Development Of Immune Checkpoint Inhibitors Research Articles

Current perspectives of the Japanese Esophageal Oncology Group on the development of immunotherapy for esophageal cancer.

Esophageal cancer is the seventh most common cancer worldwide and continues to have a poor prognosis. Starting with the development of immune checkpoint inhibitors for patients with metastatic melanoma, many clinical trials have been conducted to evaluate the efficacy and safety of immune checkpoint inhibitors against various malignancies. Although few effective drugs are available for patients with advanced esophageal cancer, two immune checkpoint inhibitors, nivolumab and pembrolizumab, have been approved as second-line treatments for advanced esophageal squamous cell carcinoma. Recently, immune checkpoint inhibitors have shown promising results as post-operative therapies and first-line treatments for advanced esophageal cancer. Nivolumab has been approved as a post-operative therapy based on the CheckMate-577 trial, and nivolumab, ipilimumab and pembrolizumab have been approved as first-line treatments based on the CheckMate-648 trial and the KEYNOTE-590 trial. In addition, many trials of immune checkpoint inhibitors plus pre-operative treatment or definitive chemoradiotherapy are ongoing. The Japan Esophageal Oncology Group was established in 1978 and has conducted numerous clinical trials, most of which have examined multimodality treatments. In the era of immunotherapy, Japan Esophageal Oncology Group is conducting a clinical trial studying multimodality treatment with an immune checkpoint inhibitor. JCOG1804E (FRONTiER) is a phase I trial to evaluate the safety and efficacy of nivolumab plus pre-operative chemotherapy followed by surgery. These results might improve the clinical outcomes of esophageal cancer patients.

Targeting KRAS: Crossroads of Signaling and Immune Inhibition.

Mutations of RAS are commonly seen in human cancers, especially in lung, colorectal, and pancreatic adenocarcinoma. Despite huge effort for decades, targeting RAS mutations has been “undruggable” because of the molecular instability of RAS protein inhibition. However, the recent discovery of the KRAS G12C inhibitor paved the way to expand therapeutic options for patients with cancer harboring the KRAS G12C mutation. At the same time, the successful development of immune checkpoint inhibitors (ICIs) drastically changed the paradigm of cancer treatment and resulted in a better understanding of the tumor immune microenvironment in patients with KRAS-mutant cancer. This review describes the following: the clinical characteristics of cancer with KRAS mutation; successful development of the KRAS G12C inhibitor and its impact on the tumor immune microenvironment; and potential new avenues such as the combination strategy using KRAS inhibitor and ICI, with preclinical and clinical rationales for overcoming resistance to inhibition of KRAS to improve therapeutic efficacy for patients with cancer harboring KRAS mutations.

Immunotherapy for Microsatellite Stable Colorectal Cancers: Challenges and Novel Therapeutic Avenues.

With the development of immune checkpoint inhibitors, immunotherapy researchers have facilitated substantial progress for patients with mismatch repair deficient/microsatellite instability-high colorectal cancer, which has led to practice changes at a head-spinning pace. However, this benefit has not been translated into microsatellite stable colorectal cancer, which carries the hallmarks of chromosomal instability. So far, clinical trials have not shown any substantial clinical benefits of immune checkpoint inhibitor therapy for patients with microsatellite stable colorectal cancer, which has been disappointing. Recently, combinations of immune checkpoint inhibitors with tyrosine kinase inhibitors and targeted therapies have been investigated for potential synergistic effects that may increase antitumor activity in the tumor microenvironment and achieve more substantial clinical and radiologic responses. In this article, we discuss the current state of the science for the use of immune checkpoint inhibitors in microsatellite stable colorectal cancers, and we review the molecular underpinnings of inherited physiologic barriers for the delivery of effective immunotherapy. We also elaborate on existing therapeutic opportunities to convert microsatellite stable colorectal cancer into an "immune hot" cancer, which may define the future treatment paradigm of colorectal cancer for which there is a great unmet need.

SY06-3 Current status and prospects for the development of immune checkpoint inhibitors in Japan

In biliary tract cancers, the efficacy of immune checkpoint inhibitor (ICI) monotherapy is limited except for patients with microsatellite instability high (MSI-H), which account for 1-2% of all biliary tract cancers. Since ICIs are not highly effective as single agents, combination therapies are being developed. Three international phase III trials (NCT04003636, NCT0375235, NCT04066491) are planned to evaluate the efficacy of ICI in addition to the current standard chemotherapy, gemcitabine/cisplatin (GEM/CDDP), and several Japanese institutions are participating these trials.

Marked Hypoleptinemia precedes Overt Fat Loss in Immune Checkpoint Inhibitor-induced Acquired Generalized Lipodystrophy

<h3>Lead Author's Financial Disclosures</h3> Nothing to disclose. <h3>Study Funding</h3> None. <h3>Background/Synopsis</h3> The development of immune checkpoint inhibitors (ICIs) targeting cancer cells that evade immune T-cell regulation has revolutionized the treatment of metastatic carcinomas. Unfortunately, secondary endocrinopathies associated with ICI use, including adrenal insufficiency, primary hypothyroidism, autoimmune diabetes, and rarely hypoparathyroidism, are increasing. Lipodystrophy, presumably due to autoimmune destruction of adipocytes, leading to metabolic complications is a less well recognized adverse effect of ICI therapy. <h3>Objective/Purpose</h3> To report the clinical features and evolution of Acquired Generalized Lipodystrophy (AGL) in a patient on ICI therapy. <h3>Methods</h3> Case Report: A 66-year-old woman with metastatic lung adenocarcinoma was started on combination chemo/immunotherapy with programmed cell death-1 (PD-1) inhibitor- pembrolizumab after surgical resection of cerebellar mass and radiation. She had good tumor response but developed primary hypothyroidism and secondary adrenal insufficiency approximately ten months after initiation of ICI. <h3>Results</h3> Approximately 15 months following the treatment, she developed new-onset insulin requiring diabetes mellitus but without autoantibodies associated with type 1 diabetes. At that time, she was also noted to have hypertriglyceridemia (436 mg/dL), and elevated liver enzymes (3-4 X ULN), and a subsequent liver biopsy revealed severe macrovesicular steatosis. Her BMI was 30 kg/m2 and she had mild loss of buccal fat. Skin fold thickness measurements over the trunk and limbs were in the normal range. However, she had an undetectable serum leptin level and whole body fluorodeoxyglucose (FDG)- positron emission tomography (PET) scan, obtained for cancer surveillance, showed mild diffuse FDG activity throughout the subcutaneous tissues. She was advised low fat diet and started on insulin therapy. Over the next three months, she lost about 20 kg weight with generalized loss of subcutaneous fat from face, trunk, and extremities. Pioglitazone was started but discontinued after 4 weeks due to pedal edema and no effect on fat loss. Despite generalized lipodystrophy, she has maintained good glucose control on moderate dose insulin therapy (0.6 â€" 0.8 units/kg) and with normalization of liver enzymes and serum triglycerides. <h3>Conclusions</h3> ICI therapy can be associated with AGL, and the diagnosis must be considered in patients who develop metabolic complications such as diabetes, dyslipidemia, or steatohepatitis. Interestingly, metabolic abnormalities may precede overt fat loss. Hypoleptinemia and diffuse FDG uptake of subcutaneous tissue suggest subclinical panniculitis and adipocyte dysfunction even before clinically evident lipodystrophy.

Immune Checkpoint Blockade Therapy in Patients With Colorectal Cancer Harboring Microsatellite Instability/Mismatch Repair Deficiency in 2022.

Immune checkpoint inhibitors (ICIs) are shown to be effective among patients with metastatic colorectal cancer (mCRC) harboring high microsatellite instability (MSI-H) and/or mismatch repair deficiency (dMMR), with U.S. Food and Drug Administration approvals for all lines of therapy. In Europe, only pembrolizumab in the first line and the combination of nivolumab and ipilimumab beyond the first line are approved. Many questions remain about the clinical management of MSI-H/dMMR CRC. Biomarkers predictive of immune checkpoint inhibitor resistance among MSI-H/dMMR tumors are needed (1) to select the best treatment for patients with CRC (anti-PD-[L]1 monotherapy alone or combined with anti-CTLA-4 or chemotherapy) and (2) to develop new treatment strategies for patients whose disease progressed after immune checkpoint inhibitor monotherapy. The development of immune checkpoint inhibitors in the adjuvant and neoadjuvant settings is also of great interest for patients harboring MSI-H/dMMR, especially as a substantial proportion have Lynch syndrome or are at high risk of developing cancers in their lifetime and sporadic MSI-H/dMMR cancers occur most frequently in elderly and frail patients. Thus, CRC is not one, but two different diseases: (1) MSI-H/dMMR CRC (seen in 5% of mCRC and 15% of non-mCRC), which is genetically unstable with a high mutational load and many neoantigens, and for which immune checkpoint inhibitors radically changed clinical management, and (2) microsatellite stable CRC with chromosomal instability, for which immune checkpoint inhibitors are not proven efficient.

Cancer Cachexia and Antitumor Immunity: Common Mediators and Potential Targets for New Therapies.

Cancer cachexia syndrome (CCS) is a multifactorial metabolic syndrome affecting a significant proportion of patients. CCS is characterized by progressive weight loss, alterations of body composition and a systemic inflammatory status, which exerts a major impact on the host’s innate and adaptive immunity. Over the last few years, the development of immune checkpoint inhibitors (ICIs) transformed the treatment landscape for a wide spectrum of malignancies, creating an unprecedented opportunity for long term remissions in a significant subset of patients. Early clinical data indicate that CCS adversely impairs treatment outcomes of patients receiving ICIs. We herein reviewed existing evidence on the potential links between the mechanisms that promote the catabolic state in CCS and those that impair the antitumor immune response. We show that the biological mediators and processes leading to the development of CCS may also participate in the modulation and the sustainment of an immune suppressive tumor microenvironment and impaired anti-tumor immunity. Moreover, we demonstrate that the deregulation of the host’s metabolic homeostasis in cancer cachexia is associated with resistance to ICIs. Further research on the interrelation between cancer cachexia and anti-tumor immunity is required for the effective management of resistance to immunotherapy in this specific but large subgroup of ICI treated individuals.

Regorafenib joins immune checkpoint inhibitors (ICIs) for previously ICIs plus TKIs failed advanced hepatocellular carcinoma (HCC) patients: A retrospective study.

e16118 Background: The development of ICIs has promoted a major breakthrough in the field of cancer therapy. A number of patients experience primary or acquired resistance to ICIs based first line therapy. Because of the similar mechanisms, PD-(L)1 inhibitors replacement after PD-(L)1 inhibitors-based therapy resistance is difficult to sustain benefits. Therefore, whether suspending immunotherapy, or maintenance immunotherapy and switching the combination drugs in the follow-up strategy is worth to explore. Regorafenib is an oral multikinase inhibitor that blocks the activity of protein kinases involved in angiogenesis, oncogenesis and metastasis. Besides, regorafenib could regulate the immune microenvironment. This retrospective trial aims to evaluate the efficacy of regorafenib in combinations with previous ICI in advanced HCC patients who failed to previous ICI-TKI treatment. Methods: In this study, eligible patients were advanced HCC, who failed to previous treatment with TKIs and PD-1 inhibitors. 17 patients were received PD-1 inhibitor the same as the first-line treatment (dosage and mode of administration according to instructions) and regorafenib (40, 80, 120mg/m2, po, qd, d1-21) every 4 weeks, until disease progression, intolerable toxicities, or physician/patient withdrawal. The safety and efficacy were assessed by investigators per CTCAE v5.0 and RECIST v1.1, respectively. The primary endpoint was objective response rate (ORR), the secondly endpoints were progression-free survival (PFS), disease control rate (DCR), overall survival (OS), duration of response (DOR) and safety. Results: From Nov 15, 2020 to Jan 31, 2022, 17 patients with advanced HCC, Child-Pugh class A liver disease, and ECOG PS 0-1 (16 male vs. 1 female, 13 second-line recipients vs. 4 third-line recipients, median age of 55 years) had been enrolled. 52.94% of the patients had BCLC stage B and others had BCLC stage C. The median follow-up was 8.8 months (range, 2.7-14.7). Confirmed ORR and DCR were 41.2% and 64.7%, respectively. The median PFS was 5.21 months (95% CI, 2.65-7.77). For 13 second line patients, confirmed ORR and DCR were 46.2% and 69.2%, respectively. Median OS and DOR had not yet been reached. 12 recipients had treatment-related adverse events (TRAEs). Most frequent TEAEs (≥5%) included fatigue (15.8%), diarrhea (15.8%), periodontal disease (10.5%), hypertension (10.5%), albuminuria (5.3%). Grade 3 TRAEs occurred in 3 (17.6%) patients included gastrointestinal bleeding, hand-foot syndrome and albuminuria. No Grade 4 TRAE and new safety signal were identified. Conclusions: Regorafenib plus PD-1 inhibitor showed a promising efficacy with favorable safety in HCC patients with PD-1 inhibitor resistance, especially in the standard second line patients. Moreover, the strategy showed a higher ORR than RESORCE study (46.2% vs. 10.6%).

Dysthyroidism during immune checkpoint inhibitors is associated with improved overall survival in solid tumors: Data-mining of 1,382 electronic patient records.

2659 Background: Medical treatment of solid tumors cancer has irreversibly changed since the development of immune checkpoint inhibitors (ICI). However, immune-related adverse events (irAE) are challenging in routine practice. Dysthyroidism is the most common endocrine irAE and small series suggest that dysthyroidism might be associated with ICI efficacy. This led us to explore the association between ICI-induced dysthyroidism and overall survival (OS) in a large cohort of solid tumor patients (pts) using data mining of electronic patient records (EPR). Methods: ConSoRe is a new generation data analytics solution using natural language processing to search aggregated data and perform advanced data mining. It was used for data extraction from EPR of pts treated with ICI for solid tumors in Institut Paoli-Calmettes (Marseille Cancer Center, France), with validation using manual screening of 28.8% EPR. All dysthyroidism were verified and only dysthyroidism ICI-induced were retained. Survival analyses were performed by Kaplan-Meier method and compared using the log-rank test (survminer R package). In the uni/multivariate analysis, the Cox proportional-hazards model was used to estimate the variables associated with OS, using hazard ratio (HR) and its associated 95% confidence interval. Results: Data extraction identified 1,385 pts treated with ICI in 2011-2021. Dysthyroidism was observed in 90 pts (6.5%), including 22 hyperthyroidism (24%), 36 hypothyroidism (40%) and 32 hyperthyroidism and hypothyroidism (36%). In this cohort, 81 % of the dysthyroidism were related to PD(L)-1 inhibitors and 19 % to CTLA-4/PD(L)-1 inhibitors combination. No statistical difference was observed in term of tumor location between patients with or without dysthyroidism. Dysthyroidism was associated with improved OS (HR=0.46, 95%CI 0.29-0.70, p=0.0005) with a median OS of 65 months (mo) vs. 30 mo in patients without dysthyroidism. Survival impact of dysthyroidism was consistent using a 2-mo landmark analysis, fixed on median time to dysthyroidism. In multivariate analysis including sex, age, tumor localization, line numbers and type of ICI, dysthyroidism was independently associated with an improved OS (HR=0.49, 95%CI 0.32-0.75, p=0.001), as presented in the Table. Conclusions: Data mining identified a large number ICI-induced dysthyroidism, associated with an improved OS. The onset of dysthyroidism might help oncologist detecting patients more likely to benefit from ICI. [Table: see text]

Impact of immune-related adverse events (irAEs) on PD-1/L1 inhibitors efficacy in advanced esophageal cancer.

4061 Background: The recent development of Immune checkpoint inhibitors (ICIs) has improved treatment outcomes for patients with esophageal cancer, although it may initiate autoimmune-related disorders in some patients. Across disease sites, patients who experience irAEs while on therapy with anti-PD-1 and anti-PD-L1 antibodies have been documented to experience improved outcomes as measured by overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Methods: We reviewed the medical records and the following characteristics of patients were collected: age, gender, Eastern Cooperative Oncology Group performance status (ECOG PS), stage, histology, history of surgery, metastatic sites, therapy line, presence of target lesion according to the response evaluation criteria in solid tumors (RECIST) version 1.1, LDH level before initiating ICIs treatment. We divided the patients treated with ICIs into two groups based on occurrence of irAEs. We compared the efficacy between the irAE - and irAE + groups. Results: There were total 295 patients. Of all the patients, 143 patients (50.2%) suffered from irAEs. The median patient age was 60 years (range, 36–84). Baseline characteristics including gender, ECOG PS, tumor location, history of surgery, histology, number of organs with metastases, site of metastases, therapy line, history of drinking, history of smoking between patients with or without irAE were not significantly different. The most frequent irAEs were Anemia(71/295, 24.07%), Pneumonitis (55/295, 18.64%), Cardiovascular toxicities (35/295, 11.86%). There were no grade 5 adverse events related to immunotherapy. Objective response was observed in 92 patients (31.19%), 54 of the 143 patients with irAEs had objective response (37.76%) in contrast with 38 of the 152 cases without irAEs (25.00%). Median PFS in patients with irAEs was 10.27 months and 6.2 months in those without irAEs (p&lt;0.001). Median OS in patients with irAEs was 15.4 months and 9.2 months in those without irAEs(p&lt;0.001).Multivariate analyses identified an ECOG PS ≥2, cycles ≤8, and without irAEs as independent poor prognostic factors (p=0.003, p &lt;0.001 and p=0.011). Multivariate analysis demonstrated that ECOG PS ≥2, Therapy line≥22nd,without radiation and absence of irAEs were associated with a poor overall survival(p=0.022, p=0.006, p. &lt;0.001 and p=0.002). Multivariable analysis also revealed that Cycles&gt;8, Radiation and Antiangiogenic therapy were positively associated with occurrence of irAEs(p&lt;0.001, p=0.002, p=0.025). Conclusions: In advanced esophageal cancer treated with PD-1/L1 inhibitors., patients with irAEs showed a markedly improved efficacy over patients without irAEs.

Is tailored systemic therapy in renal cell carcinoma realistic?

The development of immune checkpoint inhibitors has substantially altered the treatment strategy for patients with metastatic renal cell carcinoma and has improved patient survival. 1 Ljungberg B Albiges L Bedke J et al. Guidelines on renal cell carcinoma. European Association of Urology, Arnhem, the Netherlands2022 Google Scholar Several regimens are available as first-line therapy. However, there are no guidelines for choosing the best regimen for each patient in the real-world setting because of the absence of optimal biomarkers. 1 Ljungberg B Albiges L Bedke J et al. Guidelines on renal cell carcinoma. European Association of Urology, Arnhem, the Netherlands2022 Google Scholar Nivolumab, nivolumab–ipilimumab, and VEGFR-tyrosine kinase inhibitors as first-line treatment for metastatic clear-cell renal cell carcinoma (BIONIKK): a biomarker-driven, open-label, non-comparative, randomised, phase 2 trialWe demonstrate the feasibility and positive effect of a prospective patient selection based on tumour molecular phenotype to choose the most efficacious treatment between nivolumab with or without ipilimumab and a VEGFR-TKI in the first-line treatment of metastatic clear-cell renal cell carcinoma. Full-Text PDF

Immune checkpoint inhibitors in the first-line treatment of metastatic small-cell lung cancer

Small-cell lung cancer is the most aggressive form of lung cancer. Most patients are diagnosed at a late disease stage when the prognosis is poor. The treatment algorithm for small-cell lung cancer remained unchanged for years, with chemotherapy as the first-line option. However, progress has been made with the recent development of immune checkpoint inhibitors, two of which — atezolizumab and durvalumab — have been approved in combination with chemotherapy as first-line treatment for advanced small-cell lung cancer. This review presents detailed data concerning the efficacy and safety of atezolizumab and durvalumab from both registration trials and real-world studies, as well as the results of clinical trials of other immune checkpoints inhibitors. Finally, the issue of identifying biomarkers to predict the efficacy of immunochemotherapy is discussed.

Protein Kinase Inhibitor-Mediated Immunoprophylactic and Immunotherapeutic Control of Colon Cancer.

Immunotherapy has allowed major advances in oncology in the past years, in particular with the development of immune checkpoint inhibitors, but the clinical benefits are still limited, particularly in colorectal cancer (CRC). Our scientific approach is based on the search for innovative immunotherapy with a final goal that aims to induce an effective antitumor immune response in CRC. Here, we focused on a multikinase inhibitor, H89. We carried out in vivo experiments based on syngeneic mouse models of colon cancer in BALB/c mice and chemically colon tumorigenesis. Flow cytometry, RNAseq, RT-qPCR, antibody-specific immune cell depletion, and Western blot were used to identify the immune cell type involved in the preventive and antitumor activity of H89. We demonstrated that H89 delays colon oncogenesis and prevents tumor growth. This latter effect seems to involve NK cells. H89 also inhibits colon tumor growth in a T-cell-dependent manner. Analysis of the immune landscape in the tumor microenvironment showed an increase of CD4+ Th1 cells and CD8+ cytotoxic T cells but a decrease of CD4+ Treg cell infiltration. Mechanistically, we showed that H89 could promote naïve CD4+ T-cell differentiation into Th1, a decrease in Treg differentiation, and an increase in CD8+ T-cell activation and cytotoxicity ex vivo. Furthermore, H89 induced overexpression of genes involved in antitumor immune response, such as IL-15RA, which depletion counteracts the antitumor effect of H89. We also found that H89 regulated Akt/PP2A pathway axis, involved in TCR and IL-15 signaling transduction. Our findings identify the H89 as a potential strategy for immune system activation leading to the prevention and treatment of CRC.

A variety of 'exhausted' T cells in the tumor microenvironment.

In T-cell biology, 'exhaustion' was initially described as a hyporesponsive state in CD8+ T cells during chronic infections. Recently, exhaustion has been recognized as a T-cell dysfunctional state in the tumor microenvironment (TME). The term 'exhaustion' is used mainly to refer to effector T cells with a reduced capacity to secrete cytokines and an increased expression of inhibitory receptors. The up-regulation of exhaustion-related inhibitory receptors, including programmed cell death protein 1 (PD-1), in such T cells has been associated with the development of tumors, prompting the development of immune checkpoint inhibitors. In addition to CD8+ T cells, CD4+ T cells, including the regulatory T (Treg) cell subset, perform a wide variety of functions within the adaptive immune system. Up-regulation of the same inhibitory receptors that are associated with CD8+ T-cell exhaustion has also been identified in CD4+ T cells in chronic infections and cancers, suggesting a similar CD4+ T-cell exhaustion phenotype. For instance, high expression of PD-1 has been observed in Treg cells in the TME, and such Treg cells can play an important role in the resistance to PD-1 blockade therapies. Furthermore, recent progress in single-cell RNA sequencing has shown that CD4+ T cells with cytotoxic activity are also vulnerable to exhaustion. In this review, we will discuss novel insights into various exhausted T-cell subsets, which could reveal novel therapeutic targets and strategies to induce a robust anti-tumor immune response.

Efficacy and safety of nivolumab in renal cell carcinoma patients with BONE metastases: Results of the GETUG: AFU 26 nivoren multicenter phase II study.

342 Background: Bone metastases (BM) in renal cell carcinoma (RCC) are associated with a poor prognosis based on retrospective studies in which patients were treated with antiangiogenic agents. Since the development of immune checkpoint inhibitors, few data are available regarding the prognosis impact of BM or the efficacy and safety of checkpoint inhibitors in patients with bones metastatic RCC. GETUG-AFU26-NIVOREN (NIVOREN) is a French multicenter prospective study in which patients were treated with nivolumab after failure of one or more antiangiogenic tyrosine kinase inhibitors. We therefore aim to evaluate the impact of BM on prognosis, and the efficacy and safety of nivolumab in patients with BM enrolled in NIVOREN trial. Methods: All adult patients with BM at inclusion were included in our study. The primary endpoint of this ancillary study was overall survival (OS). Secondary endpoints were progression-free survival (PFS), objective response rate (ORR), safety, and skeletal-related events (SRE) in patients with BM. Clinical data were collected prospectively, except for SRE data which were collected retrospectively in a complementary consent report form. Results: Among 720 patients treated with nivolumab in the NIVOREN study, 194 had BM at inclusion. After a median follow-up of 23.9 months, the median OS was 17.9 months in patients with BM versus 26.1 months in patients without BM (HR = 1.42 CI95% [1.13-1.79], p = 0.0023). After adjustment on sex, age, IMDC group and line of treatments, the difference was not significant (HR = 1.24, CI95% [0.98-1.56], p = 0.0707). The median PFS was shorter in patients with BM even after adjustment (2.8 versus 4.6 months, HR = 1.30 CI95% [1.08-1.56]), as well as the ORR (14.8% versus 23.3%). The safety profile was similar between patients with or without BM at inclusion. The incidence of SRE in the BM population was 36% during the treatment period with nivolumab. A post-hoc analysis evaluating the impact of bone-targeting agents in association with nivolumab on SRE incidence was performed. There was a statistically significant benefit in patients treated with bone-targeting agents on the incidence of SRE (OR = 0.367, CI95% [0.151-0.895], p = 0.0276). Conclusions: Nivolumab is associated with shorter OS, PFS, and lower ORR in patients with BM. Our study confirms, in the era of immunotherapy that patients with BM are associated with poorer prognosis and suggests that association with bone-targeting agents decreases the incidence of SRE. Clinical trial information: 2015-004117-24.

Peptidic microarchitecture-trapped tumor vaccine combined with immune checkpoint inhibitor or PI3Kγ inhibitor can enhance immunogenicity and eradicate tumors

BackgroundWith the rapid development of immune checkpoint inhibitors and neoantigen (NeoV)-based personalized tumor vaccines, tumor immunotherapy has shown promising therapeutic results. However, the limited efficacy of available tumor vaccines impedes...

Comparison of Laboratory Methods for the Clinical Follow Up of Checkpoint Blockade Therapies in Leukemia: Current Status and Challenges Ahead.

The development of immune checkpoint inhibitors, the monoclonal antibodies that modulate the interaction between immune checkpoint molecules or their ligands on the immune cells or tumor tissue has revolutionized cancer treatment. While there are various studies proving their efficacy in hematological malignancies, there is also a body of accumulating evidence indicating that immune checkpoint inhibitors’ clinical benefits are limited in such diseases. In addition, due to their regulatory nature that balances the immune responses, blockade of immune checkpoints may lead to toxic side effects and autoimmune responses, and even primary or acquired resistance mechanisms may restrict their success. Thus, the need for laboratory biomarkers to identify and monitor patient populations who are more likely respond to this type of therapy and the management of side effects seem critical. However, guidelines regarding the use of immune checkpoint inhibitors in hematological cancers and during follow-up are limited while there is no consensus on the laboratory parameters to be investigated for safety and efficacy of the treatment. This review aims to provide an insight into recent information on predictive and prognostic value of biomarkers and laboratory tests for the clinical follow up of hematological malignancies, with an emphasis on leukemia.

Immune-checkpoint inhibitors: long-term implications of toxicity.

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, and providing new therapeutic indications in earlier-stage settings. As such, characterizing the long-term implications of receiving ICIs has grown in importance. An abundance of evidence exists describing the acute clinical toxicities of these agents, although chronic effects have not been as well catalogued. Nonetheless, emerging evidence indicates that persistent toxicities might be more common than initially suggested. While generally low-grade, these chronic sequelae can affect the endocrine, rheumatological, pulmonary, neurological and other organ systems. Fatal toxicities also comprise a diverse set of clinical manifestations and can occur in 0.4–1.2% of patients. This risk is a particularly relevant consideration in light of the possibility of long-term survival. Finally, the effects of immune-checkpoint blockade on a diverse range of immune processes, including atherosclerosis, heart failure, neuroinflammation, obesity and hypertension, have not been characterized but remain an important area of research with potential relevance to cancer survivors. In this Review, we describe the current evidence for chronic immune toxicities and the long-term implications of these effects for patients receiving ICIs.

Blockade of beta-adrenergic receptors reduces cancer growth and enhances the response to anti-CTLA4 therapy by modulating the tumor microenvironment

The development of immune checkpoint inhibitors (ICI) marks an important breakthrough of cancer therapies in the past years. However, only a limited fraction of patients benefit from such treatments, prompting the search for immune modulating agents that can improve the therapeutic efficacy. The nonselective beta blocker, propranolol, which for decades has been prescribed for the treatment of cardiovascular conditions, has recently been used successfully to treat metastatic angiosarcoma. These results have led to an orphan drug designation by the European Medicines Agency for the treatment of soft tissue sarcomas. The anti-tumor effects of propranolol are suggested to involve the reduction of cancer cell proliferation as well as angiogenesis. Here, we show that oral administration of propranolol delays tumor progression of MCA205 fibrosarcoma model and MC38 colon cancer model and increases the survival rate of tumor bearing mice. Propranolol works by reducing tumor angiogenesis and facilitating an anti-tumoral microenvironment with increased T cell infiltration and reduced infiltration of myeloid-derived suppressor cells (MDSCs). Using T cell deficient mice, we demonstrate that the full anti-tumor effect of propranolol requires the presence of T cells. Flow cytometry-based analysis and RNA sequencing of FACS-sorted cells show that propranolol treatment leads to an upregulation of PD-L1 on tumor associated macrophages (TAMs) and changes in their chemokine expression profile. Lastly, we observe that the co-administration of propranolol significantly enhances the efficacy of anti-CTLA4 therapy. Our results identify propranolol as an immune modulating agent, which can improve immune checkpoint inhibitor therapies in soft tissue sarcoma patients and potentially in other cancers.

First-Line Immunotherapy for Non-Small-Cell Lung Cancer.

For patients with metastatic non-small-cell lung cancer (mNSCLC), the last decade has been characterized by critical progress that has contributed to substantially improved survival. In particular, the development of specific antibodies against the programmed death (PD-1) receptor, programmed death-ligand 1 (PD-L1), and the cytotoxic T-lymphocyte-associated protein 4 receptor in the therapeutic strategy of mNSCLC either in first- or in second-line settings have led to unprecedented prolonged survival for a proportion of these patients. Although clinical development of immune checkpoint inhibitors with anti-PD-1 and PD-L1 therapies largely began as monotherapy in the second-line setting, the more recent progress has shifted toward combination approaches in first-line settings as well as the integration of immunotherapy into the clinical paradigm in earlier stages. Today, with the exception of mNSCLC harboring targetable oncogenes, nearly all patients with mNSCLC receive PD-1 or PD-L1 therapy in first-line settings. Here we report the current status of first-line immunotherapy in mNSCLC together with current challenges in selecting the best immunotherapeutic approach for the individual patient.