Predictive Biomarkers of Immune Checkpoint Inhibitors-Related Toxicities

Abstract

The emergence and continuous development of immune checkpoint inhibitors (ICIs) therapy brings a revolution in cancer therapy history, but the major hurdle associated with their usage is the concomitant ICIs-related toxicities that present a challenge for oncologists. The toxicities may involve non-specific symptoms of multiple systems as for the unique mechanism of formation, which are not easily distinguishable from traditional toxicities. A few of these adverse events are self-limiting and readily manageable, but others may limit treatment, cause interruption and need to be treated with methylprednisolone or tumor necrosis factor-α (TNF-α) antibody infliximab, and even directly threaten life. Early accurate recognition and adequate management are critical to the patient's prognosis and overall survival (OS). Several biomarkers such as the expression of programmed cell death ligand 1 (PD-L1), tumor mutation burden (TMB), and microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) have been proved to be the predictors for anti-tumor efficacy of ICIs, but there is a gap in clinical needs for effective biomarkers that predict toxicities and help filter out the patients who may benefit most from these costly therapies while avoiding major risks of toxicities. Here, we summarize several types of risk factors correlated with ICIs-related toxicities to provide a reference for oncologists to predict the occurrence of ICIs-related toxicities resulting in a timely process in clinical practice.

Sargramostim and Immune Checkpoint Inhibitors: Combinatorial Therapeutic Studies in Metastatic Melanoma

“…Conversely, increased monocytic HLA-DR expression was observed following GM-CSF treatment for sepsisassociated immunosuppression [118]. It is possible that use of validated biomarkers, in combination with potential predictive markers for immune checkpoint inhibitors (e.g., PD-L1 expression, HLA-DR expression on monocytes, Review and tumor mutation burden) could improve patient selection, enhance response rates and lower immunotherapyrelated toxicity when using sargramostim/immunotherapy combination regimens [119].…”

Leveraging NKG2D Ligands in Immuno-Oncology

“…Moreover, the description of patients with accelerated tumor growth after treatment with ICI (hyperprogression) due to ill-defined mechanisms is an additional concern ( 5 – 7 ). These drawbacks are further complicated by the lack of validated predictive biomarkers that would permit the selection of patients that optimally respond to ICI with minimal or no irAE and no hyperprogression ( 204 , 205 ). Therefore, the development of novel ICI against additional target molecules requires a deep risk mitigation to avoid irAE and hyperprogression.…”

p53 Activation Effect in the Balance of T Regulatory and Effector Cell Subsets in Patients With Thyroid Cancer and Autoimmunity

“…Immunotherapies restore different physiological mechanisms, which are evaded during cancer progression, leading to the activation or boost of effector cells against cancer cells. Nevertheless, immunotherapies can face several challenges in terms of both efficacy and safety since these treatments can generate autoimmune responses in some patients with the destruction of healthy tissues (10). Regarding immunotherapy delivery systems, these include checkpoint inhibitors, i.e., anti-PD1 (pembrolizumab, nivolumab, cemiplimab), anti-PDL1 (atezolizumab, avelumab, durvalumab), anti-PD1/PDL1 (AUNP12, under experimentation), and anti-CTLA-4 (ipilimumab) monoclonal antibodies, cytokines promoting lymphocyte activation, chimeric antigen receptor (CAR) and T cell receptor (TCR) engineered T cells, agonist antibodies against co-stimulatory receptor and cancer vaccines (9).…”

“…Regarding immunotherapy delivery systems, these include checkpoint inhibitors, i.e., anti-PD1 (pembrolizumab, nivolumab, cemiplimab), anti-PDL1 (atezolizumab, avelumab, durvalumab), anti-PD1/PDL1 (AUNP12, under experimentation), and anti-CTLA-4 (ipilimumab) monoclonal antibodies, cytokines promoting lymphocyte activation, chimeric antigen receptor (CAR) and T cell receptor (TCR) engineered T cells, agonist antibodies against co-stimulatory receptor and cancer vaccines (9). In particular, PD1-PDL1 blocking antibodies can enhance the activity of tumor-specific Teff cells, modulate Treg function, and reduce anti-inflammatory interleukin (IL-10) while enhancing proinflammatory cytokines release (10). Interestingly, in the tumor microenvironment, the balance of PD1+ CD8+ Teff and Treg lymphocytes is a putative marker of the clinical response to PD1 blockade more reliable than expression of PDL1 or cancer mutation burden (7).…”

“…Immunotherapies restore different physiological mechanisms, which are evaded during cancer progression, leading to the activation or boost of effector cells against cancer cells. Nevertheless, immunotherapies can face several challenges in terms of both efficacy and safety since these treatments can generate autoimmune responses in some patients with the destruction of healthy tissues ( 10 ). Regarding immunotherapy delivery systems, these include checkpoint inhibitors, i.e.…”