Role Of Immune Checkpoint Inhibitors Research Articles

Immunotherapy in non-small cell lung cancer: evolution of knowledge and clinical advances

Lung cancer represent the leading cause of cancer related-death worldwide. Although cytotoxic chemotherapy and targeted agents improved survival, the median overall survival for patients with metastatic disease remains poor. Docetaxel is still the corner stone of the second-line treatment, although associated with an unfavourable safety profile. Recent advances in the understanding of cancer immune escape system lead to the development of novel immunotherapies agent that can restore patient's immune response to cancer cells. Unlike vaccines, immune checkpoints inhibitors have shown promising results in non-small cell lung cancer patients. Especially, nivolumab and pembrolizumab, monoclonal antibodies against PD-1, provides as single agent therapy in chemotherapy refractory patients objective response rates ranging from 15%-25%, the majority of which arose quickly and were ongoing 1 year after starting treatment. Furthermore, the toxicity profile differs from that of cytotoxic chemotherapy and is much better tolerated. PD-L1 expression is a promising biomarker for selection and stratification of patients, although its prognostic and predictive role remains to be defined. Several trials are currently ongoing to define the role of immune checkpoint inhibitors in the treatment of patients with non-small cell lung cancer, their combination with cytotoxic chemotherapy or targeted agents and the efficacy and safety of double blockage of PD-1/PD-L1 and CTLA4. We report a review based on a MEDLINE/PubMed, searched for randomized phase II or III trials evaluating immune checkpoint inhibitors and NSCLC, considering the measured outcomes as progression free survival (PFS), overall survival (OS), and the overall response rate (ORR).

Advances in immunotherapy for melanoma.

In recent years, the introduction and Federal Drug Administration approval of immune checkpoint inhibitor antibodies has dramatically improved the clinical outcomes for patients with advanced melanoma. These antagonist monoclonal antibodies are capable of unleashing dormant or exhausted antitumor immunity, which has led to durable complete and partial responses in a large number of patients. Ipilimumab targets the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) receptor. Nivolumab and pembrolizumab target programmed cell death protein 1 (PD-1) receptors and have proven to be superior to ipilimumab alone. The combination of ipilimumab and nivolumab has yielded higher response rates, greater tumor shrinkage, and longer progression-free survival than either monotherapy alone. As other promising immunotherapies for melanoma proceed through clinical trials, future goals include defining the role of immune checkpoint inhibitors as adjuvant therapy, identifying optimal combination strategies, and developing reliable predictive biomarkers to guide treatment selection for individual patients.

Patterns of PD-L1 expression and CD8 T cell infiltration in gastric adenocarcinomas and associated immune stroma.

Recent data supports a significant role for immune checkpoint inhibitors in the treatment of solid tumours. Here, we evaluate gastric and gastro-oesophageal junction (G/GEJ) adenocarcinomas for their expression of programmed death-ligand 1 (PD-L1), infiltration by CD8+ T cells and the relationship of both factors to patient survival. Thirty-four resections of primary invasive G/GEJ were stained by immunohistochemistry for PD-L1 and CD8 and by DNA in situ hybridisation for Epstein-Barr virus (EBV). CD8+ T cell densities both within tumours and at the tumour-stromal interface were analysed using whole slide digital imaging. Patient survival was evaluated according to PD-L1 status and CD8 density. 12% of resections showed tumour cell membranous PD-L1 expression and 44% showed expression within the immune stroma. Two cases (6%) were EBV positive, with one showing membranous PD-L1 positivity. Increasing CD8+ densities both within tumours and immune stroma was associated with increasing percentage of tumour (p=0.027) and stromal (p=0.005) PD-L1 expression. Both tumour and immune stromal PD-L1 expression and high intratumoral or stromal CD8+ T cell density (>500/mm2) were associated with worse progression-free survival (PFS) and overall survival (OS). PD-L1 is expressed on both tumour cells and in the immune stroma across all stages and histologies of G/GEJ. Surprisingly, we demonstrate that increasing CD8 infiltration is correlated with impaired PFS and OS. Patients with higher CD8+ T cell densities also have higher PD-L1 expression, indicating an adaptive immune resistance mechanism may be occurring. Further characterisation of the G/GEJ immune microenvironment may highlight targets for immune-based therapy.

The Evolving Role of Immune Checkpoint Inhibitors in Cancer Treatment.

Traditional treatment modalities for advanced cancer (radiotherapy, chemotherapy, or targeted agents) act directly on tumors to inhibit or destroy them. Along with surgery, these modalities are predominantly palliative, with toxicity and only modest improvements in survival in patients with advanced solid tumors. Accordingly, long-term survival rates for most patients with advanced cancer remain low, thus there is a need for cancer treatments with favorable benefit and toxicity profiles that can potentially result in long-term survival. The immune system plays a critical role in the recognition and eradication of tumor cells ("immune surveillance"), and immunotherapies based on this concept have been used for decades with some success against a few tumor types; however, most immunotherapies were limited by a lack of either substantial efficacy or specificity, resulting in toxicity. We now have a greater understanding of the complex interactions between the immune system and tumors and have identified key molecules that govern these interactions. This information has revitalized the interest in immunotherapy as an evolving treatment modality using immunotherapeutics designed to overcome the mechanisms exploited by tumors to evade immune destruction. Immunotherapies have potentially complementary mechanisms of action that may allow them to be combined with other immunotherapeutics, chemotherapy, targeted therapy, or other traditional therapies. This review discusses the concepts and data behind immunotherapies, with a focus on the checkpoint inhibitors and their responses, toxicities, and potential for long-term survival, and explores promising single-agent and combination therapies in development. Immunotherapy is an evolving treatment approach based on the role of the immune system in eradicating cancer. An example of an immunotherapeutic is ipilimumab, an antibody that blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4) to augment antitumor immune responses. Ipilimumab is approved for advanced melanoma and induced long-term survival in a proportion of patients. The programmed death-1 (PD-1) checkpoint inhibitors are promising immunotherapies with demonstrated sustained antitumor responses in several tumors. Because they harness the patient's own immune system, immunotherapies have the potential to be a powerful weapon against cancer.

Best practice in the treatment of advanced squamous cell lung cancer.

The management of advanced stage nonsmall cell lung cancer (NSCLC) has been altered by the recognition of histology-based treatment and the use of targeted therapy. Whilst outcomes have improved with adenocarcinoma, treatment options are still limited in advanced stage squamous cell lung cancer. With advances in the molecular characterization of squamous cell cancers (SCCs), new potential targets have been identified. In this review, we discuss the role of histology in the treatment of NSCLC, cytotoxic chemotherapy, existing targeted therapies, the new molecular subsets and novel inhibitors in squamous cell lung carcinoma, and the emerging role of immune checkpoint inhibitors. Based on the results of two recent studies, nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor, has been approved by the US Food and Drug Administration (FDA) in the treatment of squamous cell NSCLC in the second-line setting. Well-designed biomarker driven studies are needed to accelerate the development and approval of novel therapies for patients with lung SCC.

Role of immunotherapy in lung cancer: Preliminary results of new vaccines and immune checkpoint inhibitors.

The two dominant approaches to manipulating cancer immunotherapeutics are active, where the immune system is directly stimulated, and passive, where antitumor antibodies stimulate an indirect immune response. At this point, the active approach is receiving more attention in the arena of lung cancer, with ongoing vaccine clinical trials and studies investigating the role of immune checkpoint inhibitors, in particular those that block the programmed death 1(PD-1) receptor and its ligands. Early results from trials of PD-1/PD-L1 ligand inhibitors in nonsmall cell lung cancer are promising, with patients experiencing rapid and durable responses in the first-, second- and third-line setting as well as in combination with chemotherapy and other immune checkpoint inhibitors. Although the number of patients in these trials is small and the results are preliminary, lung cancer physicians are encouraged that they may soon have agents that confer benefits in excess of those seen with chemotherapy to offer their patients. Further results of ongoing trials are highly anticipated.

Therapeutic Options in Advanced Squamous Cell Lung Carcinoma

SUMMARY The management of advanced-stage NSCLC has been dramatically transformed by the recognition of histology-based treatment and the use of targeted therapy for molecular selected patients with adenocarcinoma. While outcomes have improved with adenocarcinoma, treatment options and outcomes are still limited in patients with advanced-stage squamous cell lung cancer. Through advances in the molecular characterization of squamous cell cancers, exciting novel targets have identified. In this paper, we will review the importance of histology in the treatment of NSCLC, existing chemotherapy and targeted therapies, the new molecular subsets and novel inhibitors in squamous cell lung carcinoma and the emerging role of immune checkpoint inhibitors.

Possible role for immune checkpoint inhibitors in glioblastoma

Possible role for immune checkpoint inhibitors in glioblastoma

Cold Ziehl-Neelsen stain for Campylobacter in gastric biopsy specimens.

<h3>Objective:</h3> To understand the role of immune checkpoint inhibitors (ICI) particularly anti-PD1 inhibitor in anti-Hu associated paraneoplastic neurological syndrome (PNS). <h3>Background:</h3> While ICI enhance anti-tumor immune reactivity resulting in tumor regression they also reduce immune tolerance towards self-antigen and predispose to the development of autoimmunity. <h3>Design/Methods:</h3> We present an illustrative case of a 62-year-old woman with small cell lung cancer who developed progressive worsening of preexisting anti-Hu antibody associated sensorimotor polyneuropathy after treatment with programmed cell death 1(PD-1) inhibitor, nivolumab. We review the literature to understand the clinical outcomes of patients with anti-Hu PNS treated with anti-PD1 treatment. <h3>Results:</h3> Our series identified 6 previously reported cases of anti-Hu PNS treated with anti-PD1 inhibitors. These included 4 men and 2 women (median age, 48 years). The patients were receiving nivolumab (n=3), cemiplimab (n=1), pembrolizumab (n=1) and combination treatment of nivolumab and iplimumab (n=1) for treatment of neoplasm of lung (n=3), merkel cell carcinoma in breast (n=1) and thigh (n=1), and extraskeletal chondrosarcoma (n=1). The clinical spectrum of PNS comprised of encephalitis (n=3), a combination of sensory neuronopathy and anti-NMDAR encephalitis (n=1), isolated sensory neuronopathy (n=1), and encephalomyelitis (n=1). Median time to onset of PNS after anti-PD-1 treatment was 117 days. Three of the 6 (50%) patients had a fatal outcome. One of the two patients which improved was treated with Natalizumab. All patient had MRI abnormalities in the form of increased T2/Fluid Attenuated Inversion Recovery (FLAIR) hyperintenisty in medial temporal (n=4), multifocal cortical and subcortical (n=1) and spinal cord (n=2). All but one (n=4) had elevated cells on cerebrospinal fluid analysis with rest (n=5) having elevated protein. <h3>Conclusions:</h3> ICI have the potential to worsen pre-existing anti-Hu PNS and may promote the development of anti-Hu PNS. Timely identification of PNS with close monitoring for potential worsening is recommended in all patients with PNS who receive ICI. <b>Disclosure:</b> Dr. Raibagkar has nothing to disclose. Dr. Ho has nothing to disclose. Dr. Gunturu has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Sanofi, Genzyme, and Eli Lilly. Dr. Srinivasan has nothing to disclose.