The Safety of Therapeutic Monoclonal Antibodies: Implications for Cancer Therapy Including Immuno-Checkpoint Inhibitors

Monoclonal antibody-based treatment of cancer has been established as one of the most successful therapeutic strategies for both hematologic malignancies and solid tumors. In addition to targeting cancer antigens antibodies can also modulate immunological pathways that are critical to immune surveillance. Antibody therapy directed against several negative immunologic regulators (checkpoints) is demonstrating significant success in the past few years. Immune checkpoint inhibitors, ipilimumab, pembrolizumab and nivolumab, have shown significant clinical benefit in several malignancies and are already approved for advanced melanoma and squamous NSCLC. Based on their mechanism of action, these agents can exert toxicities that are unlike conventional cytotoxic chemotherapy, whose nature is close to autoimmune diseases - immune related adverse events (irAEs). In this review we focus on the spectrum of irAEs associated with immune checkpoint antibodies, discussing the pharmacological treatment strategy and possible clinical impact.

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Immune-related adverse events of immune checkpoint inhibitors: a brief review

Current Oncology ◽

10.3747/co.25.4235 ◽

2018 ◽

Vol 25 (5) ◽

Cited By ~ 41

Author(s):

G. Myers

Keyword(s):

Adverse Events ◽

Immune Checkpoint ◽

Health Care Professionals ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Hematologic Malignancies ◽

T Cell Response ◽

Proactive Management ◽

Organ Systems

Immune checkpoint inhibitors (icis) such as inhibitors of ctla-4, PD-1, and PD-L1, given as monotherapy or combination therapy have emerged as effective treatment options for immune-sensitive solid tumours and hematologic malignancies. The benefits of icis can be offset by immune-related adverse events (iraes) that leave all organ systems vulnerable and subsequently increase the risk for morbidity and mortality.Because of fluctuating onset and prolonged duration, the toxicities associated with iraes represent a shift from the understanding of conventional anticancer toxicities. The ctla-4 and PD-1/PD-L1 inhibitors modulate T-cell response differently, resulting in distinct toxicity patterns, toxicity kinetics, and dose–toxicity relationships. Using individualized patient education, screening, and assessment for the early identification of iraes is key to proactive management and is therefore key to improving outcomes and prolonging therapy.Management of iraes is guided by appropriate grading, which sets the stage for the treatment setting (outpatient vs. inpatient), ici treatment course (delay vs. discontinuation), supportive care, corticosteroid use, organ specialist consultation, and additional immunosuppression. Health care professionals in oncology must work collaboratively with emergency and community colleagues to facilitate an understanding of iraes in an effort to optimize seamless care.

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Agonistic CD40 antibody therapy induces tertiary lymphoid structures but impairs the response to immune checkpoint blockade in glioma

10.1101/2021.01.05.425377 ◽

2021 ◽

Author(s):

Luuk van Hooren ◽

Alessandra Vaccaro ◽

Mohanraj Ramachandran ◽

Konstantinos Vazaios ◽

Sylwia Libard ◽

...

Keyword(s):

T Cell ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Antibody Therapy ◽

Immune Checkpoint Blockade ◽

Cytotoxic T Cell ◽

Systemic Delivery ◽

T Cell Infiltration ◽

Tertiary Lymphoid Structures ◽

Lymphoid Structures

AbstractGliomas are brain tumors characterized by immunosuppression. Immunostimulatory agonistic CD40 antibodies (αCD40) are in clinical development for solid tumors but are yet to be evaluated for glioma. Here, systemic delivery of αCD40 led to cytotoxic T cell dysfunction and impaired the response to immune checkpoint inhibitors in preclinical glioma models. This was associated with an accumulation of suppressive CD11b+ B cells. However, αCD40 also induced tertiary lymphoid structures (TLS). In human glioma, TLS correlated with increased T cell infiltration indicating enhanced immune responses. Our work unveils the pleiotropic effects of αCD40 therapy in glioma, which is of high clinical relevance.

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ATIM-20. A RETROSPECTIVE STUDY EVALUATING THE SAFETY AND SURVIVAL OF THE COMBINATION OF PD-1 IMMUNE CHECKPOINT BLOCKADE AND BEVACIZUMAB IN RECURRENT GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noz175.019 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi5-vi5

Author(s):

Joshua Friedman ◽

Adilia Hormigo

Keyword(s):

Retrospective Study ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Recurrent Disease ◽

Checkpoint Inhibitors ◽

Immune Surveillance ◽

Immune Checkpoint Blockade ◽

Recurrent Glioblastoma ◽

Grade 3 ◽

Recurrent Gbm

Abstract INTRODUCTION Immune checkpoint inhibitors (ICI) have demonstrated clinical efficacy in a variety of cancers. It is known that cancer including glioblastoma (GBM) induces an immunosuppression. Bevacizumab by normalizing blood vessels in the tumor can facilitate immune surveillance and potentially improve the efficacy of ICI in GBM patients. We analyze GBM patients with recurrent disease treated with ICI and bevacizumab. METHODS We retrospectively review records of patients diagnosed with recurrent GBM treated at our institution with Pembrolizumab or Nivolumab and bevacizumab and evaluate for tolerance and outcomes. RESULTS Twenty-one patients, 12 men and 9 women with median age 62 (range 36–78) and KPS 70 (range 60–90) were treated with a median of 10 ICI cycles (range 4–29) and 5 of bevacizumab (range 0–21). A total of 8 patients (38%) had immune-related adverse events (IRAE): 3 grade 1, 3 grade 2 and 2 grade 3. A patient with pneumonitis required cessation of ICI. Median OS for the 21 patients was 22 months (range 6–41). The 7 patients that had MGMT detected in their tumors had a median OS of 27 months (range 23–41) compared to a survival of 21 months (range 6–24) for the 13 patients that had MGMT undetected. One had undetermined MGMT and her OS was 21 months. The median survival for all the patients from onset of ICI was 10 months (range 1–25) and 10 of them (47.6%) survived > 12 months. DISCUSSION The development of IRAE was common but self-limiting, allowing continuation of the treatment in all but one patient. The combination of ICI and bevacizumab increased survival. Our data needs to be interpreted with caution, as it is a retrospective analysis of a small group of patients. However, these results warrant prospective studies using the combination of ICI and bevacizumab to treat recurrent GBM.

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Immunmoduláló antitestek alkalmazása – az onkológia új fejezete

Orvosi Hetilap ◽

10.1556/oh.2016.30507 ◽

2016 ◽

Vol 157 (Supplement 2) ◽

pp. 9-16 ◽

Cited By ~ 1

Author(s):

Szilvia Szamosi ◽

László Váróczy ◽

Zoltán Szekanecz

Keyword(s):

Metastatic Melanoma ◽

Immune Checkpoint ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Hematologic Malignancies ◽

The United States ◽

Clinical Development ◽

Clinical Activity ◽

The European Union ◽

Tumor Types

In the past decade major advances in tumor immunology, a better understanding of antigen recognition by T-cells likewise discovering the regulatory inhibitory signals resulted in the development of new immunotherapies with promising durable responses in various solid tumor types and in hematologic malignancies. This review focuses on immunomodulatory antibodies, namely immune checkpoint inhibitor therapy. The prototype of this new class of immune stimulating agents was cytotoxic T-lymphocyte antigen-4 (CTLA-4) antagonists. After demonstrating enhanced survival, ipilimumab was approved first in the United States in 2011, further on in the European Union for second-line (2011) and for first-line therapy (2013) of metastatic melanoma. Additional T-cell intrinsic pathways were identified and targeted for clinical development. Antibodies blocking the PD-1 pathway also showed promising clinical activity and objective tumor response in several types of tumors, including metastatic melanoma, non-small- cell lung cancer. On the other hand antitumor activity is frequently accompanied by significant reversible immune-related adverse events. To explore potential new immune checkpoint targets bring forth several challanges. Future clinical development will involve identifying potential biomarkers anticipating responsiveness to pathway blockade and additional tumor types likely to respond to the therapy. Furthermore, combination strategies, immune checkpoint inhibitors combined with cancer vaccines, targeted inhibitors and traditional chemotherapies are being evaluated in pre-clinical studies. Orv. Hetil., 2016, 157(Suppl. 2), 9–16.

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Immunotherapy in Gynecologic Cancers: What We Know Now and Where We Are Headed

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_237967 ◽

2019 ◽

pp. e126-e140 ◽

Cited By ~ 8

Author(s):

Kimberly Levinson ◽

Oliver Dorigo ◽

Krista Rubin ◽

Kathleen Moore

Keyword(s):

Solid Tumors ◽

Solid Tumor ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Gynecologic Cancer ◽

Hematologic Malignancies ◽

Next Generation ◽

Gynecologic Cancers ◽

Clinical Benefits

Immunotherapy, mainly in the form of immune checkpoint inhibitors (ICIs), has been transformative in both solid tumor and hematologic malignancies. Patients with previously terminal illnesses have experienced profound responses of great durability with these agents, fueling excitement among patients and providers regarding their use. Unfortunately, the gains seen in some solid tumors have not been replicated in a large percentage of patients with gynecologic cancer. This review focuses on the clinical benefits seen to date, toxicities and management when using ICIs, ways to improve prediction of who should receive immunotherapy, and a discussion of next-generation immunotherapy with cellular therapeutics and how these might relate to gynecologic cancers.

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Infections in patients receiving immune checkpoint inhibitors.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.8_suppl.155 ◽

2019 ◽

Vol 37 (8_suppl) ◽

pp. 155-155

Author(s):

Sutthichai Sae-Tia ◽

Jarushka Naidoo ◽

Seema Mehta

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Viral Infections ◽

De Novo ◽

Checkpoint Inhibitors ◽

Laboratory Data ◽

Hematologic Malignancies ◽

Systemic Corticosteroids ◽

Improved Outcomes ◽

Infectious Diseases Consultation

155 Background: Immune checkpoint inhibitors (ICIs) - anti-PD-1 (nivolumab, pembrolizumab), anti-PD-L1 (atezolizumab, avelumab), anti-CTLA-4 (ipilimumab) - have improved outcomes for several malignancies. ICIs may cause immune-related adverse events (irAEs), often treated with immunosuppression. The incidence of infections arising de novo during ICI therapy or from immunosuppression for irAEs is not well described. Methods: In- and outpatients receiving ICIs were referred for Infectious Diseases consultation between 6/2011-6/2018. Twenty-five were randomly selected for retrospective summarization of the spectrum of infections. Diagnosis of infection was made by the primary oncologist, based upon clinical/radiographic/laboratory data. Results: Solid tumor (24, 96%) and hematologic malignancies (1, 4%) were represented (Table). All 25 had infections. 15 (60%) were male; median age 58 years (29-97). 17 (68%) had irAEs: pneumonitis (10, 40%), thyroiditis (5, 20%), colitis (5, 20%), hepatitis (4, 16%), dermatitis (4, 16%) and myocarditis (1, 4%). 17 (68%) patients developed +1 irAE. 50% with pneumonitis were concurrently treated for pneumonia. Of the 25, 17 (72%) developed de novo infections on ICIs; whereas others were receiving systemic corticosteroids (7, 28%) or infliximab (1, 4%). Initial infections included pneumonia (13, 52%), bacteremia (3, 12%), sinusitis (2, 8%), wound infection (2, 8%), viral infections (HSV, CMV, HCV; 1, 4% each) and 1 (4%) each of empyema, UTI, peritonitis, osteomyelitis, and meningitis. 44% (11) developed a second infection within 60 days of the first. Conclusions: Patients receiving ICIs for cancer developed a myriad of infections, both de novo during ICI therapy, or consequent to immunosuppression for irAEs. Second infections are common, occurring in nearly half the patients. Awareness of this is vital for early diagnosis and appropriate management. Patients with suspected ICI-related infection. (n=25). [Table: see text]

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Immune checkpoint blockade in the treatment of malignant tumor: current statue and future strategies

Cancer Cell International ◽

10.1186/s12935-021-02299-8 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Wenwen Yang ◽

Caining Lei ◽

Shaoming Song ◽

Wutang Jing ◽

Chuanwei Jin ◽

...

Keyword(s):

T Cells ◽

Malignant Tumor ◽

Immune Checkpoint ◽

Cytotoxic T Lymphocyte ◽

Malignant Tumors ◽

Checkpoint Inhibitors ◽

Immune Surveillance ◽

Immune Checkpoint Blockade ◽

Checkpoint Response ◽

Inhibitory Molecule

AbstractAfter being stagnant for decades, there has finally been a paradigm shift in the treatment of cancer with the emergence and application of immune checkpoint inhibitors (ICIs). The most extensively utilized ICIs are targeting the pathways involving programmed death-1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4). PD-1, as an crucial immune inhibitory molecule, by and large reasons the immune checkpoint response of T cells, making tumor cells get away from immune surveillance. Programmed cell death ligand-1 (PD-L1) is exceptionally expressed in most cancers cells and approves non-stop activation of the PD-1 pathway in the tumor microenvironment. PD-1/PD-L1 inhibitors can block the combination of PD-1 and PD-L1, inhibit hostile to regulatory signals, and restore the activity of T cells, thereby bettering immune response. The current researchers assume that the efficacy of these drugs is related to PD-L1 expression in tumor tissue, tumor mutation burden (TMB), and other emerging biomarkers. Although malignant tumors can benefit from the immunotherapy of PD-1/PD-L1 inhibitors, formulating a customized medication model and discovering biomarkers that can predict efficacy are the new trend in the new era of malignant tumor immunotherapy. This review summarizes the mechanism of action of PD-1/PD-L1 inhibitors, their clinical outcomes on various malignant tumors, their efficacy biomarkers, as well as predictive markers of irAEs.

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Epigenetic Mechanisms of Resistance to Immune Checkpoint Inhibitors

Biomolecules ◽

10.3390/biom10071061 ◽

2020 ◽

Vol 10 (7) ◽

pp. 1061 ◽

Cited By ~ 1

Author(s):

Alexandre Perrier ◽

Audrey Didelot ◽

Pierre Laurent-Puig ◽

Hélène Blons ◽

Simon Garinet

Keyword(s):

Dna Methylation ◽

Tumor Microenvironment ◽

Solid Tumors ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Immune Surveillance ◽

Response Rates ◽

Cell Phenotype ◽

Epigenetic Biomarkers

Immune checkpoint inhibitors (ICIs) have demonstrated to be highly efficient in treating solid tumors; however, many patients have limited benefits in terms of response and survival. This rapidly led to the investigation of combination therapies to enhance response rates. Moreover, predictive biomarkers were assessed to better select patients. Although PD-L1 expression remains the only validated marker in clinics, molecular profiling has brought valuable information, showing that the tumor mutation load and microsatellite instability (MSI) status were associated to higher response rates in nearly all cancer types. Moreover, in lung cancer, EGFR and MET mutations, oncogene fusions or STK11 inactivating mutations were associated with low response rates. Cancer progression towards invasive phenotypes that impede immune surveillance relies on complex regulatory networks and cell interactions within the tumor microenvironment. Epigenetic modifications, such as the alteration of histone patterns, chromatin structure, DNA methylation status at specific promoters and changes in microRNA levels, may alter the cell phenotype and reshape the tumor microenvironment, allowing cells to grow and escape from immune surveillance. The objective of this review is to make an update on the identified epigenetic changes that target immune surveillance and, ultimately, ICI responses, such as histone marks, DNA methylation and miR signatures. Translational studies or clinical trials, when available, and potential epigenetic biomarkers will be discussed as perspectives in the context of combination treatment strategies to enhance ICI responses in patients with solid tumors.

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Immune Checkpoint Inhibitors in AML-A New Frontier

Current Cancer Drug Targets ◽

10.2174/1568009620666200421081455 ◽

2020 ◽

Vol 20 (7) ◽

pp. 545-557

Author(s):

Rohit Thummalapalli ◽

Hanna A. Knaus ◽

Ivana Gojo ◽

Joshua F. Zeidner

Keyword(s):

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Immune Dysfunction ◽

Cytotoxic Chemotherapy ◽

Immune Checkpoints ◽

Clinical Activity ◽

Cell Mediated Immunity ◽

Hypomethylating Agents ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition

Despite recent therapeutic advancements, acute myeloid leukemia (AML) remains a challenging clinical entity with overall poor outcomes. Given the evident role of T cell-mediated immunity in response to allogeneic stem cell transplantation and donor lymphocyte infusions, strategies that enhance immune activation and mitigate immune dysfunction represent attractive therapeutic platforms to improve clinical outcomes in AML. Pre-clinical data suggest that immune dysfunction is a major contributor to AML progression and relapse. Increased expression of immune checkpoints such as programmed death 1 (PD-1) contributes to AML immune evasion and is associated with disease progression. Immune checkpoint inhibition is being explored in AML with early evidence of clinical activity, particularly in combination with cytotoxic chemotherapy and hypomethylating agents. In this review, we explore the scientific rationale behind the use of immune checkpoint inhibition either as single agents or in combination with hypomethylating agents or cytotoxic chemotherapy and provide a clinical update of both completed and ongoing trials in AML.

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Association of systemic anticancer therapy with an increased risk of death in hospitalized COVID-19 positive oncology patients.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e18594 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e18594-e18594

Author(s):

David Jacob Hermel ◽

Samantha R. Spierling Bagsic ◽

Munveer Singh Bhangoo ◽

Kathryn Blount Bollin ◽

James R. Mason ◽

...

Keyword(s):

Solid Tumors ◽

Metastatic Disease ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Hematologic Malignancy ◽

Anticancer Therapy ◽

Cytotoxic Chemotherapy ◽

Lung Involvement ◽

Risk Of Death

e18594 Background: Malignancy is thought to be an independent risk factor for increased COVID-19 morbidity and mortality. However, neoplastic diseases encompass a heterogenous group of pathologic processes, and further stratification of those patients prone to severe disease is necessary. We sought to identify predictors of poor COVID-19 outcomes among hospitalized patients with malignancy. Methods: We retrospectively reviewed all patients with a diagnosis of hematologic and solid tumor malignancy within the regional Scripps Health hospital system in San Diego County from March 1, 2020 to January 5, 2021 with a PCR confirmed diagnosis of COVID-19. Cancer diagnoses were confirmed via manual chart review; in situ non-melanoma skin cancers were excluded. Only hospitalizations greater than one day were included in the analysis and readmissions were excluded. Outcomes of interest included admission to the ICU, intubation during hospitalization, and death. Associations between outcomes of interest and tumor types, metastatic disease (with or without lung involvement) and those receiving active systemic anticancer therapy (treatment within 3 months of admission) were determined using univariable logistic regression analyses. The study was approved by the Scripps Health Institutional Review Board. Systemic anticancer therapy included cytotoxic chemotherapy, immunomodulators, immune checkpoint inhibitors, and other targeted therapies. Results: Among a total of 2,771 hospitalized patients, 204 (7.36%) met inclusion criteria. The average age was 72.7 years, 48.5% were male, 33.3% were Hispanic and the average BMI was 27.5. The majority of patients (82.8%) had solid tumors, with the most prevalent being breast carcinoma (17.6%) and prostate carcinoma (17.2%). Overall, 21.9% had metastatic disease and 16% had lung involvement. 17.2% had been receiving active cancer systemic treatment. On univariate analysis, patients who were actively receiving treatment had an increased rate of death (37.1% vs 18.9%, OR: 2.5 (1.1-5.5) p= .021). Among patients receiving systemic anticancer therapy, 48.6% received cytotoxic chemotherapy, 5.7% immune checkpoint inhibitors, 22.9% immunomodulators, 17.1% molecularly targeted agents and 2.7% other agents. Moreover, there was a trend towards increased mortality in those with lung involvement (33.3% vs 17.6%, OR: 2.3 (0.9-5.7) p= .067) and those with hematologic malignancy (31.4% vs 20.1%, OR: 0.5 (0.2-1.3) p = 0.146). Conclusions: Among patients hospitalized with a diagnosis of cancer, systemic anticancer therapy was associated with a significantly increased odds of death. Other factors potentially increasing risk of death include hematologic malignancy and solid tumors with lung involvement. Further validation of these findings in a larger sample could impact therapeutic decision making during the COVID-19 pandemic.

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