate the efficacy of CDX-3379 and cetuximab in 30 patients with recurrent/metastatic, HPV-negative, cetuximab-resistant HNSCC. The primary endpoint was objective response rate (ORR). Secondary endpoints included ORR in patients with somatic
mutations, progression-free survival (PFS), overall survival (OS), and safety. Thirty patients were enrolled from March 2018 to September 2020. The ORR in genomically unselected patients was 2/30 (6.7%; 95% confidence interval CI, 0.8-22.1). Median PFS and OS were 2.2 (95% CI: 1.3-3.6) and 6.6 months (95% CI: 2.7-7.5), respectively. Tissue was available in 27 patients including one of two responders. ORR was 1/10 (complete response; 10%; 95% CI 0.30-44.5) in the
-mutated versus 0/17 (0%; 95% CI: 0-19.5) in the
-wildtype cohorts. Sixteen patients (53%) experienced treatment-related adverse events (AEs) ≥ grade 3. The most common AEs were diarrhea (83%) and acneiform dermatitis (53%). Dose modification was required in 21 patients (70%). The modest ORR coupled with excessive, dose-limiting toxicity of this combination precludes further clinical development. Dual ErbB3-EGFR inhibition remains of scientific interest in HPV-negative HNSCC. Should more tolerable combinations be identified, development in an earlier line of therapy and prospective evaluation of the
hypothesis warrant consideration.
BackgroundImmuno-STATs are modular T cell engagers engineered to selectively activate tumor-antigen specific CD8+ T cells via targeted delivery of cytokines. CUE-101, the first Immuno-STAT in ...clinical trials, is composed of a human leukocyte antigen (HLA) complex, HLA-A*0201, a peptide epitope derived from the HPV16 E7 protein, and 4 molecules of attenuated human interleukin-2 (IL-2) designed to bind, expand, and activate HPV16-specific CD8+ T cells for the treatment of HPV16+ cancers.MethodsCUE-101–01 is an ongoing first-in-human study in HLA-A*0201 patients with HPV16+ recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Escalating doses of CUE-101 monotherapy (0.06 mg/kg to 8 mg/kg) were evaluated in R/M HNSCC refractory to ≥ 1 platinum-based or checkpoint inhibitor therapy and in combination with pembrolizumab (1 mg/kg to 4 mg/kg + 200 mg pembrolizumab) in the first line treatment of PD-L1+ R/M HNSCCs followed by expanded enrollment at the recommended phase 2 dose (RP2D). Therapy was administered every 3 weeks until disease progression or intolerable toxicity. Safety, PK/PD, and antitumor activity were assessed.ResultsAs of June 22, 2023, 71 patients have been enrolled. Following monotherapy and combination therapy dose escalation, 4 mg/kg of CUE-101 was chosen as the RP2D for both monotherapy and pembrolizumab combination cohorts. Monotherapy RP2D enrollment is complete and combination RP2D enrollment is ongoing. Adverse events have been manageable and are consistent with the CUE-101 mechanism of action and underlying disease. Grade 3 AEs reported include lymphocyte count decreased (11.3%), anemia (7.0%), decreased appetite and infusion-related reaction (4.2%). PD data demonstrate selective expansion of HPV-16 E711–20-specific CD8+ T cells, sustained increase in NK cells with only transient increase in Treg cells. Among 19 evaluable monotherapy RP2D patients, 1 PR and 6 durable SD (SD ≥ 12 weeks) were observed, with mOS of 14 months. Among 16 evaluable RP2D CUE-101 and pembrolizumab combination patients at data cut-off, 1 uCR, 4 PRs, 2 uPR, and 4 durable SDs were observed. Of the 7 patients with objective responses, 5 achieved >99% reduction in HPV16 cfDNA, 4 by week 6, with 2 patients pending analysis at time of data cut-off.ConclusionsCUE-101 demonstrates safety, tolerability and results in clinical benefit. Patients treated with CUE-101 monotherapy in 3L showed a long OS and CUE-101 and pembrolizumab combination resulted in an ORR of 44% with a corresponding decrease in HPV16 cfDNA in the 1L treatment of patients with HPV16+ R/M HNSCC.AcknowledgementsThe authors would like to thank all the patients who are participating in this study. The study is sponsored by Cue Biopharma, in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and support from LG Chem, Ltd., Seoul, South Korea.Trial RegistrationClinicaltrials.gov NCT03978689Ethics ApprovalThis study was approved by IRBs at all study sites: Advarra Pro00037736, IRB 52744, HRPO# 201905108, DF/HCC IRB# 19–374, WIRB STUDY00008948, IRB 191714, 2019–087, WIRB 2000026098, 2019–0578, WIRB 1908869642, WIRB IRB00112341, IRB 20–073, IRB00255391, IRBMED HUM00165746, US Oncol IRB00001113, WCG IRB00000533.
BackgroundT-cell targeting of mutation-derived epitopes (neoantigens) has shown to drive anti-tumor responses. Immunizing patients against such neoantigens in combination with a checkpoint inhibitor ...(CPI) may elicit greater anti-tumor responses than CPI alone. Mutations are rarely shared between patients, thus requiring a personalized approach to vaccine design. mRNA-4157 is a lipid encapsulated mRNA based personalized cancer vaccine encoding neoantigens selected using a proprietary algorithm to induce neoantigen specific T cells and associated anti-tumor responses. This report includes updates from the mRNA-4157 Phase1(P1) study. The initial data was presented at ASCO2019.1 MethodsThis study evaluates the safety and efficacy of mRNA-4157 as monotherapy in patients with resected solid tumors (Part A) and in combination with pembrolizumab in patients with advanced/metastatic solid tumors (Parts B). The selected solid tumors in Part A-B includes melanoma, bladder carcinoma, HPV-negative (HPV-neg) HNSCC, NSCLC, SCLC, MSI-High (MSI-h), or TMB-High cancers. Expansion cohorts includes patients with CPI-naïve MSS-CRC and HPV-neg HNSCC (Part C) and with resected melanoma (Part D). Patients receive up to 9 cycles (Q3W) of mRNA-4157 by intramuscular injection at up to 1 mg alone (Part A) or in combination with pembrolizumab (200 mg IV Q3W, Parts B-D). Pembrolizumab is administered for two cycles before the first dose of mRNA-4157 and may continue after 9 cycles of combination. Endpoints include safety, tolerability, efficacy and biomarker assessments.Results79 patients received mRNA-4157; 16 as monotherapy and 63 in combination with pembrolizumab. Only low grade and reversible treatment related AEs were reported. 14/16 Part A patients (3 melanoma, 11 NSCLC, 2 MSI-h CRC) remained disease free on study. 28 patients in Parts B (6 bladder, 2 HNSCC, 3 melanoma, 10 NSCLC, 2 SCLC, 4 MSI-h tumor, 1 TMB-h tumor), 27 patients in Part C (10 HNSCC and 17 MSS-CRC), and 8 patients with resected melanoma (Part D) received combination. 3 CR (1 HNSCC, 1 MSI-h CRC and 1 MSI-h prostate), and 8 PR (1 bladder, 4 HNSCC, 2 SCLC and 1 MSI-h endometrial) were observed with combination. Of 10 CPI-naïve HPV-neg HNSCC patients, the response rate was 50% (1CR, 4PR, 4SD) mPFS 9.8months, which compared favorably to published rates of ~14.6% mPFS 2.0months for pembrolizumab monotherapy.2 3 Biomarker assessments including immune gene expression profiling will be presented.Conclusions mRNA-4157 has an acceptable safety profile along with observed clinical responses in combination with pembrolizumab. Preliminary efficacy analysis from CPI-naïve relapsed/refractory HPV-neg HNSCC cohort suggests activity of this combination. Study is ongoing.Trial RegistrationNCT03313778Ethics ApprovalThe study was approved by each participating sites’ local IRB.ReferencesBurris H, et al. A phase I multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in patients with resected solid tumors and in combination with pembrolizumab in patients with unresectable solid tumors. Journal of Clinical Oncology20 May 2019;37(15):2523-2523.Seiwert T, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol 2016;17:956–65.Cohen E, et al. 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;393:10167:156-16.
SCLC remains an aggressive, deadly cancer with only modest effect on survival from standard chemotherapy. However, with the advent of immunotherapy and comprehensive genomic and transcriptomic ...profiling, multiple new targets are showing promise in the clinical arena, and just recently programmed death ligand 1 inhibition has been shown to improve the efficacy of standard chemotherapy in extended-disease SCLC. Our increasing understanding of the interactions between different pathways will enable more tailored immunotherapy and targeted therapies based on specific biomarkers and rational combinations. Here we discuss the preclinical and clinical strides in 2017 and 2018 that put us on the threshold of a new era in therapeutics and will, it is hoped, translate into significant improvements in survival.
BackgroundT-cell targeting of tumor-specific non-synonymous mutations has been demonstrated to drive antitumor responses. Developing therapies against such neoantigens as monotherapy or in ...combination with a checkpoint inhibitor (CPI) may elicit antitumor immune responses, resulting in clinical benefit. The combination of the novel INT mRNA-4157 (V940) and pembrolizumab improved recurrence-free survival and demonstrated a manageable safety profile when compared with pembrolizumab monotherapy in patients with resected high-risk stage III/IV cutaneous melanoma in the randomized phase 2 mRNA-4157-P201/KEYNOTE-942 study (NCT03897881). Here, we report results from the first-in-human phase 1 study (NCT03313778) of mRNA-4157 ± pembrolizumab to characterize the mechanism of action in patients with resected cutaneous melanoma or non-small cell lung cancer (NSCLC).MethodsBaseline tumor core biopsies and matched whole blood from patients with resected NSCLC (cohort A, 1 mg mRNA-4157, n=4) and resected cutaneous melanoma (cohort D, 1 mg mRNA-4157 and 200 mg pembrolizumab, n=12) underwent whole exome sequencing (WES). The immune response to mRNA-4157 was assessed via antigen-specific T-cell assays in peripheral blood mononuclear cells (PBMCs). T-cell responses to INT neoantigen pools or to individual neoantigens were analyzed directly ex vivo using interferon-gamma enzyme-linked ImmunoSpot (ELISpot) assays at longitudinal study timepoints. Neoantigen-specific CD4 and/or CD8 T-cell responses were characterized through restimulation of expanded cells followed by intracellular cytokine staining. Direct ex vivo immunophenotyping was performed by flow cytometry.ResultsT-cell immunogenicity analysis was assessed in available samples from cohorts A (n=3) and D (n=7) across multiple timepoints during the course of treatment. Neoantigen-specific T cells were induced in all patients tested. There was consistent induction of de novo T-cell responses in both cohorts and longitudinal immunogenicity analyses showed sustained T-cell responses to targeted neoantigens, including in blood samples collected at 30 weeks and beyond post start of treatment. Increases in pre-existing neoantigen responses that were present at baseline (endogenous) or after pembrolizumab run-in were observed following mRNA-4157 therapy. Combination of therapy drove expansion of effector CD4 and CD8 T cells with cytotoxic potential.ConclusionsIn this phase 1 first-in-human study, mRNA-4157 as a monotherapy or in combination with pembrolizumab showed immunogenicity in patients with resected NSCLC or melanoma. These data demonstrate the ability of the algorithm to select neoantigens with tumor-infiltrating lymphocyte reactivities, support the mechanism of action hypothesized for mRNA-4157, and underscore the potential clinical benefit of an INT approach.AcknowledgementsMedical writing and editorial assistance were provided by Caudex, a division of IPG Health Medical Communications, New York, NY, USA in accordance with Good Publication Practice 2022 guidelines, funded by Moderna Inc., and under the direction of the authors. Funding for this research was provided by Moderna Inc., in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.Trial RegistrationClinicalTrials.gov; NCT03313778Ethics ApprovalThe study protocol was approved by the institutional review board or ethics committee of each participating site. All patients provided written informed consent prior to study participation.
Background
Narrative medicine educational interventions may enhance patient-centered care, yet most educational interventions do not involve actual patient–provider interactions, nor do they assess ...narrative competence, a key skill for its practice. An experiential narrative medicine curriculum for medical students was developed and piloted.
Aims
The purpose of the study was to develop narrative competence, practice attentive listening, and stimulate reflection.
Participants/Setting
Participants were third-year medicine clerkship students.
Program Description
The curriculum involved 1) an introductory session, 2) a patient storytelling activity, and 3) a group reflection session. For the storytelling activity, students elicited illness narratives in storytelling form from patients, listened attentively, wrote their versions of the story, and then read them back to patients.
Program Evaluation
Five student focus groups were conducted between July 2011 and March 2012 (
n
= 31; 66 %) to explore students’ experiences, student–patient dynamics, challenges, and what they learned. Patient interviews (
n
= 17) on their experience were conducted in January 2013. Thematic analysis of the audiotaped stories of ten patients and corresponding student-written stories helped gauge narrative competence.
Discussion
The curriculum was found to be feasible and acceptable to both patients and students. Some patients and students were profoundly moved. Ongoing focus groups resulted in continual process improvement. Students’ stories showed attainment of narrative competence.
Primary or acquired resistance to cetuximab, an antiepidermal growth factor receptor monoclonal antibody (mAb), minimizes its utility in recurrent/metastatic head and neck squamous cell carcinoma ...(HNSCC). Aberrant hepatocyte growth factor/cMet pathway activation is an established resistance mechanism. Dual pathway targeting may overcome resistance.
This multicenter, randomized, noncomparative phase II study evaluated ficlatuzumab, an antihepatocyte growth factor mAb, with or without cetuximab in recurrent/metastatic HNSCC. The primary end point was median progression-free survival (PFS); an arm met significance criteria if the lower bound of the 90% CI excluded the historical control of 2 months. Key eligibility criteria were HNSCC with known human papillomavirus (HPV) status, cetuximab resistance (progression within 6 months of exposure in the definitive or recurrent/metastatic setting), and resistance to platinum and anti-PD-1 mAb. Secondary end points included objective response rate (ORR), toxicity, and the association of HPV status and cMet overexpression with efficacy. Continuous Bayesian futility monitoring was used.
From 2018 to 2020, 60 patients were randomly assigned and 58 were treated. Twenty-seven versus 33 patients were allocated to monotherapy versus combination. Arms were balanced for major prognostic factors. The monotherapy arm closed early for futility. The combination arm met prespecified significance criteria with a median PFS of 3.7 months (lower bound 90% CI, 2.3 months;
= .04); the ORR was 6 of 32 (19%), including two complete and four partial responses. Exploratory analyses were limited to the combination arm: the median PFS was 2.3 versus 4.1 months (
= .03) and the ORR was 0 of 16 (0%) versus 6 of 16 (38%;
= .02) in the HPV-positive versus HPV-negative subgroups, respectively. cMet overexpression was associated with reduced hazard of progression in HPV-negative but not HPV-positive disease (
interaction = .02).
The ficlatuzumab-cetuximab arm met significance criteria for PFS and warrants phase III development. HPV-negative HNSCC merits consideration as a selection criterion.
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