Development Of Checkpoint Inhibitors Research Articles

Immune Checkpoint Inhibitor-Related Pulmonary Toxicity: Focus on Nivolumab.

The development of checkpoint inhibitors has changed the treatment paradigm for cancer. Checkpoint inhibitors nivolumab, pembrolizumab, and cemiplimab target programmed death-1 (PD-1), whereas durvalumab, avelumab, and atezolizumab target PD-ligand 1. Ipilimumab targets cytotoxic T lymphocyte-associated antigen 4. Used as monotherapy or in combination, these inhibitors have shown remarkable efficacy in melanoma, lung cancer, urothelial cancer, and many other solid tumors, and indications are continuing to evolve. Checkpoint inhibitors are well tolerated when compared with traditional chemotherapy. The major adverse effect profiles are idiosyncratic immune-mediated toxicities resulting from the abnormal activation of autoreactive T cells, which can lead to inflammation in any organ system. The most commonly affected organs are bowel, lung, skin, and endocrine. Pulmonary toxicity is important to recognize, and it can be more challenging to diagnose in lung cancer patients, given the nature of the disease course and treatment. This review article focuses on all of the pulmonary adverse effects of a single PD-1 inhibitor (nivolumab) that have been described in the literature. These complications include dyspnea, pneumonitis, pleural effusion, pulmonary sarcoidosis, pulmonary tuberculosis, acute fibrinous organizing pneumonia, organizing pneumonia, eosinophilic pneumonia, adult respiratory distress syndrome, and lung cavitation. Clinicians must be aware of these toxicities and mindful when prescribing these medications in patients with known lung dysfunction due to chronic lung diseases or lung cancer.

Immunotherapy-Associated Myocarditis.

The influence of checkpoint inhibitors on the balance between activation and inhibition of T-lymphocytes is strong. The development of checkpoint inhibitors has led to treatments for many malignancies but has also facilitated auto-immune disease. These immunotherapeutic agents could exacerbate already present autoimmune disease or could cause new complications in patients with no prior history of autoimmunity. Monoclonal antibodies targeting immune check points, namely anti-CTLA4 or anti-PD-1/PD-L1, are generally well tolerated; however, treatment with these drugs is associated with a variety of adverse events, such as cardiotoxicity, among others. The main mechanism of cardiac damage is lymphocytic myocarditis, which can consequently cause many symptoms of cardiovascular disease - from asymptomatic elevation of cardiac markers, heart failure, and arrhythmias to cardiogenic shock. Other adverse events include pericardium damage or Tako-tsubo cardiomyopathy. The author declares she has no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

Immune Checkpoint Inhibition, the Key to Success in Renal Cell Carcinoma?

Treatment of renal cell carcinoma (RCC) has evolved rapidly since the development of checkpoint inhibitors. Most of the studies have been conducted in patients with metastatic disease and led to a significant change in the treatment landscape. Currently, many studies are investigating immune checkpoint inhibition (ICI) in the neoadjuvant and adjuvant setting and the efficacy of combination therapies. It remains difficult to predict which patients will respond best. Consequently, there is a high need for predictive biomarkers. In this review, we discuss the different studies with ICI in RCC and the molecular correlates with clinical outcome.

Checkpoint inhibition in advanced gastroesophageal cancer: clinical trial data, molecular subtyping, predictive biomarkers, and the potential of combination therapies.

The development of checkpoint inhibitors has redefined the treatment paradigm for advanced gastroesophageal cancer. While recent developments have improved clinical outcomes, the prognosis for the disease remains meager. In this review, we discuss the rationale and detail the results from recent phase I-III trials supporting the activity of PD-1 inhibitors. Specifically, we highlight the seminal clinical trials leading to the FDA approval of pembrolizumab for advanced gastroesophageal cancer. Finally, we review the current understanding and future considerations of molecular subtyping and predictive biomarkers to help guide therapy and the promise of combination therapy to further improve the efficacy of checkpoint inhibitors.

50 years of renal cell carcinoma

In the past 50 years, many knowledge gaps regarding renal cell carcinoma (RCC) have been closed. A pathological tumour classification has been developed and different histological subtypes are known today. In clear cell RCC, the (mutated) von Hippel-Lindau gene located on chromosome 3 is highly important. Operative therapy of non-metastatic RCC has evolved from radical nephrectomy to less radical techniques including procedures sparing the adrenal gland as well as nephron-sparing surgery. Surgical procedures are increasingly performed using laparoscopic or robot-assisted approaches. Even less invasive techniques such as cryoablation, radiofrequency ablation or active surveillance are applied for small renal masses, if indicated. Metastatic RCC is most commonly treated by systemic therapy. Chemotherapy has no effect in RCC. For more than 20years, cytokine therapy was the standard of care for metastatic RCC. Mutations of the von Hippel-Lindau gene associated with accumulation of hypoxia-inducible factor, followed by increased transcription of vascular endothelial growth factor, provided the scientific rationale for the successful use of tyrosine kinase inhibitors, mTOR inhibitors, and anti-VEGF antibodies introduced in 2006. The development of checkpoint inhibitors has changed the systemic treatment of RCC in yet another relevant manner.

Nivolumab and ipilimumab: immunotherapy for treatment of malignant melanoma.

As recently as 10 years ago, a diagnosis of metastatic melanoma was considered fatal, with a prognosis of typically 6 months or less from diagnosis. The development of checkpoint inhibitors, such as ipilimumab and nivolumab, which modulate the effects of the CTLA-4 and PD-1, respectively, has revolutionized outcomes for these patients. Monotherapy improves metastatic disease survival, but dual therapy provides greater benefit with 58% of patients alive at 3 years. Combination immunotherapy is even active in brain metastases. In the adjuvant setting, data show that at 1 year over 70% patients remain disease-free with PD-1 blockade. Immunotherapy is generally safe and well tolerated. However, treatment-related endocrinopathies require long-term medications. Nowadays, advanced cutaneous melanoma is a more manageable disease.

Checkpoint Inhibitors in the Treatment of Breast Cancer.

The treatment landscape for many cancers has dramatically changed with the development of checkpoint inhibitors. This article will review the literature concerning the use of checkpoint inhibitors in breast cancer. The histological subtype of BC with the strongest signal of efficacy has been triple-negative breast cancer (TNBC). Early trials of single-agent checkpoint inhibitors did not demonstrate a uniformly positive signal. Clinical studies suggest response rates between 5 and 10% in pretreated patients and roughly 20-25% for untreated advanced TNBC. However, in the small subset of patients who do respond, the response is often durable. More encouraging results have been reported with their use in combination with chemotherapy in the neoadjuvant setting. Larger phase III studies are underway to confirm these earlier findings. An immune-directed therapeutic approach for the management of BC is underway, and it is likely that combination therapy will be required to achieve a level of efficacy worthy of use in the BC treatment paradigm. These agents are not without both economic and clinical toxicity; therefore, it is imperative that we identify patients most likely to benefit from these therapies through well-designed biologically plausible clinical studies and by evaluating novel combinatorial approaches with informative biomarker driven correlative studies.

Abstract IA24: Biomarkers and checkpoint inhibition in HNSCC

Abstract There has been tremendous progress made in development of checkpoint inhibitors in HNSCC with antibodies directed against the PD1/PDL1 axis leading the way. Recent data reveal that these agents are active in patients with refractory disease and improve survival compared with standard of care even in unselected patient populations. Nonetheless, the need for biomarkers to predict which patients benefit most from PD1/PDL1 blockade remains acute while interrogating tissue samples to define mechanisms of resistance is just beginning. To date, it appears that PDL1 expression has some utility to predict activity of PD1/PDL1 blockade. Moreover, gene expression signatures corresponding to an interferon-gamma antitumor response or quantifying mutational burden seem to provide survival predictability. Furthermore, immune signatures of gene expression have been correlated with survival in patients with locally advanced disease. These aspects of checkpoint blockade will be discussed in detail with a view towards where the field is moving in the near term and what to anticipate in the extended future. Citation Format: Ezra E. W. Cohen. Biomarkers and checkpoint inhibition in HNSCC [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr IA24.

Tumor infiltrating lymphocytes in lymph node metastases of stage III melanoma correspond to response and survival in nine patients treated with ipilimumab at the time of stage IV disease.

Prognosis of metastatic melanoma improved with the development of checkpoint inhibitors. The role of tumor infiltrating lymphocytes (TILs) in lymph node metastases of stage III melanoma remains unclear. We retrospectively characterized TILs in primary melanomas and matched lymph node metastases (stage III melanoma) of patients treated with the checkpoint inhibitor ipilimumab. Tumor infiltrating lymphocytes were characterized for CD3, CD4, and CD8 expressions by immunohistochemistry. 4/9 patients (44%) responded to treatment with ipilimumab (1 complete and 2 partial remissions, 1 stable disease). All responders exhibited CD4 and CD8 T-cell infiltration in their lymph node metastases, whereas all non-responders did not show an infiltration of the lymph node metastasis with TILs. The correlation between the presence and absence of TILs in responders vs. non-responders was statistically significant (p=0.008). Median distant metastases free survival, i.e., progression from stage III to stage IV melanoma, was similar in responders and non-responders (22.1 vs. 19.3months; p=0.462). Median progression free and overall survival show a trend in favor of the patients having TIL rich lymph node metastases (6.8 vs. 3.3months, p=0.09; and all alive at last follow-up vs. 8.2months, respectively, p=0.08). Our data suggest a correlation between the T-cell infiltration of the lymph node metastases in stage III melanoma and the response to ipilimumab once these patients progress to stage IV disease.

Immune checkpoint inhibitors in cancer therapy.

In recent years immune checkpoint inhibitors have garnered attention as being one of the most promising types of immunotherapy on the horizon. There has been particular focus on the immune checkpoint molecules, cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) which have been shown to have potent immunomodulatory effects through their function as negative regulators of T cell activation. CTLA-4, through engagement with its ligands B7-1 (CD80) and B7-2 (CD86), plays a pivotal role in attenuating the activation of naïve and memory T cells. In contrast, PD-1 is primarily involved in modulating T cell activity in peripheral tissues via its interaction with PD-L1 and PD-L2. The discovery of these negative regulators of the immune response was crucial in the development of checkpoint inhibitors. This shifted the focus from developing therapies that targeted activation of the host immune system against cancer to checkpoint inhibitors, which aimed to mediate tumor cell destruction through the removal of coinhibitory signals blocking anti-tumor T cell responses.

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions.

New insights into the interaction between the immune system and the tumor microenvironment have led to the development of checkpoint inhibitors that target the PD-1/PD-L1 pathway. Pembrolizumab (MK-3475, lambrolizumab, Keytruda(®)) is a PD-1 inhibitor that has shown clinical activity in a variety of solid tumors and is currently approved for the second-line treatment of PD-L1-positive non-small-cell lung cancer and for unresectable/metastatic melanoma. This article will discuss the results of early-phase trials of pembrolizumab in thoracic malignancies as well as ongoing studies aimed to confirm clinical benefit.

Abstract 3266: Repurposing clinical kinase inhibitors to enhance chemosensitivity by overriding checkpoints.

Abstract Many conventional chemotherapies act as DNA damaging agents. Chemotherapy activates cell cycle checkpoint signaling to prevent cells from entering mitosis with either damaged or unreplicated DNA. Based on the observations that interference with the checkpoint mechanism (checkpoint override) results in cell death via mitotic catastrophe, the development of checkpoint inhibitors is actively being pursued as an anti-cancer therapy. In a cell-based screen of clinically relevant kinase inhibitors we identified three compounds that display checkpoint override properties: isomer of bosutinib, a recently FDA-approved Abl and Src inhibitor; BEZ235, a PI3K/mTOR inhibitor; and dovitinib, a multi-receptor tyrosine kinase inhibitor. Most interestingly, all compounds display off-target activity towards DNA damage checkpoint kinases including Chk1, ATR and Wee1. We determined these kinase inhibitors potently sensitized a panel of pancreatic cancer cell lines to S-phase acting (Gemcitabine, cisplatin) or G2-phase arresting (doxorubicin) DNA-damaging agents. Using a combination of live-cell videomicroscopy and immunofluorescence, we demonstrated that the inhibitors forced drug-treated cells to override the DNA damage induced checkpoint activation and aberrantly enter mitosis. The aberrant mitoses had characteristic chromatin fragmentation and that kinetochores and centromeres appeared to be detached from the chromatin mass, in a manner reminiscent of mitosis with unreplicated genomes (MUGs). As a result, cells died either in mitosis or due to mitotic catastrophe. The efficacy of pulsatile (24h and 48h after chemotherapy) administration of these previously unsuspected checkpoint inhibitors was further validated in tumor explants and cells isolated directly from a pancreatic cancer patient who is currently undergoing treatment. Tellingly, xenograft studies showed that gemcitabine and bosutinib isomer had significant activity as single agents but the combination significantly prevented tumor growth, even after drug removal. Our findings suggest that kinase inhibitors targeting cell cycle checkpoints, albeit in an off-target manner, may be fast-tracked into the clinic to enhance the efficacy of standard chemotherapies. Citation Format: Neil Beeharry, Lauren Fink, Eugenia Banina, Vladimir Khazak, Natalia Skobeleva, Jeffrey R. Peterson, Igor Astsaturov, Timothy J. Yen. Repurposing clinical kinase inhibitors to enhance chemosensitivity by overriding checkpoints. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3266. doi:10.1158/1538-7445.AM2013-3266