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dc.contributor.authorSridharan, Vishwajith
dc.date.accessioned2019-05-07T09:18:35Z
dc.date.created2019-05
dc.date.issued2019-05-06
dc.date.submitted2019
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:39712820*
dc.description.abstractImmune checkpoint inhibitors (ICPi) have demonstrated activity and survival benefit in advanced head and neck squamous cell carcinomas (HNSCC), but many patients still do not respond. It is also uncertain whether other less common types of head and neck cancers may benefit from ICPi. Head and neck cancers are frequently treated with conventional therapies such as chemotherapy and radiation and preclinical and clinical studies have suggested potential synergies between chemoradiation (CRT) and immune checkpoint inhibition (ICPi) to boost response rates. However, there exists uncertainty about how to best combine CRT with ICPi. Therefore, we conducted a series of studies on predictors of ICPi response, as well as immunologic changes with CRT alone to build a case for combination therapy. We first studied a large cohort of advanced HNSCC patients treated with ICPi to identify patterns and predictors of response. We showed that decreased total tumor burden (TB), calculated as the sum of the largest diameter of all measurable lesions according to RECIST 1.1, was associated with clinical benefit and improved OS. We also showed that instances of pseudoprogression were rare in HNSCC, and that any increase in TB on first interval scan was associated with poor OS. These findings suggested that by decreasing overall tumor burden, CRT could have beneficial effects when combined with ICPi. In addition to reducing overall tumor burden, preclinical studies have suggested CRT induces immunologic changes, some of which may be systemic. Therefore, we sought to prospectively confirm this in a localized cohort of HNSCC patients receiving definitive CRT. We showed that fractionated CRT leads to quantifiable effects in circulating immune and angiogenic mediators, including increased circulating CD-8+ T- effector cells, myeloid-derived suppressor cells, regulatory T cells, and checkpoint receptor-expressing T cells, particularly PD-1+ T cells. We also showed that CRT increased the percentage of unique and dominant TCR clones, and increased humoral responses as measured by proteomic array. We also profiled the immune landscape of adenoid cystic carcinoma, a rarer salivary gland malignancy with limited treatment options, to see whether treatment- induced immunologic effects extend more broadly outside HNSCC. We examined tissue from primary and metastatic ACC deposits for infiltrating immune cells, PD-L1/L2 expression, and mRNA profiles for 1400 oncogenic and immune-related genes. We found that most tumors expressed PD-L2 but had few infiltrating immune cells, and that lack of immune-cell infiltrate was associated with expression of genes in the β-catenin/Wnt and PI3K pathways. Our data suggested a potential role for combination radiation + ICPi as a treatment for ACC patients, and serves as the basis for an ongoing phase II trial. Collectively, our work provides rationale and framework to understand potential synergies between CRT and ICPi in patients with head and neck malignancies.
dc.format.mimetypeapplication/pdf
dc.language.isoen
dash.licenseLAA
dc.titleRationale for Combination Chemoradiation and Immune Checkpoint Blockade in Head and Neck Malignancies
dc.typeThesis or Dissertation
dash.depositing.authorSridharan, Vishwajith
dc.date.available2019-05-07T09:18:35Z
thesis.degree.date2019
thesis.degree.grantorHarvard Medical School
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Medicine
dc.type.materialtext
dash.identifier.vireohttp://etds.lib.harvard.edu/hms/admin/view/882
dc.description.keywordscheckpoint blockade; immunotherapy; radiation; head and neck cancer
dash.author.emailsvishwajith@gmail.com


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