The Emerging Role of Immune Checkpoint Inhibitors in SCCHN and
Added on - 20 Sep 2019
The Emerging Role of Immune CheckpointInhibitors in SCCHN and Predictive Biomarkers
Table of ContentIntroductionBiomarkersImmunotherapy in head and neck cancerBiomarkersCTLA-4PD-1GITRCombination ImmunotherapyCTLA-4 and PDl-1LAG3 and NivolumabCombination with viral therapyCombination with chemo radiotherapyResponse assessmentPredictive biomarkers and recent advancesTumor mutation burdenCancer vaccinesLiquid biopsiesGenomic profilingMicrosatellitesMicroRNAConclusion
IntroductionThe prevalence of squamous cell carcinoma among all cancers affecting head and neckregion is about 90%. The etiology is mainly associated with tobacco and its products, alcohol,virus etc. Early detection and treatment is associated with a better prognosis. Despite the recentadvances in the treatment modalities, there have been nominal improvement in the survival ratesof the patients in advanced cases. The treatment modalities include surgery, radiotherapy, andchemotherapy. The success rates of the treatment especially in advanced cases have shown onlymarginal improvement. This calls for a quest into newer treatment modalities showing promisingresults without compromising on the prognosis and the quality of life of the patients.1,2Immunotherapy in head and neck cancersBiomarkersSince the role of immune system in tumorigenesis and its progression had come to light, researchhas been devoted into developing immunotherapy. Biomarkers are biological substances that arefound in the body as a part of a normal or disease process and can be used to evaluate theresponse of treatment. Although the association of human papilloma virus as etiological factor ofSCC has long been established, studies are being conducted to envisage the outcome and thushelp in making the choice of the particular biomarker. They have been classified as predictiveand prognostic biomarkers.HPV has proved to be useful both as a predictive and prognostic marker. As a predictive marker,it has been found that HPV positive HNSCC respond better to chemotherapy, radiotherapy andchemoradiation. IMRT with concurrent cetuximab should be considered in chemotherapyresponding patients among risk patients of HPV positive HNSCC. In its prognostic role, authorsclaimed that cases having HPV genotypes other than HPV-16 have been found poor survival ratethan HPV 16 positive cases.Plasma EBV DNA is considered as both a predictive and prognostic biomarker fornasopharyngeal carcinoma cases. EBV before treatment is associated with a worse prognosis assuch patients have been reported with higher recurrent rates and more progressed disease.
Higher expression of cyclin D1 in HNSCC are associated with poor prognosis and resistance tocisplatin and EGFR inhibition. EGFR is associated with cell multiplication and if not inhibitedleads to aggravated growth and spread of HNSCC.Tumor hypoxia is associated with tumor angiogenesis and thus in initiating and further spread oftumor. Hypoxia inducible factor-1- alpha (HIF-1α) overexpression is seen in tumors that areaggressive and have poor compliance to treatment such as radiotherapy.3Interleukins particularly IL-8 has been proven as a prognostic factor for the HNSCC patients andthis was not dependent on the kind of treatment. A randomized study investigated the prognosticand predictive significance of IL-8 and hepatocyte growth factor. The latter controls IL-8expression, on the efficacy of tirapazamine. The two groups of patients comprised of thosereceiving cisplatin with RT and cisplatin plus tirapazamine. This study proved beyond doubt thatIL-8 is a reliable prognostic indicator of treatment of HNSCC and the HGF level had a majorrole to play. While selecting the patients, the ration of HGF/IL-8 must be kept in mind.3Immune checkpoint inhibitorsThe antigens of tumor cells interact with the antigen presenting cells of the host and results in acytotoxic response from the activated T cells. This coupled with the delayed response of memoryT cells proves lethal for the cancer cells. Overtime cancer cells have developed mechanisms toevade the immune system through T cell related pathways. These pathways are called ascheckpoints and involved in preventing any autoimmune response in the body. The coinhibitoryones are PDL1, CTLA4, LAG3, TIM3, KIR while the immunostimulatory ones are OX40,CD137/4-1BB, CD40.4,5CTLA-4CTLA-4 which is seen on the surface of CD4 and CD8, has the ability to relay an inhibitorysignal to the T cells by binding to ligands CD80 and CD86. Both CD28 and CTLA-4 competefor the same ligands i.e CD80 and CD86. However, the affinity of CTLA-4 is stronger thanCD28 on T cells.4two CTLA4-blocking mAbs, ipilimumab (IgG1) and tremelimumab (IgG2),were developed and are undergoing research as per CheckMate 356 Phase I/II.2,6,7PD-1