scholarly journals Il-2 in combination with immune checkpoints inhibitors as a promising approach for cancer immunotherapy: A literature review

2021 ◽  
Vol 62 (4) ◽  
pp. 43-47
Author(s):  
M. Kiselevsky ◽  
S. Sitdikova ◽  
A. Petkevich
Keyword(s):  
Tumor Regression ◽  
Checkpoint Inhibitors ◽  
Interleukin 2 ◽  
Immune Checkpoints ◽  
Metastatic Renal Cancer ◽  
Killer Activity ◽  
Promising Area ◽  
Anticancer Treatment ◽  
Checkpoint Inhibitor Therapy ◽  
Meta Analyses

Relevance: Interleukin-2 (IL-2) alone has been shown to induce tumor regression and approved to treat metastatic renal cancer and melanoma. Checkpoint inhibitors realize their therapeutic effect through stimulation of immune system effectors; one of such mechanisms is the enhancement of IL-2 production by T-helpers. The purpose of the study was to determine the effectiveness of IL-2 administration as a component of combined immunotherapy with immune checkpoint inhibitors and to suggest the mechanisms by which IL-2 can reduce the frequency and severity of side effects during checkpoint inhibitor therapy without reducing their effectiveness. Methods: The literature search was performed in the PubMed, SCOPUS, and Web of Science databases by the keywords in article titles: “immunotherapy,” “checkpoint inhibitors,” “interleukin-2,” and “combination therapy” for the period 2011-2021. A total of 248 relevant articles were found. The review’s inclusion criteria were: clinical cases; data of clinical research methods; data on humans/body fluids from humans; literature reviews and meta-analyses. The selected 24 articles met the search criteria and were included in the review. Results: The combined action of IL-2 and сheckpoint inhibitors increases the proliferative and killer activity of the antitumor immunity effectors compared to the action of the same drugs in mono-mode at a level exceeding the summation effect. Conclusion: The combination of IL-2 and сheckpoint inhibitors can increase the effectiveness of anticancer treatment and is a promising area of immunotherapy

scholarly journals Autoimmunity linked protein phosphatase PTPN22 as a target for cancer immunotherapy

2020 ◽  
Vol 8 (2) ◽  
pp. e001439 ◽  
Author(s):  
Rafael Cubas ◽  
Zia Khan ◽  
Qian Gong ◽  
Marina Moskalenko ◽  
Huizhong Xiong ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Immunotherapy ◽  
Phosphatase Activity ◽  
Tumor Regression ◽  
Checkpoint Inhibitors ◽  
Therapeutic Option ◽  
Interleukin 2 ◽  
Cell Functions ◽  
Increased Risk

BackgroundCancer immunotherapy has evolved from interferon-alpha (IFNα) and interleukin-2 in the 1980s to CTLA-4 and PD-1/PD-L1 checkpoint inhibitors (CPIs), the latter highlighting the importance of enhancing T-cell functions. While the search for novel immunomodulatory pathways continues, combination therapies augmenting multiple pathways can also increase efficacy. The association of autoimmune-related adverse events with clinical efficacy following CPI treatment has been inferred and suggests that breaking tolerance thresholds associated with autoimmunity may affect host immune responses for effective cancer immunotherapy.ResultsHere, we show that loss of autoimmune associated PTPN22, a key desensitization node for multiple signaling pathways, including IFNα receptor (IFNAR) and T-cell receptor, can augment tumor responses. Implantation of syngeneic tumors in Ptpn22-/- mice led to expansion and activation of peripheral and intratumoral T cells and, in turn, spontaneous tumor regression as well as enhanced responses in combination with anti-PD-L1 treatment. Using genetically modified mice expressing a catalytically inactive PTPN22 or the autoimmunity-associated human single-nucleotide polymorphism variant, augmentation of antitumor immunity was dependent on PTPN22 phosphatase activity and partially on its adaptor functions. Further, antitumor responses were dependent on both CD4+ and CD8+T cells and, in part, IFNAR function. Finally, we demonstrate that the autoimmune susceptibility Ptpn22(C1858T) variant is associated with lower risk of developing non-melanoma skin cancers, improved overall survival and increased risk for development of hyperthyroidism or hypothyroidism following atezolizumab (anti-PD-L1) treatment.ConclusionsTogether, these data suggest that inhibition of PTPN22 phosphatase activity may provide an effective therapeutic option for cancer immunotherapy and that exploring genetic variants that shift immune tolerance thresholds may serve as a paradigm for finding new cancer immunotherapy targets.

scholarly journals At the Cutting Edge against Cancer: A Perspective on Immunoproteasome and Immune Checkpoints Modulation as a Potential Therapeutic Intervention

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4852
Author(s):  
Grazia R. Tundo ◽  
Diego Sbardella ◽  
Francesco Oddone ◽  
Anna A. Kudriaeva ◽  
Pedro M. Lacal ◽  
...  
Keyword(s):  
Antigen Processing ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoints ◽  
Antigenic Peptides ◽  
Class I Mhc ◽  
Mhc Molecules ◽  
Promising Area ◽  
Potential Therapeutic Intervention ◽  
Antigen Repertoire

Immunoproteasome is a noncanonical form of proteasome with enzymological properties optimized for the generation of antigenic peptides presented in complex with class I MHC molecules. This enzymatic property makes the modulation of its activity a promising area of research. Nevertheless, immunotherapy has emerged as a front-line treatment of advanced/metastatic tumors providing outstanding improvement of life expectancy, even though not all patients achieve a long-lasting clinical benefit. To enhance the efficacy of the currently available immunotherapies and enable the development of new strategies, a broader knowledge of the dynamics of antigen repertoire processing by cancer cells is needed. Therefore, a better understanding of the role of immunoproteasome in antigen processing and of the therapeutic implication of its modulation is mandatory. Studies on the potential crosstalk between proteasome modulators and immune checkpoint inhibitors could provide novel perspectives and an unexplored treatment option for a variety of cancers.

scholarly journals Targeting dual signaling pathways in concert with immune checkpoints for the treatment of pancreatic cancer

2019 ◽  
Author(s):  
Erik S Knudsen ◽  
Vishnu Kumarasamy ◽  
Sejin Chung ◽  
Paris Vail ◽  
Stephanie Tzetzo ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Interferon Response ◽  
Immune Checkpoints ◽  
Mek Inhibition ◽  
T Cell Infiltration ◽  
Cycle Arrest ◽  
Checkpoint Inhibitor Therapy ◽  
Effector Pathways

ABSTRACTPancreatic cancer harbors a poor prognosis due to the lack of effective systemic therapies. Here we interrogated means to target key effector pathways down-stream from KRAS. We found that combination treatment with MEK and CDK4/6 inhibitors was effective across a broad range of PDX models in delaying tumor progression. These effects were associated with stable cell cycle arrest, as well as the induction of multiple genes associated with interferon response and antigen presentation in an RB-dependent fashion. Using single cell sequencing and complementary approaches, we found that the combination of CDK4/6 and MEK inhibition had a significant impact on increasing T-cell infiltration and altering myeloid populations, while potently cooperating with immune checkpoint inhibitors. Together, these data indicate that there are canonical and non-canonical features of CDK4/6 and MEK inhibition that impact on the tumor and host that can contribute to durable control for tumors in combination with immune checkpoint inhibitor therapy.

scholarly journals Genomic data from NSCLC tumors reveals correlation between SHP-2 activity and PD-L1 expression and suggests synergy in combining SHP-2 and PD-1/PD-L1 inhibitors

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0256416
Author(s):  
Keller J. Toral ◽  
Mark A. Wuenschel ◽  
Esther P. Black
Keyword(s):  
Gene Expression ◽  
Protein Expression ◽  
Rna Sequencing ◽  
Tumor Regression ◽  
Checkpoint Inhibitors ◽  
The Cancer Genome Atlas ◽  
Immune Checkpoints ◽  
Sequencing Data ◽  
Lung Cancers ◽  
Lung Adenocarcinomas

The identification of novel therapies, new strategies for combination of therapies, and repurposing of drugs approved for other indications are all important for continued progress in the fight against lung cancers. Antibodies that target immune checkpoints can unmask an immunologically hot tumor from the immune system of a patient. However, despite accounts of significant tumor regression resulting from these medications, most patients do not respond. In this study, we sought to use protein expression and RNA sequencing data from The Cancer Genome Atlas and two smaller studies deposited onto the Gene Expression Omnibus (GEO) to advance our hypothesis that inhibition of SHP-2, a tyrosine phosphatase, will improve the activity of immune checkpoint inhibitors (ICI) that target PD-1 or PD-L1 in lung cancers. We first collected protein expression data from The Cancer Proteome Atlas (TCPA) to study the association of SHP-2 and PD-L1 expression in lung adenocarcinomas. RNA sequencing data was collected from the same subjects through the NCI Genetic Data Commons and evaluated for expression of the PTPN11 (SHP-2) and CD274 (PD-L1) genes. We then analyzed RNA sequencing data from a series of melanoma patients who were either treatment naïve or resistant to ICI therapy. PTPN11 and CD274 expression was compared between groups. Finally, we analyzed gene expression and drug response data collected from 21 non-small cell lung cancer (NSCLC) patients for PTPN11 and CD274 expression. From the three studies, we hypothesize that the activity of SHP-2, rather than the expression, likely controls the expression of PD-L1 as only a weak relationship between PTPN11 and CD274 expression in either lung adenocarcinomas or melanomas was observed. Lastly, the expression of CD274, not PTPN11, correlates with response to ICI in NSCLC.

scholarly journals Immune checkpoint inhibitors and prostate cancer: a new frontier?

2016 ◽  
Author(s):  
Alessandra Modena ◽  
Chiara Ciccarese ◽  
Roberto Iacovelli ◽  
Matteo Brunelli ◽  
Rodolfo Montironi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Tumor Regression ◽  
Current Knowledge ◽  
Checkpoint Inhibitors ◽  
Immune Surveillance ◽  
Predictive Biomarkers ◽  
Immune Checkpoints ◽  
Term Survival

Despite recent advances in the treatment of metastatic castrationresistant prostate cancer (mCRPC), agents that provide durable disease control and long-term survival are still needed. It is a fact that a tumor-induced immunosuppressive status (mediated by aberrant activation of inhibitory immune checkpoint pathways as a mechanism to evade host immune surveillance) plays a crucial role in the pathogenesis of cancer, including prostate cancer (PC), making CRPC patients suitable candidates for immunotherapy. Therefore, growing interest of anticancer research aims at blocking immune checkpoints (mainly targeting CTLA-4 and PD1/PD-L1 pathways) to restore and enhance cellular-mediated antitumor immunity and achieve durable tumor regression. In this review, we describe the current knowledge regarding the role of immune checkpoints in mediating PC progression, focusing on CTLA-4 and PD1 pathways. We also provide current clinical data available, an update on ongoing trials of immune checkpoint inhibitors in PC. Finally, we discuss the necessity to identify prognostic and predictive biomarkers of immune activity, and we analyze new immune checkpoints with a role as promising targets for PC therapy.

scholarly journals Results of combined nivolumab and ipilimumab therapy in patients with cancer

2021 ◽  
pp. 18-23
Author(s):  
M. A. Lyadova ◽  
V. K. Lyadov ◽  
O. A. Pardabekova ◽  
I. A. Pokataev ◽  
M. E. Ivannikov ◽  
...  
Keyword(s):  
Disease Control ◽  
Tumor Regression ◽  
Checkpoint Inhibitors ◽  
Immune Therapy ◽  
Objective Response ◽  
Real Life ◽  
Complete Response ◽  
High Rate ◽  
Immune Checkpoints ◽  
Disease Stabilization

Introduction. The discovery of immune checkpoints and immune checkpoint inhibitors (ICI) became a breakthrough in medical oncology. Currently a search for most effective and safe schemes of ICI therapy for different cancers is ongoing.Aim. To evaluate the efficacy and tolerability of a combination of nivolumab and ipilimumab in cancer patients in real-life clinical practice.Materials and methods. The study included 30 patients: 13 patients with melanoma, 10 patients with renal cell carcinoma (RCC) and 7 patients with colorectal cancer (CRC). All patients underwent 4 courses of combined immune therapy (melanoma - nivolumab 1 mg/kg + ipilimumab 3 mg/kg; RCC, CRC – nivolumab 3 mg/kg + ipilimumab 1 mg/kg once per 21 days). Nivolumab monotherapy was continued after the achievement of disease control. Objective tumor response was registered in cases of partial or complete tumor regression. Treatment response was determined using iRECIST criteria.Results. Treatment effect assessment was performed in 91 patients. Complete response (CR) was registered in 1 (5%) patient, partial response (PR) – in 3 (16%) patients, disease stabilization – in 8 (42%) patients, unconfirmed progression – in 7 (37%) patients. No cases of disease progression were registered. Thus, objective response rate was 21%; disease control was achieved in 63% of patients. The most significant immune-mediated adverse effects (imAEs) were gastric toxicity (20%), 1–2 grade fatigue (13%) and 2–3 grade hepatotoxicity (10%).Conclusions. Combined nivolumab and ipilimumab therapy in patients with melanoma, CRC and RCC is associated with a high rate of disease control with acceptable toxicity profile. 

Immune checkpoint and checkpoint inhibitors in hepatocellular carcinoma

2018 ◽  
Vol 1 (1) ◽  
pp. 28-32
Author(s):  
Piyawat Komolmit
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell Receptor ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cell Receptor ◽  
Immune Checkpoints ◽  
Histocompatibility Complex

การรักษามะเร็งด้วยแนวความคิดของการกระตุ้นให้ภูมิต้านทานของร่างกายไปทำลายเซลล์มะเร็งนั้น ปัจจุบันได้รับการพิสูจน์ชัดว่าวิธีการนี้สามารถหยุดยั้งการแพร่กระจายของเซลล์มะเร็ง โดยไม่ก่อให้เกิดภาวะแทรกซ้อนทางปฏิกิริยาภูมิต้านทานต่ออวัยวะส่วนอื่นที่รุนแรง สามารถนำมาใช้ทางคลินิกได้ ยุคของการรักษามะเร็งกำลังเปลี่ยนจากยุคของยาเคมีบำบัดเข้าสู่การรักษาด้วยภูมิต้านทาน หรือ immunotherapy ยากลุ่ม Immune checkpoint inhibitors โดยเฉพาะ PD-1 กับ CTLA-4 inhibitors จะเข้ามามีบทบาทในการรักษามะเร็งตับในระยะเวลาอันใกล้ จำเป็นแพทย์จะต้องมีความรู้ความเข้าใจในพื้นฐานของ immune checkpoints และยาที่ไปยับยั้งโมเลกุลเหล่านี้ Figure 1 เมื่อ T cells รับรู้แอนทิเจนผ่านทาง TCR/MHC จะมีปฏิกิริยาระหว่าง co-receptors หรือ immune checkpoints กับ ligands บน APCs หรือ เซลล์มะเร็ง ทั้งแบบกระตุ้น (co-stimulation) หรือยับยั้ง (co-inhibition) TCR = T cell receptor, MHC = major histocompatibility complex

Immune Checkpoint Inhibitors in Patients with Recurrent Hepatocellular Carcinoma after Liver Transplantation: A Case Report and Literature Review

2020 ◽  
Vol 20 (9) ◽  
pp. 720-727
Author(s):  
Jianguo Qiu ◽  
Wei Tang ◽  
Chengyou Du
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Transplantation ◽  
Immune Checkpoint ◽  
Graft Rejection ◽  
Checkpoint Inhibitors ◽  
Liver Graft ◽  
Immune Checkpoints ◽  
Term Survival ◽  
Liver Preservation ◽  
Programmed Death

Background: Immune checkpoint modulators, such as the programmed death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitor, cytotoxic T-Lymphocyte-associated antigen 4 (CTLA-4) inhibitor have been investigated with encouraging results for hepatocellular carcinoma (HCC). However, the safety of this strategy in patients with previous liver transplantation (LT) is not well studied. Objective: To explore the safety and feasibility of immune checkpoints inhibitors in recurrent and metastatic HCC patients on a background of LT. Methods: A case of recurrent, refractory, metastatic HCC after LT, where PD-1 inhibitor was initiated, was described and related literature was reviewed. Results: There was complete remission in lung metastases and the partial radiological response of metastatic retroperitoneal lymph node to the drug with no liver graft rejection after 13 cycles of PD- 1 inhibitor injection. PD-1inhibitor, at least in this patient, was verified to play an important role in controlling tumor progression and prolonging patient survival. Conclusions: This novel drug might be a useful method to allow doctors to guarantee a better chance for long-term survival in recurrent, metastatic HCC patients with the previous LT. However, it should be used with caution in allograft recipients due to the risk of acute graft rejection, further larger, prospective studies are needed to determine optimal immunomodulatory therapy to achieve optimal anti-tumor efficacy with transplant liver preservation.

scholarly journals Novel immune checkpoints beyond PD-1 in advanced melanoma

2021 ◽  
Author(s):  
Nina Zila ◽  
Christoph Hoeller ◽  
Verena Paulitschke
Keyword(s):  
Clinical Trials ◽  
Checkpoint Inhibitors ◽  
Short Review ◽  
Therapy Resistance ◽  
Advanced Melanoma ◽  
Immune Checkpoints ◽  
Malignant Diseases ◽  
Foreseeable Future ◽  
Cell Responses ◽  
Therapeutic Landscape

SummaryIn malignant diseases, targeting of immune checkpoints successfully changed the therapeutic landscape and helped to unleash anti-tumor T cell responses, resulting in durable clinical outcomes, but only in up to 50% of patients. The success of these therapies and the need to overcome intrinsic and acquired therapy resistance stimulated research to identify new pathways and targets. Numerous clinical trials are currently evaluating novel checkpoint inhibitors or recently developed strategies like modulating the tumor microenvironment, mostly in combination with approved therapies. This short review briefly discusses promising therapeutic targets, currently still under investigation, with the chance to realize clinical application in the foreseeable future.

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