Development Of Immune Checkpoint Inhibitors Research Articles

Neoadjuvant Immune Checkpoint Inhibition in Metastatic Conjunctival Melanoma.

The development of immune checkpoint inhibitors (ICI) has transformed the treatment of advanced-stage cutaneous melanoma; however, most trials did not include patients with conjunctival melanoma. Herein the authors describe a patient with recurrent conjunctival melanoma who developed locally advanced, b-raf and v-raf murine sarcoma viral oncogene homolog B1-negative melanoma in her nasal cavity and extensive, metabolically active, bilateral lymphadenopathy in her thorax. Her nasal mass measured 4.3 × 1.7 cm and was determined to be unresectable. She was treated with 4 cycles of combination ipilimumab and nivolumab therapy followed by maintenance nivolumab. She experienced a dramatic treatment response with a reduction in the size of her nasal mass to 3.0 × 1.1 cm and a complete resolution of her adenopathy. She then underwent complete surgical resection of her residual mass (approximately 75% of her original tumor size) and remains melanoma-free at 1 year of follow-up. Given the underlying genetic similarities of conjunctival melanoma to cutaneous melanoma, providers should consider the use of neoadjuvant immune checkpoint inhibitors for patients with locally advanced or limited metastatic disease.

Immune checkpoint inhibitor therapy-induced autoimmune polyendocrine syndrome type II and Crohn’s disease: A case report

The development of immune checkpoint inhibitors (ICIs) has heralded a new era in cancer treatment, enabling the possibility of long-term survival in patients with metastatic disease. Unfortunately, ICIs are increasingly implicated in the development of autoimmune diseases. We present a man with squamous cell carcinoma of the oropharynx on a combination of teriprizumab, docetaxel, and cisplatin therapy who developed autoimmune polyendocrine syndrome type II (APS-2) including thyroiditis and type 1 diabetes mellitus and Crohn's disease (CD). He developed thirst, abdominal pain, and fatigue after two-week treatment with the protein 1 ligand inhibitor teriprizumab. Biochemistry confirmed APS-2 and thyrotoxicosis. He was commenced on an insulin infusion. However, his abdominal pain persisted. Follow-up surgery confirmed CD and his abdominal pain was relieved by mesalazine. He was continued on insulin and mesalazine therapy. Immunotherapy can affect all kinds of organs. When clinical symptoms cannot be explained by a single disease, clinicians should consider the possibility of multisystem damage.

An overview of immune checkpoint inhibitors toxicities

The development of immune checkpoint inhibitors has led to many breakthroughs in cancer treatment. As their use in many types of cancer expands, oncologists have seen the emergence of a whole new set of adverse events that require specific treatment and attention as they can lead to treatment discontinuation, hospitalization, and death. The molecular pathways targeted by these new pharmaceutical agents aim to remove the inhibition on the anti-tumoral immune response exerted by cancer cells. However, in doing so, they also impact mechanisms important for self-tolerance, and lead to autoimmune-related reactions. Those adverse events can affect every organ, with various frequencies, sometimes a long time after the end of treatment. The following presentation endeavours to list the reported immune adverse events classified by affected organs and gives an overview of the proposed treatment and patient care.

Metastatic Castration-Resistant Prostate Cancer, Immune Checkpoint Inhibitors, and Beyond.

The therapeutic landscape of several genitourinary malignancies has been revolutionized by the development of immune checkpoint inhibitors (ICIs); however, the utility of immunotherapies in prostate cancer has been limited, partly due to the immunologically "cold" tumor terrain of prostate cancer. As of today, pembrolizumab is the only immune checkpoint inhibitor approved for the treatment of metastatic castration resistant prostate cancer (mCRPC) in a select group of patients with high microsatellite instability (MSI-H), deficient mismatch repair (dMMR), or high tumor mutational burden (TMB). Looking ahead, several combinatorial approaches with ICIs involving radioligands, radiotherapy, PARP inhibitors, interleukin inhibitors, and cancer vaccines are exploring a potential synergistic effect. Furthermore, B7-H3 is an alternative checkpoint that may hold promise in adding to the treatment landscape of mCRPC. This review aims to summarize previous monotherapy and combination therapy trials of ICIs as well as novel immunotherapy combination therapeutic strategies and treatment targets in mCRPC.

Implications of the Organ-Specific Immune Environment for Immune Priming Effect of Radiotherapy in Metastatic Setting.

With the development of immune checkpoint inhibitors (ICIs), the tumour immune microenvironment (TIME) has been increasingly considered to improve cancer management. The TIME of metastatic lesions is strongly influenced by the underlying immune contexture of the organ in which they are located. The metastatic location itself appears to be an important prognostic factor in predicting outcomes after ICI treatment in cancer patients. Patients with liver metastases are less likely to respond to ICIs than patients with metastases in other organs, likely due to variations in the metastatic TIME. Combining additional treatment modalities is an option to overcome this resistance. Radiotherapy (RT) and ICIs have been investigated together as an option to treat various metastatic cancers. RT can induce a local and systemic immune reaction, which can promote the patient's response to ICIs. Here, we review the differential impact of the TIME according to metastatic location. We also explore how RT-induced TIME modifications could be modulated to improve outcomes of RT-ICI combinations.

Patient-derived xenografts or organoids in the discovery of traditional and self-assembled drug for tumor immunotherapy.

In addition to the rapid development of immune checkpoint inhibitors, there has also been a surge in the development of self-assembly immunotherapy drugs. Based on the immune target, traditional tumor immunotherapy drugs are classified into five categories, namely immune checkpoint inhibitors, direct immune modulators, adoptive cell therapy, oncolytic viruses, and cancer vaccines. Additionally, the emergence of self-assembled drugs with improved precision and environmental sensitivity offers a promising innovation approach to tumor immunotherapy. Despite rapid advances in tumor immunotherapy drug development, all candidate drugs require preclinical evaluation for safety and efficacy, and conventional evaluations are primarily conducted using two-dimensional cell lines and animal models, an approach that may be unsuitable for immunotherapy drugs. The patient-derived xenograft and organoids models, however, maintain the heterogeneity and immunity of the pathological tumor heterogeneity.

Abstract 6270: Combination therapy with selective SMARCA2 (BRM) degraders for treatment of SMARCA4 (BRG1)-deficient cancers

Abstract SMARCA2 (BRM) and SMARCA4 (BRG1) are mutually exclusive core catalytic subunits of the SWI/SNF complexes and use their ATPase domain to regulate the composition of nucleosomes. Between 4-5% of Non-Small Cell Lung Cancer (NSCLC) patients harbor SMARCA4 damaging mutations or SMARCA4 homo-deletions, resulting in loss of SMARCA4 protein expression. These SMARCA4-deleted cancer cells are predicted to be highly dependent on the paralog gene SMARCA2 for their survival. Therefore, targeting SMARCA2 in SMARCA4-deleted cancers using selective SMARCA2 degraders induces synthetic lethality while sparing SMARCA4 wild type normal cells. Although the treatment of lung cancer has improved considerably in recent years with the development of immune checkpoint inhibitors (ICIs) and specific KRASG12C covalent inhibitors, KRASG12C mutations significantly co-occur in 15-17% of SMARCA4-deleted NSCLC patients and have also been shown to correlate with a worse clinical outcome. The co-occurrence of KRASG12C/SMARCA4-deletion mutations in NSCLC led us to investigate whether combining our selective SMARCA2 degraders with KRASG12C or other MAPK pathway inhibitors would demonstrate synergistic effects. To test this hypothesis, we treated SMARCA4 damaging/low expression KRASG12C mutant cell lines with our SMARCA2 degraders and several KRASG12C inhibitors, in addition to SHP2 and MEK inhibitors. Robust synergy was observed with these combinations, suggesting that targeting SMARCA2 together with agents that inhibit distinct nodes of the MAPK pathway in patients with SMARCA4-deleted cancer may be a promising therapeutic strategy. To further understand the mechanisms underpinning the synergy between our SMARCA2 degraders and KRASG12C/MAPK pathway inhibitors, we conducted RNA-seq and found unique transcriptional signatures in the synergistic combinations relative to those of either agent alone. We are currently testing if this in vitro synergy with our SMARCA2 degraders extends to in vivo combination efficacy in CDX and PDX models. Furthermore, early data suggested that SMARCA4 deletion may indicate poor outcomes of ICIs in lung cancer patients. Interestingly, our SMARCA2 degraders promote the antigen presentation pathway and induce pro-inflammatory cytokine expression in SMARCA4-deleted cancer cells. We are currently investigating combinations of our SMARCA2 degraders with ICIs using syngeneic mouse models and human ex-vivo approaches. In summary, our preclinical data suggest that potent and selective SMARCA2 targeted degraders may potentially improve patient outcomes when combined with therapeutic agents targeting the RAS/MAPK pathway and/or ICIs in SMARCA4-deleted cancers. The combination of SMARCA2 degraders with standard of care agents warrants further investigation as a potential novel, effective, and highly targeted combination approach. Citation Format: Michael Hulse, Margot Elkins, Jessica Burtell, Komali Vykuntam, Kris Vaddi, Andrew Combs, Koichi Ito, Peggy Scherle. Combination therapy with selective SMARCA2 (BRM) degraders for treatment of SMARCA4 (BRG1)-deficient cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6270.

Immunotherapy and Targeted Therapy for Advanced Biliary Tract Cancer: Adding New Flavors to the Pizza.

Biliary tract cancers (BTCs) are a rare pathology and can be divided into four major subgroups: intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, and gallbladder cancer. In the era of precision oncology, the development of next-generation sequencing (NGS) allowed a better understanding of molecular differences between these subgroups. Thus, the development of drugs that can target these alterations and inhibit the abnormal pathway activation has changed the prognosis of BTC patients. Additionally, the development of immune checkpoint inhibitors and a better understanding of tumor immunogenicity led to the development of clinical trials with immunotherapy for this scenario. The development of biomarkers that can predict how the immune system acts against the tumor cells, and which patients benefit from this activation, are urgently needed. Here, we review the most recent data regarding targeted treatment and immunotherapy in the scenario of BTC treatment, while also discussing the future perspectives for this challenging disease.

Pituitary and adrenal disorders induced by immune checkpoint inhibitors

Over the past decade, the development of ICI (immune checkpoint inhibitors) has constituted a revolution in the treatment of many cancers, but with a specific toxicity profile including endocrine IRAEs (immune-related adverse events). As the indications for these molecules are constantly increasing due to their efficacy, it is important that endocrinologists and oncologists know how to detect, manage and monitor this type of toxicity. Many guidelines and recommendations have been proposed in the last few years for the management of endocrinopathies. French guidelines on immunotherapy-related endocrine IRAEs were published in 2018, with a specific algorithm for hypophysitis and primary adrenal insufficiency (PAI), based on clinical suspicion followed by biochemical and imaging evaluation, and are still relevant today. Here we present the general pathophysiological mechanisms of these toxicities, and discuss the incidence, diagnosis, treatment, progression, management and monitoring of pituitary and adrenal disorders in patients treated by immunotherapy, with emphasis on hypophysitis, which is much more frequent than PAI with this type of molecule. We also highlight several key points, such as the need for emergency treatment by hydrocortisone with the possibility of continuing immunotherapy in these endocrinopathies, and the long-term persistence of corticotropin or adrenal deficiency in most cases, requiring specific “hydrocortisone education”. These points should be kept in mind by oncologists and endocrinologists who treat and monitor patients treated by immunotherapy.

All-round counterattack to conquer lung cancer

Background: Lung cancer is increasing exponentially as the population ages. To conquer lung cancer, early diagnosis, developing new treatments, and combining multidisciplinary treatment modalities are essential.Current Concepts: Since the national lung cancer screening program for high-risk individuals using low-dose chest computed tomography has launched, the rate of early diagnosis of lung cancer is expected to increase. The development of immune checkpoint inhibitors and target agents is paying off in terms of producing new anticancer drugs. Immune checkpoint inhibitors are administered in combination with existing treatment modalities in various clinical situations, such as for not only patients with metastatic lung cancer but also for those with resectable lung cancer and with surgically unresectable locally advanced disease. These trials dramatically improved survival outcomes. The development of targeted anticancer drugs is also advancing at a rapid pace. The survival rate of patients with lung cancer who have specific gene mutations has greatly improved when targeted anticancer drugs are administered alone or in combination with conventional therapies.Discussion and Conclusion: Early diagnosis of lung cancer and the development of new treatment modalities are greatly improving the prognosis of patients with lung cancer. Attempts to combine conventional and new treatment modalities should continue. It is necessary to discuss changing medical policies for long-term survivors, which will inevitably increase.

Immunotherapy for Solid Tumors

The development of immune checkpoint inhibitors (ICIs) constitutes a major therapeutic advance in the treatment of a number of malignancies [...].

"Cold" colorectal cancer faces a bottleneck in immunotherapy.

The advent of immunotherapy and the development of immune checkpoint inhibitors (ICIs) are changing the way we think about cancer treatment. ICIs have shown clinical benefits in a variety of tumor types, and ICI-based immunotherapy has shown effective clinical outcomes in immunologically "hot" tumors. However, for immunologically "cold" tumors such as colorectal cancer (CRC), only a limited number of patients are currently benefiting from ICIs due to limitations such as individual differences and low response rates. In this review, we discuss the classification and differences between hot and cold CRC and the current status of research on cold CRC, and summarize the treatment strategies and challenges of immunotherapy for cold CRC. We also explain the mechanism, biology, and role of immunotherapy for cold CRC, which will help clarify the future development of immunotherapy for cold CRC and discovery of more emerging strategies for the treatment of cold CRC.

Neoadjuvant Therapy in Melanoma: Where Are We Now?

This review summarizes the current state of neoadjuvant immunotherapy and targeted therapy for locoregionally advanced melanoma. Melanoma systemic therapy has witnessed major advances with the development of immune checkpoint inhibitors and molecularly targeted therapy that have been translated into the neoadjuvant setting in managing locoregionally advanced disease. PD1 blockade as monotherapy and combined with CTLA4 blockade or LAG3 inhibition has demonstrated major improvements in reducing the risk of relapse and death that were associated with high pathologic response rates. Similar results were reported with BRAF-MEK inhibition for BRAF mutant melanoma with high pathologic response rates that appear to be less durable compared to immunotherapy. More importantly, in a recent randomized trial, event-free survival was significantly improved with neoadjuvant pembrolizumab compared to standard surgery and adjuvant therapy. Neoadjuvant therapy has become the standard of care for locoregionally advanced melanoma. Ongoing studies will define the most optimal combination regimens.

At the crossroads of immunotherapy for oncogene-addicted subsets of NSCLC.

Non-small-cell lung cancer (NSCLC) has become a paradigm of precision medicine, with the discovery of numerous disease subtypes defined by specific oncogenic driver mutations leading to the development of a range of molecularly targeted therapies. Over the past decade, rapid progress has also been made in the development of immune-checkpoint inhibitors (ICIs), especially antagonistic antibodies targeting the PD-L1-PD-1 axis, for the treatment of NSCLC. Although many of the major oncogenic drivers of NSCLC are associated with intrinsic resistance to ICIs, patients with certain oncogene-driven subtypes of the disease that are highly responsive to specific targeted therapies might also derive benefit from immunotherapy. However, the development of effective immunotherapy approaches for oncogene-addicted NSCLC has been challenged by a lack of predictive biomarkers for patient selection and limited knowledge of how ICIs and oncogene-directed targeted therapies should be combined. Therefore, whether ICIs alone or with chemotherapy or even in combination with molecularly targeted agents would offer comparable benefit in the context of selected oncogenic driver alterations to that observed in the general unselected NSCLC population remains an open question. In this Review, we discuss the effects of oncogenic driver mutations on the efficacy of ICIs and the immune tumour microenvironment as well as the potential vulnerabilities that could be exploited to overcome the challenges of immunotherapy for oncogene-addicted NSCLC.

Immune suppressive cells in the tumor microenvironment of multiple myeloma

With the development of immune checkpoint inhibitors in cancer therapy, tumor microenvironments have attracted the attention of many researchers as a critical compartment of immune therapies. Immune suppressive cells such as regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages play important roles in regulating anti-tumor immunity in the bone marrow microenvironment in multiple myeloma, in addition to decreased immunogenicity of tumor cells and increased expression of immune checkpoint molecules. These cells are activated by numerous chemicals released by tumor cells or their surroundings, and they suppress dendritic, tumor-specific cytotoxic T, NK, and NKT cells. Multiple myeloma cells use immunological suppressive effects to escape the patients' immune surveillance system. In the future, we hope a better understanding of these immune suppressive cells leads to further improvements in immune therapies.

Immune checkpoint inhibitor-based therapy for advanced acral and mucosal melanoma.

Acral melanoma (AM) and mucosal melanomas (MM) are rare clinical subtypes of melanoma. AM and MM are etiologically, biologically, and molecularly distinct from cutaneous melanoma (CM). Despite the recent development of immune checkpoint inhibitors (ICIs) for the treatment of advanced CMs, the true therapeutic efficacy of ICIs for these rare subtypes remains unclear. Since these subtypes are rare, especially in the Caucasian population, their biological features and corresponding novel therapies are underexplored than those of CM. Even in the larger phase III clinical trials for ICIs, the sample size of patients with AM and MM is limited. Consequently, establishment of standard of care for advanced AM and MM has been challenging. This review covers current update and overview on clinical efficacy of ICIs and ICI-based therapy for advanced AM and MM, based mainly on the reported clinical trials, prospective observational studies, and retrospective studies, to provide a better understanding of the current landscape of this field. In addition, we discuss the future direction of treatment for those rare clinical subtypes, focusing on issues relevant to dermatology and medical oncology.

Peptide self-assembled nanomedicine induces antitumor immunity by blocking the PD-1/PD-L1 axis

The development of immune checkpoint inhibitors (ICIs) revolutionizes cancer treatment, which has been applied in the treatment of several kinds of malignancies in the clinic. Due to their specific affinity and controllable cost, the emerging peptide-based ICI therapeutics have attracted great attention. However, peptide-based drugs generally show poor bioavailability and a short in vivo half-life. Peptide-based nanomedicine is a promising approach to increase the efficacy of therapeutic peptides. In this work, an amphiphilic peptide based on the reported D-peptide for ICIs has been developed. The constructed amphiphilic peptide can self-assemble into a stable nanostructure (noted as CD-NPs). The prepared CD-NPs have a spherical shape with a hydrodynamic size of about 35 nm. In vivo studies show that the prepared nanomedicine can effectively inhibit tumor growth in 4T1 tumor-bearing mice. Moreover, we found that the CD-NPs increase the infiltration of effector T cells and natural killer cells as well as the immune cytokines in the tumor tissues, implying that they activated the immune response for antitumor activity. Finally, no obvious changes in the major organs, tissues, or the body weight caused by the nanomedicine can be observed, demonstrating their good biocompatibility. Taken together, this study provides a basic idea for designing a novel peptide-based nanomedicine for enhanced antitumor efficacy by enhancing the blockade of ICIs and activating the immune response.

Immune Checkpoint Inhibitors Related to Cardiotoxicity.

Immune checkpoint inhibitors (ICIs) have now emerged as a mainstay of treatment for various cancers. Along with development of ICIs, immune-related adverse effects (irAEs) have aroused wide attention. The cardiac irAE, one of the rare but potentially fatal effects, have been reported recently. However, the clinical comprehension of cardiac irAEs remains limited and guidelines are inadequate for cardio-oncologists to tackle the problem. In this review, we have summarized current classifications of, manifestations of, potential mechanisms of, and treatment for ICI-related myocardial injury in order to provide some clues for the understanding of cardiac irAEs in clinical work.

Cancer bronchique à petites cellules : quoi de neuf ?

This article describes recent advances in the diagnostic and therapeutic management of small cell lung cancer, particularly, the development of immune checkpoint inhibitors and new agents targeting DLL3. He also cites still debatable issues such as pre-therapeutic explorations, thoracic radiotherapy, and prophylactic cerebral irradiation. Finally, therapeutic approaches targeting DNA damage repair abnormalities are discussed.1877-1203/© 2022 SPLF. Published by Elsevier Masson SAS. All rights reserved.

V-Set and immunoglobulin domain containing (VSIG) proteins as emerging immune checkpoint targets for cancer immunotherapy.

The development of immune checkpoint inhibitors is becoming a promising approach to fight cancers. Antibodies targeting immune checkpoint proteins such as CTLA-4 and PD-1 can reinvigorate endogenous antitumor T-cell responses and bring durable advantages to several malignancies. However, only a small subset of patients benefit from these checkpoint inhibitors. Identification of new immune checkpoints with the aim of combination blockade of multiple immune inhibitory pathways is becoming necessary to improve efficiency. Recently, several B7 family-related proteins, TIGIT, VSIG4, and VSIG3, which belong to the VSIG family, have attracted substantial attention as coinhibitory receptors during T-cell activation. By interacting with their corresponding ligands, these VSIG proteins inhibit T-cell responses and maintain an immune suppressive microenvironment in tumors. These results indicated that VSIG family members are becoming putative immune checkpoints in cancer immunotherapy. In this review, we summarized the function of each VSIG protein in regulating immune responses and in tumor progression, thus providing an overview of our current understanding of VSIG family members.