**2. Novel immune checkpoint inhibitors/combinatorial therapeutic regimens**

Recently, many studies and clinical trials have focused on various aspects of immunotherapy including novel immune checkpoint inhibitors, combination therapeutic regimens, identification of predictive and prognostic biomarkers, management of immune related adverse events etc. The insights from these pre-clinical and clinical studies indicate unexplored pathways that need attention at a global scale to improve the role of these ICIs in cancers. Importantly, the novel immune checkpoint inhibitors, apart from anti-CTLA-4, anti-PD-1 and anti-PD-L1, can serve as a paradigm

shift for patients, giving them a chance for additional treatment options. For e.g. recently, FDA approved anti-LAG-3 (Relatlimab) monoclonal antibody, that targets Lymphocyte-activation gene 3 (LAG-3) immune checkpoint and recommended it for untreated unresectable or metastatic melanoma in patients >12 years of age. Relatlimab is approved to be given in combination with anti-PD-1 (Nivolumab) as patients on this combination demonstrate better progression free survival than on Nivolumab alone. However, higher incidence of immune-related side effects have been associated with this combination indicating that new and novel immune checkpoint inhibitors need efficient monitoring for patient management [4]. On the other hand, many novel immune checkpoints are still under still investigation in clinical trials with promising results [5]. Some of these include


In addition to novel immune checkpoints, several studies are also focusing on finding optimal combination therapeutic regimens of ICIs with other biomolecules to augment the immune response for better progression free and overall survival [5]. Some of these include:


*Introductory Chapter: Introduction to New Insights and Recent Progress in Immune Checkpoint… DOI: http://dx.doi.org/10.5772/intechopen.107901*

It is postulated that with the advent of novel and combinatorial immune checkpoint therapies, improved overall survival for solid, hematological, rare, and hard-totreat cancers will improve the prospect of improved cancer management.

### **3. Predictive and prognostic biomarkers**

In addition to novel therapeutic regimens, another area of immense importance is the identification of predictive and prognostic biomarkers for immune related adverse events/treatment dynamics. This is a vastly growing field, particularly due to the limited response rates (20–40%) observed in patients on ICI treatment. Finding predictive and prognostic biomarkers can not only help stratify patients for optimal treatment regimen but will also reduce the economic cost on patients. Furthermore, it can help to avoid the generation of drug resistance as the use of ICI for a specific cohort (such as responding patients) will control excess use of this precious drug. In lieu of this, soluble biomarkers (secreted in plasma, serum, urine, ascitic fluids etc.) are gaining a lot of attention. This is due to major advantages including ease of sampling, longitudinal monitoring, and less heterogeneity (as compared to tissue biomarkers). Several studies investigating the role of soluble CTLA-4 (sCTLA-4), soluble PD-1 (sPD-1), soluble PD-L1 (sPD-L1) and soluble PD-L2 (sPD-L2), especially in melanoma and NSCLC patients have shown promising results. The studies observed that soluble markers can exert enhancement and inhibitory effects on the immune system including early activation of CD8+lymphocytes, increased lytic activity of macrophages, up regulation of pro- and anti-inflammatory cytokines/chemokines, inhibition of IL-2 production/T cell activation and reverse signaling on dendritic cells (DC) leading to reduction in DC maturation. These soluble markers have also been postulated to bind and block the active site of ICI monoclonal antibodies, thus making the treatment regimen inefficient [6–16]. On the other hand, several predictive biomarkers such as C-Reactive proteins (CRP), Blood cell counts, IL-5, IL-6, IL-8, CXCL9, 10, 11, 13, CCL3, CCR3, sPD-L2 etc. have been associated as predictors of immune related adverse events in ICI treated patients indicating the importance of soluble markers [8, 17, 18]. However, this is still an untapped area with limited studies and larger prospective clinical trials are warranted to fully understand their role in immunotherapy.

Last, but not the least, the gut microbiome is an area of immense interest for their role in ICI treatment dynamics. Emerging evidence/clinical trials suggest that gut microbiota influences clinical response to immunotherapy [19]. For e.g., a study on fecal microbiota transplant (FMT) in metastatic melanoma from responding patients (on anti-PD-1 treatment) to non-responding patient lead to improved response rates [20]. In addition to this, various studies have documented the microbes *Blautia obeum, Collinsella aerofaciens, Enterococcus faecium, Klebsiella pneumonia, Parabacteroides merdae, Roseburia intestinalis, Veillonella parvula, Ruminococcaceae* to be associated with enhanced/inhibitory effects on anti-PD-1 treatment mainly due to their interaction with the cells of the tumor microenvironment [19, 21–23]. Therefore, the value of assessing the gut microbiome in immunotherapy is an area of significant interest and randomized controlled trials, examining modulatory effects of the gut microbiome in ICI treated patients, is recommended for better understanding of treatment dynamics.

In summary, a vast avenue of areas can be explored with regards to immune checkpoint inhibitors to provide novel insights into this emerging field. The

above-mentioned areas are just the tip of the iceberg and exploration of other aspects such as genomics, transcriptomics, proteomics, metabolomics etc. can serve valuable for treatment management and better overall survival for ICI treated patients.
