Abstract 4289: Targeting of phosphatidylserine by monoclonal antibodies enhances the activity of immune checkpoint inhibitors in breast tumors

Recently immune checkpoint inhibitors amazingly changed the landscape of cancer therapy worldwide. The number of immune checkpoint molecules in clinical practice is constantly increasing. There are some monoclonal antibodies recently registered in the Russian Federation: anti-PD1 antibodies (nivolumab, pembrolizumab), anti-PD-L1 (atezolizumab, durvalumab), anti-CTLA-4 (ipilimumab). Immune-mediated endocrinopathies are some of the most common complications of immunotherapy. According to the results of clinical studies, the incidence of serious endocrine immuno-mediated adverse events with anti-PD1 monoclonal antibodies is low (3.5–8%). The use of anti-CTLA4 antibodies, combined regimens, and the use of immunotherapy after chemoradiotherapy significantly increase the incidence of serious adverse events to 30%. In clinical practice of N.N. Blokhin Cancer Research Center among 245 non-small cell lung cancer and hepatocellular carcinoma patients treated with immunotherapy, 22 (8,9%) developed an immune-mediated endocrinopathy. Most patients developed adverse events of 1–2 degrees, in two patients – 3 degrees, requiring discontinuation of treatment. The aim of this article was to provide useful information and recommendations regarding the management of common immuno-related endocrine adverse events (including hypothyroidism, hyperthyroidism, pituitary, adrenal insufficiency) for clinical oncologists.

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Tumor-Infiltrating Lymphocytes and Breast Cancer: Are Immune Checkpoint Inhibitors Ready for Prime Time in Breast Cancer?

Acta Facultatis Medicae Naissensis ◽

10.1515/afmnai-2016-0026 ◽

2016 ◽

Vol 33 (4) ◽

pp. 237-246 ◽

Cited By ~ 1

Author(s):

Ana Cvetanović ◽

Slađana Filipović ◽

Nikola Živković ◽

Miloš Kostić ◽

Svetislav Vrbić ◽

...

Keyword(s):

Breast Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Tumor Biology ◽

Predictive Biomarkers ◽

Tumor Infiltrating Lymphocytes ◽

Breast Tumors ◽

Prime Time ◽

Infiltrating Lymphocytes

SummaryIn recent years, results obtained from different studies with large cohorts have revealed a bond between the presence of extensive lymphocytic infiltration and favourable prognostic associations in the early-stage of breast cancer (BC) and high response rates to neoadjuvant chemotherapy. Examiners used tumors from large cohorts of patients who took part in randomized neoadjuvant and adjuvant clinical trials. The importance of tumor infiltrating lymphocytes (TILs) appears to be subtype-specific and varies depending on the histological characteristics of the tumor. TILs have proven to be a good prognostic marker, but only in highly proliferative breast tumors such as triple negative breast tumors (TNBC) or HER 2 positive BC.In the era when standard, well-known, prognostic and predictive biomarkers are ever changing and the use of molecular profiling analyses are increasing, we are looking for techniques to improve our understanding of tumor biology and improve patient outcome. The relevance of TILs cannot be ignored but needs to be properly evaluated in larger prospective studies which must encompass the parameters set out in previous studies. The use of TILs as prognostic biomarkers in early breast cancer may represent a new dawn, and use of immunotherapy, especially immune checkpoint inhibitors, probably is the future for the breast cancer but it is not yet ready for prime time.

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Autoimmune Endocrine Dysfunctions Associated with Cancer Immunotherapies

International Journal of Molecular Sciences ◽

10.3390/ijms20102560 ◽

2019 ◽

Vol 20 (10) ◽

pp. 2560 ◽

Cited By ~ 22

Author(s):

Silvia Martina Ferrari ◽

Poupak Fallahi ◽

Giusy Elia ◽

Francesca Ragusa ◽

Ilaria Ruffilli ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Clinical Signs ◽

Gonadal Hormones ◽

Thyroid Storm ◽

Insulin Dependent ◽

Cancer Immunotherapies ◽

Thyroid Dysfunctions

Immune checkpoint inhibitors block the checkpoint molecules. Different types of cancer immune checkpoint inhibitors have been approved recently: CTLA-4 monoclonal antibodies (as ipilimumab); anti-PD-1 monoclonal antibodies (as pembrolizumab and nivolumab); and anti-PD-L1 monoclonal antibodies (as atezolizumab, avelumab, and durmalumab). We collect recent published results about autoimmune endocrine dysfunctions associated with cancer antibody immunotherapies. These agents cause a raised immune response leading to immune-related adverse events (irAEs), varying from mild to fatal, based on the organ system and severity. Immune-related endocrine toxicities are usually irreversible in 50% of cases, and include hypophysitis, thyroid dysfunctions, type 1 diabetes mellitus, and adrenal insufficiency. Anti-PD-1-antibodies are more frequently associated with thyroid dysfunctions (including painless thyroiditis, hypothyroidism, thyrotoxicosis, or thyroid storm), while the most frequent irAE related to anti-CTLA-4-antibodies is hypophysitis. The combination of anti-CTLA-4 and anti-PD-1 antibodies is associated with a 30% chance of irAEs. Symptoms and clinical signs vary depending on the target organ. IrAEs are usually managed by an oncological therapist, but in more challenging circumstances (i.e., for new onset insulin–dependent diabetes, hypoadrenalism, gonadal hormones dysfunctions, or durable hypophysitis) an endocrinologist is needed.

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Evaluation of tolerability and reactions of immune checkpoint inhibitors.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e14605 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e14605-e14605 ◽

Cited By ~ 2

Author(s):

Ozlem Nuray Sever ◽

Ozlem Sonmez ◽

Osman Gokhan Demir

Keyword(s):

Monoclonal Antibodies ◽

Side Effects ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Treatment Interruption ◽

Ease Of Use ◽

Treatment Change ◽

Function Test ◽

Cessation Of Treatment

e14605 Background: Immunotherapies have revolutionized the treatment of cancer, especially in recent years. Today, there are anti-CTLA-4 antibodies and PD-L1 monoclonal antibodies which are active in use as checkpoint inhibitors. Side effects of these agents have a different spectrum in the form of immuno-related side effects. Methods: In this study, we aimed to evaluate the side effect and tolerability in patients treated with immune checkpoint inhibitors in our clinic. Results: 32 patients who were treated with PD-L1 monoclonal antibodies between August 2015 and January 2017 were screened retrospectively in our clinic. Six of the cases had immuno-related side effects (18.75%). 2 patients had a elevated liver function test. Both patients were diagnosed with NSCLC. In both of them, elevation was detected in the second course of nivolumab treatment, and the USG and hepatitis markers of the patients were normal. Enzymes returned to normal after treatment interruption. In a patient diagnosed with malignant melanoma that receiving pembrolizumab colitis was developed after 3th cycles of the therapy. The treatment of the patient who recovered after steroid administration and treatment interruption continued until the 8th cure. In the third cure of the patient with NSCLC, when nivolumab was used pneumonitis was diagnosed. Steroid treatment was applied for 2 weeks. Our patient continued to use nivolumab for up to 22 cycles. In our patient with malign melanoma that treated with pembrolizumab autoimmune thyroiditis developed. We started prednisolone treatment. After recovery our patient's treatment continued. In one of our patient who was diagnosed with malign melanoma, after the second cure of the treatment, diffuse edema and shortness of breath due to heart failure was detected. Echocardiography revealed a low ejection fraction. Methylprednisolone was started by cessation of treatment. Control ejection fractions normalized. Conclusions: İmmuno-related side effects were regarded as manageable side effects and no treatment change was needed. Immune Checkpoint inhibitors, which have been shown to be useful for survival every day, are proceeding to take a favorable position in the treatment of cancer with ease of use and lack of side effects.

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Current Immunotherapeutic Approaches in T Cell Non-Hodgkin Lymphomas

Cancers ◽

10.3390/cancers10090339 ◽

2018 ◽

Vol 10 (9) ◽

pp. 339 ◽

Cited By ~ 6

Author(s):

Teresa Poggio ◽

Justus Duyster ◽

Anna Illert

Keyword(s):

Clinical Trials ◽

Monoclonal Antibodies ◽

T Cell ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Tumor Antigens ◽

Checkpoint Inhibitors ◽

Cell Physiology ◽

Cell Therapies ◽

Car T

T cell non-Hodgkin lymphoma (T-NHL) is a rare and heterogeneous group of neoplasms of the lymphoid system. With the exception of a few relatively indolent entities, T-NHL is typically aggressive, treatment resistant, and associated with poor prognosis. Relatively few options with proven clinical benefit are available for patients with relapsed or refractory disease. Immunotherapy has emerged as a promising treatment for the management of patients with hematological malignancies. The identification of tumor antigens has provided a large number of potential targets. Therefore, several monoclonal antibodies (alemtuzumab, SGN-30, brentuximab vedotin, and mogamulizumab), directed against tumor antigens, have been investigated in different subtypes of T-NHL. In addition to targeting antigens involved in cancer cell physiology, antibodies can stimulate immune effector functions or counteract immunosuppressive mechanisms. Chimeric antigen receptor (CAR)-T cells directed against CD30 and immune checkpoint inhibitors are currently being investigated in clinical trials. In this review, we summarize the currently available clinical evidence for immunotherapy in T-NHL, focusing on the results of clinical trials using first generation monoclonal antibodies, new immunotherapeutic agents, immune checkpoint inhibitors, and CAR-T cell therapies.

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PolyI:C and CpG Synergize with Anti-ErbB2 mAb for Treatment of Breast Tumors Resistant to Immune Checkpoint Inhibitors

Cancer Research ◽

10.1158/0008-5472.can-16-1873 ◽

2016 ◽

Vol 77 (2) ◽

pp. 312-319 ◽

Cited By ~ 19

Author(s):

Roxanne Charlebois ◽

Bertrand Allard ◽

David Allard ◽

Laurence Buisseret ◽

Martin Turcotte ◽

...

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Breast Tumors

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Immune checkpoint inhibitors in advanced or metastatic mucosal melanoma: a systematic review

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835920922028 ◽

2020 ◽

Vol 12 ◽

pp. 175883592092202 ◽

Cited By ~ 3

Author(s):

Jiarui Li ◽

Haoxuan Kan ◽

Lin Zhao ◽

Zhao Sun ◽

Chunmei Bai

Keyword(s):

Systematic Review ◽

Monoclonal Antibodies ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Single Agent ◽

Progression Free Survival ◽

Mucosal Melanoma ◽

One Year

Background: Conventional cytotoxic chemotherapy offers minor benefit to patients with mucosal melanoma (MM). Although immune checkpoint inhibitors (ICIs) have become the preferred approach in patients with advanced or metastatic cutaneous melanoma, the evidence of their clinical use for MM is still limited. This systematic review aims to summarize the efficacy and safety of ICIs in advanced or metastatic MM. Methods: We searched electronic databases, conference abstracts, clinical trial registers and reference lists for relevant studies. The primary outcomes included the overall response rate (ORR), median progression-free survival (PFS), median overall survival (OS), one-year PFS rate, and one-year OS rate. Results: This review identified 13 studies assessing anti-CTLA-4 monotherapy, 22 studies assessing anti-PD-1 monotherapy, two studies assessing anti-CTLA-4 and anti-PD-1 combination therapy, one study assessing anti-PD-1 antibodies combined with axitinib, and three studies assessing anti-PD-1 antibodies combined with radiotherapy. For most patients who received ipilimumab monotherapy, the ORR ranged from 0% to 17%, the median PFS was less than 5 months, and the median OS was less than 10 months. For patients who received nivolumab or pembrolizumab monotherapy, most studies showed an ORR of more than 15% and a median OS of more than 11 months. The combined administration of anti-CTLA-4 and anti-PD-1 agents showed benefits over single-agent therapy with an ORR of more than 33.3%. In a phase Ib trial of toripalimab in combination with axitinib, approximately half of patients had complete or partial responses. Three retrospective studies that investigated anti-PD-1 antibodies combined with radiotherapy showed an ORR of more than 50%, which was higher than each single modality treatment. Conclusions: Immune checkpoint inhibitors, especially anti-PD-1 monoclonal antibodies alone and in combination with anti-CTLA-4 monoclonal antibodies or other modalities, are promising treatment options for advanced or metastatic MM. However, high-level evidence is still needed to support the clinical application.

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Current Possibilities of Gynecologic Cancer Treatment with the Use of Immune Checkpoint Inhibitors

International Journal of Molecular Sciences ◽

10.3390/ijms20194705 ◽

2019 ◽

Vol 20 (19) ◽

pp. 4705 ◽

Cited By ~ 13

Author(s):

Ewelina Grywalska ◽

Małgorzata Sobstyl ◽

Lechosław Putowski ◽

Jacek Roliński

Keyword(s):

Monoclonal Antibodies ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Gynecological Cancer ◽

Gynecologic Cancer ◽

Gynecological Cancers ◽

Cancer Burden ◽

Medical Need

Despite the ongoing progress in cancer research, the global cancer burden has increased to 18.1 million new cases and 9.6 million deaths in 2018. Gynecological cancers, such as ovarian, endometrial, and cervical cancers, considerably contribute to global cancer burden, leading to $5,862.6, $2,945.7, and $1,543.9 million of annual costs of cancer care, respectively. Thus, the development of effective therapies against gynecological cancers is still a largely unmet medical need. One of the novel therapeutic approaches is to induce anti-cancer immunity by the inhibition of the immune checkpoint pathways using monoclonal antibodies. The molecular targets for monoclonal antibodies are cytotoxic T lymphocyte-associated protein-4 (CTLA-4), programmed cell death protein-1 (PD-1), and programmed death-ligand 1 (PD-L1). The rationale for the use of immune checkpoint inhibitors in patients with gynecological cancers was based on the immunohistological studies showing high expression levels of PD-1 and PD-L1 in those cancers. Currently available immune checkpoint inhibitors include nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, and ipilimumab. The efficacy and safety of these inhibitors, used as monotherapy and with combination with chemotherapy, is being currently evaluated in several clinical studies. As the results are promising, more clinical trials are being planned, which may lead to the development of efficient therapies for gynecological cancer patients.

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