Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance

Immune checkpoint inhibitors (ICIs) have made an indelible mark in the field of cancer immunotherapy. Starting with the approval of anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA-4) for advanced-stage melanoma in 2011, ICIs—which now also include antibodies against programmed cell death 1 (PD-1) and its ligand (PD-L1)—quickly gained US Food and Drug Administration approval for the treatment of a wide array of cancer types, demonstrating unprecedented extension of patient survival. However, despite the success of ICIs, resistance to these agents restricts the number of patients able to achieve durable responses, and immune-related adverse events complicate treatment. Thus, a better understanding of the requirements for an effective and safe antitumor immune response following ICI therapy is needed. Studies of both tumoral and systemic changes in the immune system following ICI therapy have yielded insight into the basis for both efficacy and resistance. Ultimately, by building on these insights, researchers should be able to combine ICIs with other agents, or design new immunotherapies, to achieve broader and more durable efficacy as well as greater safety. Here, we review the history and clinical utility of ICIs, the mechanisms of resistance to therapy, and local and systemic immune cell changes associated with outcome. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 16 is January 25, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Gut Microbiota and Immune Checkpoint Inhibitors-Based Immunotherapy

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520621666210706110713 ◽

2021 ◽

Vol 21 ◽

Author(s):

Mingming Tian ◽

Si Zhang ◽

Yujen Tseng ◽

Xizhong Shen ◽

Ling Dong ◽

...

Keyword(s):

Immune System ◽

Gut Microbiota ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Recent Progress ◽

Checkpoint Inhibitors ◽

Antitumor Response ◽

Number Of Patients ◽

Cancer Types ◽

Patients Experience

: Application of immune checkpoint inhibitors (ICIs) is a major breakthrough in the field of cancer therapy, which has displayed tremendous potential in various types of malignancies. However, their response rates range widely in different cancer types and a significant number of patients experience immune-related adverse effects (irAEs) induced by these drugs, limiting the proportion of patients who can truly benefit from ICIs. Gut microbiota has gained increasing attention due to its emerging role in regulating the immune system. In recent years, numerous studies have shown that gut microbiota can modulate antitumor response, as well as decrease the risk of colitis due to ICIs in patients receiving immunotherapy. The present review analyzed recent progress of relevant basic and clinical studies in this area and explored new perspectives to enhance the efficacy of ICIs and alleviate associated irAEs via manipulation of the gut microbiota.

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Combinatorial immunotherapies overcome MYC-driven immune evasion

10.1101/2021.05.07.442684 ◽

2021 ◽

Author(s):

Joyce V. Lee ◽

Filomena Houseley ◽

Christina Yau ◽

Daniel Van de Mark ◽

Rachel Nakagawa ◽

...

Keyword(s):

Tumor Cell ◽

Immune Evasion ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Immune Cell ◽

Tumor Regression ◽

Checkpoint Inhibitors ◽

Mhc I ◽

Number Of Patients ◽

Tumor Outgrowth

For many human cancers, including triple negative breast cancer (TNBC), a modest number of patients benefit from immune checkpoint inhibitors, and few experience cancer remission. Expression of programed death-ligand 1 (PD-L1), tumor immune infiltration, or tumor mutation burden have been widely investigated for predicting cancer immunotherapy response. Whether specific oncogenes diminish response to immunotherapy and whether these effects are reversible remains poorly understood. We predicted that MYC, an oncogene that is frequently overexpressed and is associated with worse prognosis, may predict immunotherapy response in patients with TNBC. Here, we report that MYC-elevated TNBCs are resistant to immune checkpoint inhibitors. Using mouse models of TNBC and patient data we report that MYC signaling is associated with low tumor cell PD-L1, low overall immune cell infiltration, and low tumor cell MHC-I expression. Restoring interferon signaling in the tumor reduces MYC expression and increases MHC-I expression. By combining a TLR9 agonist and an agonistic antibody against OX40 with anti-PD-L1, most mice experience complete tumor regression and are protected from new TNBC tumor outgrowth. Our findings demonstrate that MYC-dependent immune evasion is reversible and druggable, and if strategically targeted, may improve outcomes for patients treated with immune checkpoint inhibitors.

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Exclusive Cutaneous and Subcutaneous Sarcoidal Granulomatous Inflammation due to Immune Checkpoint Inhibitors: Report of Two Cases with Unusual Manifestations and Review of the Literature

Case Reports in Dermatological Medicine ◽

10.1155/2019/6702870 ◽

2019 ◽

Vol 2019 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Narciss Mobini ◽

Rummit Dhillon ◽

Jason Dickey ◽

Jordan Spoon ◽

Kaviyon Sadrolashrafi

Keyword(s):

T Cell ◽

T Cell Activation ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Cell Activation ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Granulomatous Inflammation ◽

Number Of Patients ◽

Recent Emergence

Recent emergence of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of cancers and produced prolonged response by boosting the immune system against tumor cells. The primary target antigens are cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), a downregulator of T-cell activation, and programmed cell death-1 receptor (PD-1), a regulator of T-cell proliferation. This enhanced immune response can induce autoimmune adverse effects in many organs. Although skin toxicities are the most common, sarcoidal inflammation with exclusive cutaneous involvement is a rare occurrence with only 6 cases reported to date. We report 2 cases with unusual features. One patient is a female who was treated for metastatic renal cell carcinoma with combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1). She developed deep nodules showing sarcoidal dermatitis and panniculitis on histopathologic exam. The second patient is a male with melanoma of eyelid conjunctiva who was treated prophylactically with ipilimumab. He presented with papules/plaques confined to black tattoos, where the biopsy revealed sarcoidal dermatitis. By a comprehensive literature review, we intend to raise awareness about this potential skin side effect in the growing number of patients receiving targeted immunotherapies. It is crucial to have a high index of suspicion and perform timely biopsies to implement appropriate management strategies.

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Immune Checkpoint Blockade in Gynecologic Cancers: State of Affairs

Cancers ◽

10.3390/cancers12113301 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3301

Author(s):

Maureen L. Drakes ◽

Cheryl M. Czerlanis ◽

Patrick J. Stiff

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Gynecologic Cancer ◽

Immune Checkpoint Blockade ◽

Gynecologic Cancers ◽

Programmed Death 1 ◽

Cancer Types ◽

State Of Affairs

This review provides an update on the current use of immune checkpoint inhibitors (ICI) in female gynecologic cancers, and it addresses the potential of these agents to provide therapy options for disease management and long-term remission in advanced disease patients, where surgery, chemotherapy, and/or radiation fail to meet this goal. The topic of immune checkpoint inhibitors (ICI) blocking cytotoxic T lymphocyte associated protein-4 (CTLA-4) and the programmed death-1 (PD-1) axis has come to the forefront of translational medicine over the last decade for several malignancies. The text will focus primarily on a discussion of ovarian cancer, which is the most frequent cause of death of gynecologic cancers; endometrial cancer, which is the most often diagnosed gynecologic cancer; and cervical cancer, which is the third most common female gynecologic malignancy, all of which unfavorably alter the lives of many women. We will address the critical factors that regulate the outcome of these cancer types to ICI therapy, the ongoing clinical trials in this area, as well as the adverse immune responses that impact the outcome of patients given ICI regimens.

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Current and Future Scenario of Immunotherapy for the Treatment of Hepatocellular Carcinoma

Current Cancer Therapy Reviews ◽

10.2174/1573394716999200818103724 ◽

2020 ◽

Vol 16 ◽

Author(s):

Shvetank Bhatt ◽

Jovita Kanoujia ◽

Arghya Kusum Dhar ◽

Rakesh Kumar Singh ◽

Jayaraman Rajangam

Keyword(s):

Hepatocellular Carcinoma ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Check Point ◽

Programmed Death ◽

Check Point Inhibitors ◽

Cancer Types ◽

Programed Cell Death

: The discovery of the immune checkpoint inhibitors such as programed cell death-1 protein/Programmed death ligand-1 or 2 and (PD-1/PD-L1 or PD-L2) and Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) paved the way for developing novel cancer treatment. The check point inhibitors are found to be very efficient in treating many hot tumors (with immune environment) such as bladder cancer, melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC) etc. Numerous clinical trials have been initiated to evaluate the safety and effectiveness of immune checkpoint inhibitors for patients with different cancer types, including hepatocellular carcinoma (HCC), pancreatic and prostate cancer. The results and findings of these trials are highly appreciated. However the search of check point inhibitors with better efficacy for the treatment of HCC is still going on. The present review focuses on advancement in HCC treatments with respect to various standard therapies and immunotherapy.

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Autoimmune Endocrinopathies: An Emerging Complication of Immune Checkpoint Inhibitors

Annual Review of Medicine ◽

10.1146/annurev-med-050219-034237 ◽

2020 ◽

Vol 72 (1) ◽

Author(s):

Zoe Quandt ◽

Arabella Young ◽

Ana Luisa Perdigoto ◽

Kevan C. Herold ◽

Mark S. Anderson

Keyword(s):

Immune Suppression ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Thyroid Dysfunction ◽

Checkpoint Inhibitors ◽

Tumor Control ◽

Annual Review ◽

Publication Date ◽

Malignant Growth ◽

Specific Organ

Immune checkpoint inhibitors (CPIs) reverse immune suppression that is thought to allow malignant growth. Despite remarkable efficacy in a subset of cancers, their use is accompanied by immune-related adverse events, including endocrinopathies such as hypophysitis, thyroid dysfunction, diabetes, and adrenalitis. These conditions are heterogenous, with differing incidence across CPI types, but are unified by the acuity and extremity of tissue-specific organ failure. Their occurrence may be associated with beneficial tumor control. Further understanding of the risk factors and mechanisms of these endocrine immunotoxicities can help optimize CPI use as well as improve understanding of spontaneous autoimmune diseases. Expected final online publication date for the Annual Review of Medicine, Volume 72 is January 27, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Immune Checkpoint Inhibitors: Basics and Challenges

Current Medicinal Chemistry ◽

10.2174/0929867324666170804143706 ◽

2019 ◽

Vol 26 (17) ◽

pp. 3009-3025 ◽

Cited By ~ 8

Author(s):

Bin Li ◽

Ho Lam Chan ◽

Pingping Chen

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Complete Response ◽

Modern World ◽

Basic Principles ◽

Mutation Status ◽

Anti Cancer ◽

Cancer Types ◽

Shed Light

Cancer is one of the most deadly diseases in the modern world. The last decade has witnessed dramatic advances in cancer treatment through immunotherapy. One extremely promising means to achieve anti-cancer immunity is to block the immune checkpoint pathways – mechanisms adopted by cancer cells to disguise themselves as regular components of the human body. Many review articles have described a variety of agents that are currently under extensive clinical evaluation. However, while checkpoint blockade is universally effective against a broad spectrum of cancer types and is mostly unrestricted by the mutation status of certain genes, only a minority of patients achieve a complete response. In this review, we summarize the basic principles of immune checkpoint inhibitors in both antibody and smallmolecule forms and also discuss potential mechanisms of resistance, which may shed light on further investigation to achieve higher clinical efficacy for these inhibitors.

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363 Vactosertib and durvalumab as second or later line treatment for PD-L1 positive non-small cell lung cancer: interim result

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0363 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A388-A388

Author(s):

Byoung Chul Cho ◽

Ki Hyeong Lee ◽

Ji-Youn Han ◽

Byoung Yong Shim ◽

Hye Ryun Kim ◽

...

Keyword(s):

Immune Checkpoint ◽

Objective Response Rate ◽

Immune Checkpoint Inhibitors ◽

Advanced Nsclc ◽

Response Rate ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Platinum Based Chemotherapy ◽

Number Of Patients ◽

Anti Tumor Activity

BackgroundTargeting transforming growth factor-β (TGF-β) is reported to augment the efficacy of immune checkpoint inhibitors (ICIs) through either enhanced anti-tumor immunity or the correction of tumor microenvironment (TME). Therefore, the combination of vactosertib, a highly selective TGF-β RI kinase inhibitor, and durvalumab is anticipated to improve anti-tumor activity of the ICI. A phase 1b/2a study was conducted to evaluate the combination of vactosertib and durvalumab in patients with advanced NSCLC who progressed after platinum-based chemotherapy.MethodsPatients were treated with vactosertib at a dose of 200 mg twice daily (five days on and two days off) and durvalumab at a dose of 1500 mg every four weeks. Eligible patients were ≥19 years old with good performance status (ECOG 0–1) and have no prior exposure to immune checkpoint inhibitors or other TGF- β R1 kinase inhibitors. The objectives of this analysis were to evaluate the safety, antitumor activity including objective response rate (ORR), duration of response (DOR), and time to response (TTR) as well as circulating pharmacodynamic biomarkers related to TGF-β signaling. Response was assessed per RECIST (v1.1).ResultsBy August 4 2020, twenty-six PD-L1 positive (SP263 assay) patients were analyzed. Median age was 61.5 years (range 48–83), 69.2% were male, median number of previous lines of chemotherapy was 1 (range 1–4), and all patients were PD-L1 positive (15 patients with PD-L1≥25% and 11 patients with PD-L1 1–24%). The most frequently reported treatment-related adverse events (TRAE) were itching (38.5%) and skin rash (34.6%), but no Gr≥3 itching and rash were observed. Each case of the following was reported as Grade 3 TRAEs: adrenal insufficiency, anemia, and pneumonitis; Grade 4 TRAE, CPK increase, was observed in one patient. Objective response rate was 30.8% and 40.0% in patients with PD-L1≥1% and ≥25% respectively. Circulating PAI-1 and CTGF evaluated in 15 patients decreased significantly on Cycle 1 day 5. Ongoing biomarker results will be presented.ConclusionsThe combination of vactosertib and durvalumab has demonstrated a manageable safety profile and encouraging anti-tumor activity as a potential therapeutic strategy in patients with advanced NSCLC. The efficacy outcomes of this combination in a larger number of patients with advanced NSCLC will be followed.Trial RegistrationNCT03732274Ethics ApprovalThe study was approved by Ethics Board of Severance Hospital (4-2018-0892), National Cancer Center (NCC2019-0057), St. Vincent’s Hospital (VC19MDDF0205), and Chungbuk National University Hospital (2019-08-015).

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Determinants of resistance to VEGF-TKI and immune checkpoint inhibitors in metastatic renal cell carcinoma

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01961-3 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Revati Sharma ◽

Elif Kadife ◽

Mark Myers ◽

George Kannourakis ◽

Prashanth Prithviraj ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Immune Checkpoint ◽

Renal Cell ◽

Immune Checkpoint Inhibitors ◽

Kinase Inhibitors ◽

Checkpoint Inhibitors ◽

Resistance Mechanisms ◽

Number Of Patients ◽

Angiogenesis Pathway

AbstractVascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) have been the mainstay of treatment for patients with advanced renal cell carcinoma (RCC). Despite its early promising results in decreasing or delaying the progression of RCC in patients, VEGF-TKIs have provided modest benefits in terms of disease-free progression, as 70% of the patients who initially respond to the treatment later develop drug resistance, with 30% of the patients innately resistant to VEGF-TKIs. In the past decade, several molecular and genetic mechanisms of VEGF-TKI resistance have been reported. One of the mechanisms of VEGF-TKIs is inhibition of the classical angiogenesis pathway. However, recent studies have shown the restoration of an alternative angiogenesis pathway in modulating resistance. Further, in the last 5 years, immune checkpoint inhibitors (ICIs) have revolutionized RCC treatment. Although some patients exhibit potent responses, a non-negligible number of patients are innately resistant or develop resistance within a few months to ICI therapy. Hence, an understanding of the mechanisms of VEGF-TKI and ICI resistance will help in formulating useful knowledge about developing effective treatment strategies for patients with advanced RCC. In this article, we review recent findings on the emerging understanding of RCC pathology, VEGF-TKI and ICI resistance mechanisms, and potential avenues to overcome these resistance mechanisms through rationally designed combination therapies.

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Immune checkpoint inhibitors-related myocarditis in patients with cancer: an analysis of international spontaneous reporting systems

BMC Cancer ◽

10.1186/s12885-020-07741-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Rulan Ma ◽

Quanziang Wang ◽

Deyu Meng ◽

Kang Li ◽

Yong Zhang

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Adverse Drug Events ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Adverse Event Reporting System ◽

Adverse Event Reporting ◽

Reporting Odds Ratio ◽

Real World Data ◽

Safety Issues

Abstract Background Immune checkpoint inhibitors-induced myocarditis presents unique clinical challenges. Here, we assessed post-marketing safety of cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), programmed cell death-1 (PD-1), and programmed death-ligand 1 (PD-L1) inhibitors by mining the real-world data reported in two international pharmacovigilance databases. Methods We analyzed immune checkpoint inhibitors (ICIs)-associated fatal adverse drug events (ADEs) reports from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) collected from July 1, 2014 to December 31, 2019 and data from EudraVigilance (EV) database accessed on February 29, 2020. Three different data mining approaches were used to detect the signal of fatal myocarditis caused by ICIs. Results Based on 7613 ICIs-related ADEs reported to the EV database and 5786 ICIs-associated ADEs submitted to the FAERS database, the most frequently reported ADE was ipilimumab-related colitis. For myocarditis, nivolumab-associated myocarditis was the most common. Among the five fatal toxic effects associated with ICIs, the lethality rate of myocarditis was the highest. Therefore, we further analyzed ICI-associated myocarditis and found that elderly patients and male patients were more likely to develop ICIs-related myocarditis. The results of signal detection showed that the risk signal of avelumab-related myocarditis detected by reporting odds ratio (ROR) method and proportional reporting ratios (PRR) method was the highest, whereas the signal strength of ipilimumab-related myocarditis detected by Bayesian confidence propagation neural networks (BCPNN) method was the strongest. Conclusion The findings of this study indicated the potential safety issues of developing myocarditis when using ICIs, which were consistent with the results of previous clinical trials and could provide a reference for clinical workers when using ICIs.

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