Expert consensus on the clinical application of recombinant adenovirus human p53 for head and neck cancers.
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ABSTRACT:
SUBMITTER: Li Y
PROVIDER: S-EPMC8595718 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Recently, considerable progress has been achieved in cancer immunotherapy. Targeted immune checkpoint therapies have been established for several forms of cancers, which resulted in a tremendous positive impact on patient survival, even in more advanced tumor stages. With a better understanding of cellular responses to immune checkpoint therapies, it will soon be feasible to find targeted compounds which will make personalized medicine practicable. This is a great opportunity, but it also sets tremendous challenges on both the scientific and clinical aspects. Head and neck tumors evade immune surveillance through various mechanisms. They contain fewer lymphocytes (natural killer cells) than normal tissue with an accumulation of immunosuppressive regulatory T cells. Standard therapies for HNSCC, such as surgery, radiation, and chemotherapy, are becoming more advantageous by targeting immune checkpoints and employing combination therapies. The purpose of this review is to provide an overview of the expanded therapeutic options, particularly the combination of immune checkpoint inhibition with various conventional and novel therapeutics for head and neck tumor patients.
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Project description:The authors present the application of the reduced order constrained optimization (ROCO) method, previously successfully applied to the prostate and lung sites, to the head-and-neck (H&N) site, demonstrating that it can quickly and automatically generate clinically competitive IMRT plans. We provide guidelines for applying ROCO to larynx, oropharynx, and nasopharynx cases, and report the results of a live experiment that demonstrates how an expert planner can save several hours of trial-and-error interaction using the proposed approach.The ROCO method used for H&N IMRT planning consists of three major steps. First, the intensity space of treatment plans is sampled by solving a series of unconstrained optimization problems with a parameter range based on previously treated patient data. Second, the dominant modes in the intensity space are estimated by dimensionality reduction using principal component analysis (PCA). Third, a constrained optimization problem over this basis is quickly solved to find an IMRT plan that meets organ-at-risk (OAR) and target coverage constraints. The quality of the plan is assessed using evaluation tools within Memorial Sloan-Kettering Cancer Center (MSKCC)'s treatment planning system (TPS).The authors generated ten H&N IMRT plans for previously treated patients using the ROCO method and processed them for deliverability by a dynamic multileaf collimator (DMLC). The authors quantitatively compared the ROCO plans to the previously achieved clinical plans using the TPS tools used at MSKCC, including DVH and isodose contour analysis, and concluded that the ROCO plans would be clinically acceptable. In our current implementation, ROCO H&N plans can be generated using about 1.6 h of offline computation followed by 5-15 min of semiautomatic planning time. Additionally, the authors conducted a live session for a plan designated by MSKCC performed together with an expert H&N planner. A technical assistant set up the first two steps, which were performed without further human interaction, and then collaborated in a virtual meeting with the expert planner to perform the third (constrained optimization) step. The expert planner performed in-depth analysis of the resulting ROCO plan and deemed it to be clinically acceptable and in some aspects superior to the clinical plan. This entire process took 135 min including two constrained optimization runs, in comparison to the estimated 4 h that would have been required using traditional clinical planning tools.The H&N site is very challenging for IMRT planning, due to several levels of prescription and a large, variable number (6-20) of OARs that depend on the location of the tumor. ROCO for H&N shows promise in generating clinically acceptable plans both more quickly and with substantially less human interaction.
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Project description:In this study, we investigated the consensus gene modules in head and neck cancer (HNC) and cervical cancer (CC). We used a publicly available gene expression dataset, GSE6791, which included 42 HNC, 14 normal head and neck, 20 CC and 8 normal cervical tissue samples. To exclude bias because of different human papilloma virus (HPV) types, we analyzed HPV16-positive samples only. We identified 3824 genes common to HNC and CC samples. Among these, 977 genes showed high connectivity and were used to construct consensus modules. We demonstrated eight consensus gene modules for HNC and CC using the dissimilarity measure and average linkage hierarchical clustering methods. These consensus modules included genes with significant biological functions, including ATP binding and extracellular exosome. Eigengen network analysis revealed the consensus modules were highly preserved with high connectivity. These findings demonstrate that HPV16-positive head and neck and cervical cancers share highly preserved consensus gene modules with common potentially therapeutic targets.
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Project description:Head and neck squamous cell carcinoma is the sixth most common cancer worldwide and despite advances in treatment over the last years, there is still a relapse rate of 50%. New therapeutic agents are awaited to increase the survival of patients. DNA repair targeted agents in combination with standard DNA damaging therapies are a recent evolution in cancer treatment. These agents focus on the DNA damage repair pathways in cancer cells, which are often involved in therapeutic resistance. Interesting targets to overcome these cancer defense mechanisms are: PARP, DNA-PK, PI3K, ATM, ATR, CHK1/2, and WEE1 inhibitors. The application of DNA targeted agents in head and neck squamous cell cancer showed promising preclinical results which are translated to multiple ongoing clinical trials, although no FDA approval has emerged yet. Biomarkers are necessary to select the patients that can benefit the most from this treatment, although adequate biomarkers are limited and validation is needed to predict therapeutic response.
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Project description:Checkpoint inhibitors have recently gained FDA approval for the treatment of cisplatin-resistant recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) by outperforming standard of care chemotherapy and inducing durable responses in a subset of patients. These monoclonal antibodies unleash the patient's own immune system to target cancer cells. HNSCC is a good target for these agents as there is ample evidence of active immunosurveillance in the head and neck and a number of immune evasion mechanisms by which HNSCCs form progressive disease including via the PD-1/PD-L1 axis. As HNSCCs typically possess a moderately high mutation burden, they should express numerous mutation-derived antigen targets for immune detection. However, with response rates less than 20% in clinical trials, there is a need for biomarkers to screen patients as well as clinical trials evaluating novel combinations to improve outcomes. The aim of this review is to provide historical and mechanistic context for the use of checkpoint inhibitors in head and neck cancer and provide a perspective on the role of novel checkpoints, biomarkers, and combination therapies that are evolving in the near term for patients with HNSCC.
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Project description:Head and neck cancers (HNCs) encompass a heterogeneous group of cancers between the mouth and larynx. Familial clustering in HNCs has been described, but how it influences individual sites and to which extent known risk factors, such as human papilloma virus (HPV) infection, may contribute is not well established. We employed standardized incidence ratios (SIRs) to estimate familial risks for HNC with same (concordant) and different (discordant) cancers among first-degree relatives using data from the Swedish Cancer Registry from 1958 to 2018. Incidence for male and female oropharyngeal cancer increased close to four-fold in the past 39 years. Familial HNC was found in 3.4% of the study population, with an overall familial SIR of 1.78. Patients with concordant nasopharyngeal cancer showed a high risk of 23.97, followed by hypopharyngeal cancer (5.43). The husbands of wives with cervical cancer had an increased risk of oropharyngeal cancer. Nasopharyngeal cancers lacked associations with lifestyle or HPV associated cancers, suggesting a role for germline genetics, which was also true for the high-risk families of three HNC patients. In the Swedish population with low smoking levels, HPV is becoming a dominant risk factor, emphasizing the need for sexual hygiene and HPV vaccination.
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