Research Projects

Immune check point inhibitors (ICIs) are the humanized monoclonal antibodies which work by blocking the checkpoint and stimulate T-cell mediated immune responses (Centanni M et al., 2019). These inhibitors are becoming frontline treatment for multiple cancers, such as melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCCs), and bladder or urothelial cancer which account 90% of the total cancer burden in India (Alsaab HO et al., 2017; Mathur P et al., 2020). In India, these ICIs i.e. pembrolizumab and nivolumab (PD-1 inhibitor), ipilimumab (anti-CTLA4) and atezolizumab (PD-L1 inhibitor) are under phase IV clinical trials for the treatment of various cancers. ICIs they cause immune related adverse events (irAEs) in about 80% patients who receive monotherapy and in up to 95% with combination therapy (Jamal S et al., 2020). These irAEs affect all organs and vary from a mild skin rash to fulminant colitis or myocarditis, requiring hospitalisation (Ali HO et al., 2019). A recent metaanalysis reported a fatality rate of 1.3% and one third of patients were forced to stop ICIs therapy because of toxicity (Wang DY et al., 2018). Immune related adverse events (irAEs) and high cost are the two main causes for less usage of these drugs in India (Gupta VG et al., 2019). Currently, there are no predictive markers for irAEs to individualize therapy with ICIs. Some of these irAEs resemble well-characterised autoimmune disorders with defined human leukocyte antigen (HLA) risk alleles (Lenz TL et al., 2015). Few studies have explored HLA alleles (HLA class I A, B, C and HLA class II (DRB1, DQB1 and DPB1) with skin toxicity, colitis and inflammatory bowel disease in limited number of patients (Ali HO et al., 2019; Cappelli LC et al., 2019). There is a need of predictive biomarkers for serious irAEs in patients receiving ICIs therapy. This will aid in selection of patients at lowest risk of toxicities for treatment with ICIs and therefore reduce overall treatment cost. Anti-drug antibodies (ADAs) that develop after administration of these therapeutic monoclonal antibodies are the another limitation of ICIs therapy as these antibodies result in suboptimal levels of active drug and loss of treatment efficacy and finally lead to inter patient variability in ICIs levels (Enrico D et al., 2019). Hence, clinical evaluation of these antibodies along with ICIs blood levels is of high importance because currently no tools are available to adequately predict clinical immunogenicity based on experimental data (Brummelen EMJV et al., 2016). Currently published Indian data with reference to ICIs and irAEs are restricted to isolated case reports. Hence this study is being planned to study germline expression of HLA alleles (HLA class I A, B, C and HLA class II (DRB1, DQB1 and DPB1) in cancer patients who are receiving immune check point inhibitors (PD1/ PD-L1/CTLA-4) and correlate it with irAEs, ADAs levels and therapeutic monoclonal antibodies levels