Targeted therapy refers to agents that target molecular pathways altered in cancer cells. Ipilimumab is an immune checkpoint inhibitor targeted therapy for melanoma. It can cause immune-related adverse events (irAEs) including dermatitis, diarrhea/colitis, and hepatotoxicity as the immune system attacks healthy tissue. Management of irAEs involves monitoring for symptoms, testing to rule out other causes, and administering corticosteroids to suppress the immune response. Ipilimumab also has a unique kinetic of response unlike chemotherapy.
Cancer immunotherapy harnesses the power of the immune system to fight cancer. Various immunotherapy approaches have been developed including vaccines, cytokines, monoclonal antibodies, and engineered T cells. Many immunotherapies have received FDA approval based on clinical trials demonstrating improved outcomes for cancer patients. New clinical trial designs are exploring immunotherapy combinations in "basket trials" that group patients by biomarkers rather than cancer type and "umbrella trials" that test multiple therapies in one study. Immunotherapy is transforming cancer treatment by activating the immune system against tumors.
The document discusses various approaches to immunotherapy in cancers, including targeted therapies, biologic therapies, angiogenesis inhibitors, and immune-based therapies. It describes cellular processes like the cell cycle and cell kinetics that are relevant for cancer growth. It provides details on specific targeted therapies for pathways like EGFR, HER2/neu, VEGF, and PI3K/Akt/mTOR that are dysregulated in cancers. Immunotherapies like HPV vaccines have been successful in preventing cervical cancers associated with HPV infection. Overall, the document outlines current understandings and therapeutic approaches regarding tumor proliferation and immunotherapies for cancer.
n overview of current immunotherapy therapies used to treat cancer. Also provides MOA of various medications, and updates on SITC guidelines for metastatice melanoma.
Cancer immunotherapy nivedita shah msc.biotech- 13937eureka1
This document provides an overview of cancer immunotherapy. It discusses how immunotherapy harnesses the immune system to fight cancer through techniques like monoclonal antibodies, cytokines, adoptive cell therapy, and cancer vaccines. Monoclonal antibodies target specific antigens on cancer cells, while cytokines are proteins that serve as messenger molecules between immune cells. Adoptive cell therapy transfers immune cells back into patients to improve immune function against tumors. Cancer vaccines stimulate the immune system to attack existing or prevent future cancer cells. The document also outlines some limitations of immunotherapy approaches and notes how cancer immunotherapy was named Breakthrough of the Year by the journal Science in 2013.
In 3 sentences:
Envigo is a global contract research organization dedicated to helping customers advance human and animal health. They provide contract research services and research models across 5 continents, employing over 3,800 people at 52 locations. The presentation discussed key considerations for the non-clinical safety evaluation of drugs targeting immune checkpoints, including challenges assessing immunotoxicity and predicting autoimmune risks in animal models.
This document provides an overview of immunotherapy for cancer. It discusses how immunotherapy works by boosting the body's natural immune response against cancer cells. The main types of immunotherapy discussed are monoclonal antibodies, cancer vaccines, and non-specific immunotherapies like cytokines and interferons. Monoclonal antibodies are engineered antibodies that target specific antigens on cancer cells, while cancer vaccines are designed to trigger an immune response against tumor antigens. Together, these immunotherapies help the immune system better recognize and destroy cancer cells.
This presentation is part of MIU CE Pharmacy Program and is designed primarily for pharmacists with the following learning objectives:
1- Explain the mechanisms of action behind immune response to cancer and the application of immunotherapy in cancer treatment
2- Distinguish new and emerging immunotherapy classes and individual agents efficacy, safety to therapy in cancer treatment
3-Strategies to counsel and assist patients to overcome barriers to therapy, including Treatment side effects to improve adherence to therapy
Cancer immunotherapy harnesses the power of the immune system to fight cancer. Various immunotherapy approaches have been developed including vaccines, cytokines, monoclonal antibodies, and engineered T cells. Many immunotherapies have received FDA approval based on clinical trials demonstrating improved outcomes for cancer patients. New clinical trial designs are exploring immunotherapy combinations in "basket trials" that group patients by biomarkers rather than cancer type and "umbrella trials" that test multiple therapies in one study. Immunotherapy is transforming cancer treatment by activating the immune system against tumors.
The document discusses various approaches to immunotherapy in cancers, including targeted therapies, biologic therapies, angiogenesis inhibitors, and immune-based therapies. It describes cellular processes like the cell cycle and cell kinetics that are relevant for cancer growth. It provides details on specific targeted therapies for pathways like EGFR, HER2/neu, VEGF, and PI3K/Akt/mTOR that are dysregulated in cancers. Immunotherapies like HPV vaccines have been successful in preventing cervical cancers associated with HPV infection. Overall, the document outlines current understandings and therapeutic approaches regarding tumor proliferation and immunotherapies for cancer.
n overview of current immunotherapy therapies used to treat cancer. Also provides MOA of various medications, and updates on SITC guidelines for metastatice melanoma.
Cancer immunotherapy nivedita shah msc.biotech- 13937eureka1
This document provides an overview of cancer immunotherapy. It discusses how immunotherapy harnesses the immune system to fight cancer through techniques like monoclonal antibodies, cytokines, adoptive cell therapy, and cancer vaccines. Monoclonal antibodies target specific antigens on cancer cells, while cytokines are proteins that serve as messenger molecules between immune cells. Adoptive cell therapy transfers immune cells back into patients to improve immune function against tumors. Cancer vaccines stimulate the immune system to attack existing or prevent future cancer cells. The document also outlines some limitations of immunotherapy approaches and notes how cancer immunotherapy was named Breakthrough of the Year by the journal Science in 2013.
In 3 sentences:
Envigo is a global contract research organization dedicated to helping customers advance human and animal health. They provide contract research services and research models across 5 continents, employing over 3,800 people at 52 locations. The presentation discussed key considerations for the non-clinical safety evaluation of drugs targeting immune checkpoints, including challenges assessing immunotoxicity and predicting autoimmune risks in animal models.
This document provides an overview of immunotherapy for cancer. It discusses how immunotherapy works by boosting the body's natural immune response against cancer cells. The main types of immunotherapy discussed are monoclonal antibodies, cancer vaccines, and non-specific immunotherapies like cytokines and interferons. Monoclonal antibodies are engineered antibodies that target specific antigens on cancer cells, while cancer vaccines are designed to trigger an immune response against tumor antigens. Together, these immunotherapies help the immune system better recognize and destroy cancer cells.
This presentation is part of MIU CE Pharmacy Program and is designed primarily for pharmacists with the following learning objectives:
1- Explain the mechanisms of action behind immune response to cancer and the application of immunotherapy in cancer treatment
2- Distinguish new and emerging immunotherapy classes and individual agents efficacy, safety to therapy in cancer treatment
3-Strategies to counsel and assist patients to overcome barriers to therapy, including Treatment side effects to improve adherence to therapy
In this presentation, I discuss a new standard of treatment in cancers which is immunotherapy. I also discuss the few cancers for which it has been approved.
This document discusses the growing field of anticancer immunotherapy and summarizes key points:
1) Immunotherapy harnesses the immune system to fight cancer and represents a relatively new approach, with the number of immunotherapies in development rising from 1 in 1995 to over 170 currently.
2) Three immunotherapies have been successfully launched, including ipilimumab, nivolumab, and pembrolizumab, which target checkpoints like CTLA-4 and PD-1 to activate antitumor immune responses.
3) Many more immunotherapies are in clinical trials, especially those targeting PD-1 and PD-L1, and CAR T-cell therapies show promise in hematological
Immunological Checkpoints and Cancer Immunotherapyimgcommcall
Immunological checkpoints and cancer immunotherapy were reviewed. Immune checkpoint inhibitors like anti-CTLA-4 and anti-PD-1/PD-L1 antibodies can activate the immune system against cancer by blocking inhibitory signals to T cells. Clinical trials show these drugs produce durable responses in various cancers like melanoma, lung cancer, and Merkel cell carcinoma. Combining different immunotherapies or with other treatments may help more patients by overcoming resistance. Ongoing research aims to better understand combination approaches and biomarkers of response.
A common goal in pediatric oncology is a treatment protocol that minimizes risk and maximizes success. The overall survival rate of children with solid tumor metastasis (Stage IV) has shown little improvement in that the extent of the relocation of metastatic cells, and their progression, is not well
understood. To better understand the limits of metastasis, an alternative treatment strategy is discussed; based on maladaptive immunity. A skin cream having natural and recombinant allergens, associated with immunologic adjuvants, is vectored into the cancer patient by topical dermal absorption. After that, humoral immunity increases the expression of cross-reactive Immunoglobulin-E (cIgE) primed effector cells, designed to decrease the incidence and prevalence of endogenous proteins that support the metastatic environment. The objective of this review is to explore an alternative cancer-immunotherapy intended to increase the overall survival rate and quality-of-life for children and adolescents struggling with solid tumor metastasis.
Immuno-Oncology: An Evolving Approach to Cancer Care
Review a downloadable slide deck by Thomas F. Gajewski, MD, PhD, covering the most clinically relevant new data reported from Immuno-Oncology: An Evolving Approach to Cancer Care.
Target Audience
This activity is designed to meet the educational needs of oncologists and other healthcare professionals involved in cancer care.
Format: Microsoft PowerPoint (.ppt) | File size: 26.2 MB | Date posted: 6/20/2012
Slide Deck Disclaimer
This slide deck in its original and unaltered format is for educational purposes and is current as of June 2012. All materials contained herein reflect the views of the faculty, and not those of IMER, the CE provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice, diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity.
Usage Rights
This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published in print or electronically as a promotional or certified educational activity without prior written permission from IMER. Additional terms may apply. See Terms of Service on IMERonline.com for details.
This document discusses cancer immunotherapy. It begins by describing tumor antigens that can be recognized by the immune system, such as tumor-specific antigens, tumor-associated antigens, and antigens from oncogenic viruses. It then discusses how tumors evade the immune system and various approaches to immunotherapy, including active immunotherapies using vaccines made of tumor cells, purified antigens, or antigen-loaded dendritic cells. Passive immunotherapies discussed include adoptive cellular therapy, monoclonal antibodies, and immunotoxins. Clinical trials and effectiveness of different immunotherapies are also summarized.
The immunotherapy of cancer: past, present & the next frontierThe ScientifiK
The immunotherapy of cancer has progressed through several phases from past to present:
1) Early attempts focused on vaccines and cytokines with limited success and understanding.
2) Anti-CTLA4 therapy showed the first durable responses in metastatic melanoma.
3) Anti-PD-1 therapy was found to be superior to anti-CTLA4, with better responses and tolerability. This established that overcoming immunosuppression is key.
4) Combination strategies are now the focus, exploring combinations of immunotherapies or with targeted/chemotherapies to extend responses. Biomarkers like PD-L1 are being used to identify patients most likely to benefit from anti-PD-1
Immune check point inhibitors and adverse effectsSCGH ED CME
Immune checkpoint inhibitors can cause immune-related adverse events by removing inhibitory checkpoints and excessively activating the immune system. Common adverse effects include dermatitis in over 50% of patients, enterocolitis in under 20%, hepatitis in under 10%, and endocrinopathies. Symptoms usually onset several months after treatment. Management involves stopping the immune checkpoint inhibitor and administering corticosteroids in most cases. Life-threatening hyperimmunity is possible so consulting the oncologist and other specialists is important.
A talk presented by Prof. Mohamed Labib Salem at Minofia University محاضرة للأستاذ الدكتور محمد لبيب سالم جامعة طنطا يوم الثلاثاء السادس عشر من فبراير بجامعة المنوفية
Radiotherapy can be used in combination with immunotherapy to help the body's immune system fight cancer. Radiation damages cancer cells, causing them to release proteins that allow white blood cells to target the cancer cells. Low doses of radiation activate receptors on cancer cells to release more proteins without suppressing the immune response. The combination approach utilizes irradiated cancer cells to increase the effectiveness of immunotherapy against primary and secondary cancers. However, very high radiation doses cause cancer cells to enter a wound healing state where they secrete chemicals that inhibit the immune attack.
This document summarizes various targeted anticancer therapies. It discusses targeted therapies that interfere with molecular structures implicated in tumor growth like nuclear factors, cell survival factors, and angiogenesis factors. Primary targeted therapy tools are monoclonal antibodies and small synthetic molecules. Protein kinases and their role in signaling pathways are described. Examples of targeted therapies discussed include BCR-ABL tyrosine kinase inhibitors, EGFR inhibitors, HER2/NEU inhibitors, angiogenesis inhibitors targeting VEGF, mTOR inhibitors, proteasome inhibitors, MAPK pathway inhibitors, and monoclonal antibodies. Resistance mechanisms and newer agents to overcome resistance are also summarized.
This document discusses recent advances in cancer immunotherapy. It describes how improved understanding of immunology has led to new immunotherapies using toll-like receptor agonists, T cells, NK cells, dendritic cells, and monoclonal antibodies. Major cellular immunotherapies discussed include using T cells activated outside the body with cytokines like IL-2, and engineering T cells to express tumor-targeting receptors.
This document discusses immunotherapeutics and immunity. It defines immunity as the body's ability to protect itself from infectious disease. There are two main types of immunity: innate and adaptive. Immunotherapy involves stimulating, enhancing, suppressing, or desensitizing the immune system to treat or prevent disease like cancer or autoimmune disorders. The document outlines various immunotherapeutic approaches including immunostimulants, monoclonal antibodies, antibody-directed enzyme prodrug therapy, immunotoxins, and immunomodulators like adaptive cell therapy and cancer vaccines.
Cancer Immunotherapies (Focus on Melanoma & Lung Cancers)Zeena Nackerdien
Effective immunotherapy i.e. enlisting the patient’s own immune system to fight disease may mark a milestone in the fight against certain cancers. Three lymphocytes – T cells, B cells and NK-cells – involved in specific immune responses against cancers and other diseases. T cells recognize specific antigens via a T-cell antigen-receptor. The two main types of T cells, CD4- and CD8 T-cells, are categorized according to their respective CD4 and CD8 surface markers. The latter group includes cytotoxic T cells, also known as killer T lymphocytes. These cells kill invading pathogens or other disease-causing agents. Scientists discovered that a type of protein receptor, cytotoxic T-Lymphocyte Antigen 4 (CTLA-4), prevented T cells from launching immune attacks [1]. In the early 1990s, another “brake” was discovered in dying T cells namely programmed death 1 or PD-1. The rationale underlying cancer immunotherapy is that exposing CTLA-4, PD-1 or using other appropriate immune-system-based therapies may enable the activation of the immune system to destroy cancer.
Genetically engineering a patient’s T cells to target tumor cells marked one of the promising turning points in cancer immunotherapy, particularly for certain blood cancers and solid tumors. Melanoma and lung cancer, two often-fatal diseases, are treatable in the early stages with surgery or other standards of care. However, some patients are diagnosed during the later stages of the disease or relapse with refractory/unresectable tumors. For these subgroups, the latest National Comprehensive Cancer Network (NCCN) tailored algorithms coupled with systemic treatment options, including immunotherapies, could potentially improve outcomes. Here, I summarize the latest approved immunotherapies mentioned in the NCCN guidelines, along with other examples of investigational agents such as monoclonal antibodies, cancer vaccines, and natural killer cells. Additional examples of targeted therapies, novel “druggable” and other immunotargets are presented in the section, ”Future Directions.”
Reference
1. Couzin-Frankel, J., Breakthrough of the year 2013. Cancer immunotherapy. Science, 2013. 342(6165): p. 1432-3.
Immunotherapy is a type of cancer treatment that uses components of the immune system to fight cancer. There are several types of immunotherapy including passive immunotherapy using monoclonal antibodies that target tumor antigens, active immunotherapies using cytokines, cancer vaccines, and cell-based therapies. Monoclonal antibodies can directly kill cancer cells, block proteins that help cancer grow, or be linked to chemotherapy drugs. Cancer vaccines work by boosting the immune system against tumor antigens. Adoptive immunotherapy transfers modified immune cells to the body to attack cancer. Immunotherapy has shown success in treating various cancer types and continues to be improved and developed further.
This slideshare conatins detailed overview of immunotheraphy,humanisation of antibodies and its clinical application
this is the topic from cellular and molecular pharmacology of m pharmacy first year
immunotheraphy is further classified to its various types which has been discussed individually
its also conatins various immunotheraphy drugs which has other clinical advantages
The document discusses a clinical trial comparing the monoclonal antibodies obinutuzumab and rituximab for treating diffuse large B-cell lymphoma. Obinutuzumab is a glycoengineered, humanized antibody that clusters the CD20 antigen more effectively than rituximab. In a phase III trial, obinutuzumab plus chemotherapy did not significantly improve progression-free survival over rituximab plus chemotherapy. However, obinutuzumab's glycoengineering may enhance its antibody-dependent cellular cytotoxicity and direct cell death mechanisms relative to rituximab.
Humanisation of antibodies & immunotherapeutics in clinical practice Aaqib Naseer
This document discusses humanization of monoclonal antibodies and immunotherapeutics used in clinical practice. It describes the techniques used to humanize antibodies, including CDR grafting, phage display, and transgenic animals. It then discusses various immunotherapeutics used clinically such as monoclonal antibodies, cytokines, cancer vaccines, and cell-based therapies. Monoclonal antibodies target specific antigens on cancer cells and can be naked or conjugated. Checkpoint inhibitors like anti-CTLA-4 and anti-PD-1 antibodies work by releasing brakes on the immune system. Cytokines such as interferons and interleukins modulate immune responses. Cancer vaccines aim to stimulate immunity against tumor antigens.
The document discusses humanized monoclonal antibodies (hmAbs), including their development and mechanisms of action. It provides examples of several hmAbs used to treat different cancers and autoimmune diseases. Specifically, it describes how hmAbs are developed by cloning mouse antibody genes and fusing them to human frameworks to reduce immunogenicity. It then highlights several FDA-approved hmAbs like bevacizumab, trastuzumab, ocrelizumab, and tocilizumab and discusses their mechanisms and clinical trial results in treating conditions like breast cancer, multiple sclerosis, and rheumatoid arthritis. Finally, it outlines areas for future work, such as developing multifunctional antibodies and improving targeting of specific epitopes.
In this presentation, I discuss a new standard of treatment in cancers which is immunotherapy. I also discuss the few cancers for which it has been approved.
This document discusses the growing field of anticancer immunotherapy and summarizes key points:
1) Immunotherapy harnesses the immune system to fight cancer and represents a relatively new approach, with the number of immunotherapies in development rising from 1 in 1995 to over 170 currently.
2) Three immunotherapies have been successfully launched, including ipilimumab, nivolumab, and pembrolizumab, which target checkpoints like CTLA-4 and PD-1 to activate antitumor immune responses.
3) Many more immunotherapies are in clinical trials, especially those targeting PD-1 and PD-L1, and CAR T-cell therapies show promise in hematological
Immunological Checkpoints and Cancer Immunotherapyimgcommcall
Immunological checkpoints and cancer immunotherapy were reviewed. Immune checkpoint inhibitors like anti-CTLA-4 and anti-PD-1/PD-L1 antibodies can activate the immune system against cancer by blocking inhibitory signals to T cells. Clinical trials show these drugs produce durable responses in various cancers like melanoma, lung cancer, and Merkel cell carcinoma. Combining different immunotherapies or with other treatments may help more patients by overcoming resistance. Ongoing research aims to better understand combination approaches and biomarkers of response.
A common goal in pediatric oncology is a treatment protocol that minimizes risk and maximizes success. The overall survival rate of children with solid tumor metastasis (Stage IV) has shown little improvement in that the extent of the relocation of metastatic cells, and their progression, is not well
understood. To better understand the limits of metastasis, an alternative treatment strategy is discussed; based on maladaptive immunity. A skin cream having natural and recombinant allergens, associated with immunologic adjuvants, is vectored into the cancer patient by topical dermal absorption. After that, humoral immunity increases the expression of cross-reactive Immunoglobulin-E (cIgE) primed effector cells, designed to decrease the incidence and prevalence of endogenous proteins that support the metastatic environment. The objective of this review is to explore an alternative cancer-immunotherapy intended to increase the overall survival rate and quality-of-life for children and adolescents struggling with solid tumor metastasis.
Immuno-Oncology: An Evolving Approach to Cancer Care
Review a downloadable slide deck by Thomas F. Gajewski, MD, PhD, covering the most clinically relevant new data reported from Immuno-Oncology: An Evolving Approach to Cancer Care.
Target Audience
This activity is designed to meet the educational needs of oncologists and other healthcare professionals involved in cancer care.
Format: Microsoft PowerPoint (.ppt) | File size: 26.2 MB | Date posted: 6/20/2012
Slide Deck Disclaimer
This slide deck in its original and unaltered format is for educational purposes and is current as of June 2012. All materials contained herein reflect the views of the faculty, and not those of IMER, the CE provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice, diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity.
Usage Rights
This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published in print or electronically as a promotional or certified educational activity without prior written permission from IMER. Additional terms may apply. See Terms of Service on IMERonline.com for details.
This document discusses cancer immunotherapy. It begins by describing tumor antigens that can be recognized by the immune system, such as tumor-specific antigens, tumor-associated antigens, and antigens from oncogenic viruses. It then discusses how tumors evade the immune system and various approaches to immunotherapy, including active immunotherapies using vaccines made of tumor cells, purified antigens, or antigen-loaded dendritic cells. Passive immunotherapies discussed include adoptive cellular therapy, monoclonal antibodies, and immunotoxins. Clinical trials and effectiveness of different immunotherapies are also summarized.
The immunotherapy of cancer: past, present & the next frontierThe ScientifiK
The immunotherapy of cancer has progressed through several phases from past to present:
1) Early attempts focused on vaccines and cytokines with limited success and understanding.
2) Anti-CTLA4 therapy showed the first durable responses in metastatic melanoma.
3) Anti-PD-1 therapy was found to be superior to anti-CTLA4, with better responses and tolerability. This established that overcoming immunosuppression is key.
4) Combination strategies are now the focus, exploring combinations of immunotherapies or with targeted/chemotherapies to extend responses. Biomarkers like PD-L1 are being used to identify patients most likely to benefit from anti-PD-1
Immune check point inhibitors and adverse effectsSCGH ED CME
Immune checkpoint inhibitors can cause immune-related adverse events by removing inhibitory checkpoints and excessively activating the immune system. Common adverse effects include dermatitis in over 50% of patients, enterocolitis in under 20%, hepatitis in under 10%, and endocrinopathies. Symptoms usually onset several months after treatment. Management involves stopping the immune checkpoint inhibitor and administering corticosteroids in most cases. Life-threatening hyperimmunity is possible so consulting the oncologist and other specialists is important.
A talk presented by Prof. Mohamed Labib Salem at Minofia University محاضرة للأستاذ الدكتور محمد لبيب سالم جامعة طنطا يوم الثلاثاء السادس عشر من فبراير بجامعة المنوفية
Radiotherapy can be used in combination with immunotherapy to help the body's immune system fight cancer. Radiation damages cancer cells, causing them to release proteins that allow white blood cells to target the cancer cells. Low doses of radiation activate receptors on cancer cells to release more proteins without suppressing the immune response. The combination approach utilizes irradiated cancer cells to increase the effectiveness of immunotherapy against primary and secondary cancers. However, very high radiation doses cause cancer cells to enter a wound healing state where they secrete chemicals that inhibit the immune attack.
This document summarizes various targeted anticancer therapies. It discusses targeted therapies that interfere with molecular structures implicated in tumor growth like nuclear factors, cell survival factors, and angiogenesis factors. Primary targeted therapy tools are monoclonal antibodies and small synthetic molecules. Protein kinases and their role in signaling pathways are described. Examples of targeted therapies discussed include BCR-ABL tyrosine kinase inhibitors, EGFR inhibitors, HER2/NEU inhibitors, angiogenesis inhibitors targeting VEGF, mTOR inhibitors, proteasome inhibitors, MAPK pathway inhibitors, and monoclonal antibodies. Resistance mechanisms and newer agents to overcome resistance are also summarized.
This document discusses recent advances in cancer immunotherapy. It describes how improved understanding of immunology has led to new immunotherapies using toll-like receptor agonists, T cells, NK cells, dendritic cells, and monoclonal antibodies. Major cellular immunotherapies discussed include using T cells activated outside the body with cytokines like IL-2, and engineering T cells to express tumor-targeting receptors.
This document discusses immunotherapeutics and immunity. It defines immunity as the body's ability to protect itself from infectious disease. There are two main types of immunity: innate and adaptive. Immunotherapy involves stimulating, enhancing, suppressing, or desensitizing the immune system to treat or prevent disease like cancer or autoimmune disorders. The document outlines various immunotherapeutic approaches including immunostimulants, monoclonal antibodies, antibody-directed enzyme prodrug therapy, immunotoxins, and immunomodulators like adaptive cell therapy and cancer vaccines.
Cancer Immunotherapies (Focus on Melanoma & Lung Cancers)Zeena Nackerdien
Effective immunotherapy i.e. enlisting the patient’s own immune system to fight disease may mark a milestone in the fight against certain cancers. Three lymphocytes – T cells, B cells and NK-cells – involved in specific immune responses against cancers and other diseases. T cells recognize specific antigens via a T-cell antigen-receptor. The two main types of T cells, CD4- and CD8 T-cells, are categorized according to their respective CD4 and CD8 surface markers. The latter group includes cytotoxic T cells, also known as killer T lymphocytes. These cells kill invading pathogens or other disease-causing agents. Scientists discovered that a type of protein receptor, cytotoxic T-Lymphocyte Antigen 4 (CTLA-4), prevented T cells from launching immune attacks [1]. In the early 1990s, another “brake” was discovered in dying T cells namely programmed death 1 or PD-1. The rationale underlying cancer immunotherapy is that exposing CTLA-4, PD-1 or using other appropriate immune-system-based therapies may enable the activation of the immune system to destroy cancer.
Genetically engineering a patient’s T cells to target tumor cells marked one of the promising turning points in cancer immunotherapy, particularly for certain blood cancers and solid tumors. Melanoma and lung cancer, two often-fatal diseases, are treatable in the early stages with surgery or other standards of care. However, some patients are diagnosed during the later stages of the disease or relapse with refractory/unresectable tumors. For these subgroups, the latest National Comprehensive Cancer Network (NCCN) tailored algorithms coupled with systemic treatment options, including immunotherapies, could potentially improve outcomes. Here, I summarize the latest approved immunotherapies mentioned in the NCCN guidelines, along with other examples of investigational agents such as monoclonal antibodies, cancer vaccines, and natural killer cells. Additional examples of targeted therapies, novel “druggable” and other immunotargets are presented in the section, ”Future Directions.”
Reference
1. Couzin-Frankel, J., Breakthrough of the year 2013. Cancer immunotherapy. Science, 2013. 342(6165): p. 1432-3.
Immunotherapy is a type of cancer treatment that uses components of the immune system to fight cancer. There are several types of immunotherapy including passive immunotherapy using monoclonal antibodies that target tumor antigens, active immunotherapies using cytokines, cancer vaccines, and cell-based therapies. Monoclonal antibodies can directly kill cancer cells, block proteins that help cancer grow, or be linked to chemotherapy drugs. Cancer vaccines work by boosting the immune system against tumor antigens. Adoptive immunotherapy transfers modified immune cells to the body to attack cancer. Immunotherapy has shown success in treating various cancer types and continues to be improved and developed further.
This slideshare conatins detailed overview of immunotheraphy,humanisation of antibodies and its clinical application
this is the topic from cellular and molecular pharmacology of m pharmacy first year
immunotheraphy is further classified to its various types which has been discussed individually
its also conatins various immunotheraphy drugs which has other clinical advantages
The document discusses a clinical trial comparing the monoclonal antibodies obinutuzumab and rituximab for treating diffuse large B-cell lymphoma. Obinutuzumab is a glycoengineered, humanized antibody that clusters the CD20 antigen more effectively than rituximab. In a phase III trial, obinutuzumab plus chemotherapy did not significantly improve progression-free survival over rituximab plus chemotherapy. However, obinutuzumab's glycoengineering may enhance its antibody-dependent cellular cytotoxicity and direct cell death mechanisms relative to rituximab.
Humanisation of antibodies & immunotherapeutics in clinical practice Aaqib Naseer
This document discusses humanization of monoclonal antibodies and immunotherapeutics used in clinical practice. It describes the techniques used to humanize antibodies, including CDR grafting, phage display, and transgenic animals. It then discusses various immunotherapeutics used clinically such as monoclonal antibodies, cytokines, cancer vaccines, and cell-based therapies. Monoclonal antibodies target specific antigens on cancer cells and can be naked or conjugated. Checkpoint inhibitors like anti-CTLA-4 and anti-PD-1 antibodies work by releasing brakes on the immune system. Cytokines such as interferons and interleukins modulate immune responses. Cancer vaccines aim to stimulate immunity against tumor antigens.
The document discusses humanized monoclonal antibodies (hmAbs), including their development and mechanisms of action. It provides examples of several hmAbs used to treat different cancers and autoimmune diseases. Specifically, it describes how hmAbs are developed by cloning mouse antibody genes and fusing them to human frameworks to reduce immunogenicity. It then highlights several FDA-approved hmAbs like bevacizumab, trastuzumab, ocrelizumab, and tocilizumab and discusses their mechanisms and clinical trial results in treating conditions like breast cancer, multiple sclerosis, and rheumatoid arthritis. Finally, it outlines areas for future work, such as developing multifunctional antibodies and improving targeting of specific epitopes.
This document discusses chemotherapy treatment for cancer in pregnant women. It outlines the goals of treatment as trying to benefit the mother's life, treat curable malignant disease, protect the fetus and newborn, and retain the mother's reproductive system. It describes several classes of chemotherapeutic agents that may be used including alkylating agents, antimetabolites, plant agents, hormonal agents, and targeted/immunotherapies. The document cautions that the period from weeks 3-8 of pregnancy poses the highest risk for teratogenic effects, so chemotherapy is not generally recommended in the first trimester unless the mother's life is at grave risk. Later treatment appears to be associated with risks like preterm delivery and growth
Monoclonal antibodies (mAbs) are identical antibodies produced by a single clone of B cells or hybridoma cell line. Paul Ehrlich first described antibodies as "magic bullets" in search of toxins. Key developments included methods to isolate hybrid cell lines producing mAbs. mAbs can be murine, chimeric, humanized, or human. They have diagnostic applications like pregnancy tests and therapeutic uses like treating cancer, transplants, and autoimmune disorders. Common side effects include allergic reactions and infusion reactions. mAbs have revolutionized biotechnology and improved human health.
Tumor antigens & cancer immunotherapy.pptxRagavi32
Tumor antigens are proteins, glycoproteins, glycolipids, or carbohydrates expressed uniquely on tumor cells. There are two types: tumor specific antigens produced from mutations and tumor associated antigens normally expressed during development but reactivated in cancer. The immune system mounts responses against these antigens via antibodies and cytotoxic T cells to eliminate tumor cells. However, tumors can evolve to escape immune destruction by losing antigen expression or inhibiting immune responses. Immunotherapies aim to enhance antigen presentation, co-stimulation, and pro-inflammatory cytokines to strengthen anti-tumor immunity.
cellular and molecular pharmacology - presentationSIMRAN VERMA
Immunotherapy involves boosting the body's natural defenses against cancer and certain infections. It works by stimulating or suppressing the immune system. Types of immunotherapy include monoclonal antibodies, fusion proteins, soluble cytokine receptors, recombinant cytokines, small molecule mimetics, and cellular therapies. Immunotherapy is used to treat cancer, infections, and allergies. It involves substances made by living organisms or in a laboratory that are administered through intravenous injection, orally, topically, or intravesically. Treatment length depends on the type of cancer and immunotherapy. Common side effects include flu-like symptoms, rashes, and gastrointestinal issues.
This document discusses tumor immunology and immunotherapy. It provides evidence that the immune system can recognize and react against tumors. It describes tumor-associated antigens that can be recognized by the immune system. However, tumors also have mechanisms for escaping immune surveillance, such as not expressing immunogenic antigens or secreting immunosuppressive molecules. The document discusses various tumor-associated antigens and oncofetal antigens. It also outlines approaches for tumor immunotherapy, including using cytokines and immunopotentiating agents to enhance anti-tumor immunity.
This document summarizes several plasma cell disorders including multiple myeloma, Waldenstrom's macroglobulinemia, POEMS syndrome, heavy chain diseases, and amyloidosis. Multiple myeloma is a malignant proliferation of plasma cells that commonly presents with bone pain, anemia, kidney dysfunction, and infections. Diagnosis involves detection of monoclonal proteins by serum protein electrophoresis and treatment involves chemotherapy, stem cell transplantation, and newer agents. Waldenstrom's macroglobulinemia is characterized by lymphadenopathy, hyperviscosity, and peripheral neuropathy and is associated with IgM paraproteinemia. Heavy chain diseases involve truncated immunoglobulin heavy chains without light chains. POEMS syndrome is associated with polyneuropathy
This document discusses cancer immunology and immunotherapy. It begins by introducing cancer nomenclature and hallmarks. It describes how the immune system normally responds to cancer cells through immune surveillance and tumor antigen recognition. However, tumors can evolve mechanisms to evade the immune system through cancer immunoediting, where the immune response shapes tumors over time to select for less immunogenic variants. Immunotherapy aims to overcome tumor immune evasion and enhance anti-tumor immune responses.
Monoclonal antibodies in cancer treatment By Ankit TribhuvaneMumbai University
Monoclonal antibodies are identical antibodies produced by a single clone of B cells that specifically bind to target cells. They can be used for cancer therapy by triggering immune system attacks on cancer cells, blocking growth signals, or preventing new blood vessel formation. Monoclonal antibodies are produced through hybridoma technology, fusing B cells with myeloma cells. This produces immortal clones that secrete identical antibodies. Monoclonal antibodies have applications in cancer diagnosis and treatment, with therapeutic antibodies targeting tumors through mechanisms like antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.
Combining Old and New: Sensitising Drugs and Other Vaccines To Augment Effica...NeuroAcademy
1) The document discusses combining existing drugs and vaccines like levamisole, BCG, imiquimod, mifamurtide, and dendritic cell vaccines to augment the efficacy of dendritic cell immunotherapy.
2) It provides details on the mechanisms and effects of these drugs, including how they stimulate immune responses and dendritic cell activation.
3) Experimental results are presented showing improved survival rates in cancer patients receiving combined immunotherapy and chemotherapy compared to immunotherapy alone.
Targeted therapy is a new generation of cancer treatment that is more specific to tumor cells than traditional chemotherapy. It works by blocking critical molecular targets involved in processes like uncontrolled cell growth, angiogenesis, tissue invasion and metastasis. Several types of targeted therapies have been developed including monoclonal antibodies, tyrosine kinase inhibitors, angiogenesis inhibitors and proteasome inhibitors. Monoclonal antibodies in particular have shown effectiveness against cancers like breast, colorectal and lymphoma cancers when used alone or in combination with other treatments. They work by direct action on signaling pathways in tumor cells or by delivering toxic compounds specifically to tumor sites. Targeted therapies are an important new approach in cancer treatment and integrating them with other treatments offers potential benefits.
Cancer chemotherapy originated from observations of mustard gas exposure during World Wars I and II. Luis Goodman and Alfred Gillmen first demonstrated anti-cancer effects of chemotherapy drugs in 1943. Currently, nearly all successful cancer chemotherapy regimens use combination chemotherapy with multiple drugs given simultaneously to achieve synergistic tumor cell kill. Chemotherapy drugs can be classified based on their mechanism of action and cell cycle specificity. Alkylating agents are commonly used chemotherapy drugs that produce reactive carbonium ions to alkylate cellular macromolecules like DNA, causing cytotoxic and radiomimetic effects on both dividing and resting cells. Individual alkylating agent drugs have different dosing schedules and are used to treat various cancer types.
This document summarizes the results of a clinical trial investigating the efficacy and safety of pembrolizumab (anti-PD-1 antibody) in patients with advanced melanoma that progressed after treatment with ipilimumab. The overall response rate was 26% in the 2 mg/kg group and 10% in the 10 mg/kg group, with responses ongoing after 1 year. Pembrolizumab demonstrated a manageable safety profile, with grade 3-4 drug-related adverse events occurring in 12% of patients. This trial provides evidence that pembrolizumab is an effective treatment option for patients with advanced melanoma who have progressed on ipilimumab.
This document summarizes research on using protein biomarkers to monitor disease progression in advanced non-small cell lung cancer patients treated with icotinib. The researchers identified multiple immunoinflammation-related protein complexes (IIRPCs) in patient plasma samples and found patterns associated with disease status. They also identified a transferrin-related protein complex (TRPC) that was commonly expressed across patterns and remained stable during icotinib treatment, making it suitable as an internal reference. Some patients showed changes in IIRPC patterns during treatment, associated with developing resistance or disease progression, then returned to their original pattern. The biomarkers were found to be a convenient way to monitor disease and treatment response in these patients.
Zauderer, M.G., et al. Clinical Cancer Research, 2017.sellasq4
1. This randomized phase II trial evaluated the WT1 peptide vaccine galinpepimut-S combined with GM-CSF and Montanide in patients with malignant pleural mesothelioma after multimodality therapy.
2. The trial randomized 41 patients to galinpepimut-S plus adjuvants or adjuvants alone. The control arm was stopped early due to a futility analysis showing progression within 1 year in over 10 of the first 20 patients.
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This document summarizes newer drugs and treatment approaches for cancer management, focusing on head and neck cancers. It describes the use of neoadjuvant, concurrent, and adjuvant chemotherapy to reduce metastasis, tumor burden, and increase survival. Common chemotherapy drugs discussed include methotrexate, 5-fluorouracil, cisplatin, carboplatin, paclitaxel, and docetaxel. Newer targeted therapies targeting the EGFR pathway like cetuximab, gefitinib, and erlotinib are presented. Emerging areas of immunotherapy, gene therapy, angiogenesis inhibitors, and antibody-based therapies are also summarized.
Management of the premenopausal er+ve breast cancerAhmed Allam
This document discusses the management of premenopausal estrogen receptor positive (ER+) breast cancer. It notes that approximately 25% of breast cancers occur in women under age 50 and that estrogen plays a key role in breast cancer development. Estrogen receptor modulators, aromatase inhibitors, medical or surgical oophorectomy are effective endocrine therapies. Tamoxifen for 5 years is the standard adjuvant therapy for ER+ disease based on evidence from large trials. Ongoing studies are exploring optimal combinations and durations of ovarian suppression plus aromatase inhibitors or tamoxifen.
This document provides a nomenclature system for monoclonal antibodies (mAbs) based on suffixes added to the root "mab". The suffixes indicate the type and application of the mAb, such as "-mo-mab" denoting a mouse mAb, "-zu-mab" a humanized mAb that is 95% human, and suffixes like "-tu-xx-mab" indicating a tumor-directed mAb. The nomenclature system aims to concisely convey whether mAbs are mouse, chimeric, humanized, or human as well as their intended therapeutic area.
FIRE 3 Trail FOLFIRI+Cetuximab Vs FOLFIRI+BevacizumabAhmed Allam
This randomized, open-label, phase 3 trial compared FOLFIRI plus cetuximab (C+F) versus FOLFIRI plus bevacizumab (B+F) as first-line treatment for KRAS wild-type metastatic colorectal cancer. The trial found that C+F resulted in improved progression-free survival and overall survival compared to B+F. C+F was associated with increased rates of acneiform rash, paronychia, and hypomagnesemia but similar rates of other adverse events compared to B+F. The trial demonstrated that for patients with KRAS wild-type mCRC, first-line treatment with C+F provided superior
Hairy cell leukemia is a chronic B-cell lymphoproliferative disorder characterized by "hairy" appearing cells. It was first described in the 1950s and primarily affects middle-aged white men. Diagnosis involves identification of characteristic cells in blood and bone marrow samples. Treatment options have evolved over time from splenectomy to purine analogs like cladribine and pentostatin, which achieve high response rates. Rituximab is also effective, especially for relapsed/refractory cases. The goal of treatment is long-term remission and management of symptoms.
1. Adjuvant therapies like tamoxifen and chemotherapy have been shown to decrease the risk of recurrence and mortality from early breast cancer based on large meta-analyses.
2. Molecular classification of early breast cancer into subgroups like luminal A, luminal B, HER2-positive, and triple-negative helps determine which patients are likely to benefit most from adjuvant chemotherapy, hormonal therapy, or targeted therapies.
3. Large randomized controlled trials have demonstrated improved outcomes with anthracycline-based chemotherapy compared to CMF and the addition of taxanes to anthracycline regimens compared to anthracyclines alone in the adjuvant setting.
This document summarizes guidelines for the management of febrile neutropenia. It describes definitions of fever and neutropenia and risk factors. Initial evaluation involves blood cultures, site-specific cultures as indicated, and monitoring. Risk is stratified using tools like the MASCC index. Prophylaxis includes hand hygiene, oral care, and sometimes antibiotics or antifungals. Empiric antibiotic therapy is recommended, with modifications based on risk and response. Therapy typically continues until resolution of fever and recovery of neutrophils. Empiric antifungals may be considered for persistent fever.
1) The document discusses various treatment options for esophageal cancer including surgery, radiation therapy, and chemotherapy.
2) Key trials evaluated preoperative chemoradiation, which resulted in improved overall survival rates compared to surgery alone. The CROSS trial showed a 5-year survival rate of 47% with preoperative chemoradiation versus 34% with surgery alone.
3) For locally advanced disease, concurrent chemoradiation is the standard treatment approach based on trials showing improved outcomes compared to radiation alone. The optimal radiation dose when combined with chemotherapy is 50-50.4 Gy.
The document discusses the EGFR pathway in colorectal cancer. It notes that EGFR is overexpressed in 25-82% of colorectal cancers and is involved in cell proliferation pathways. While EGFR overexpression is sometimes associated with worse outcomes, the significance is unclear due to inconsistent measurement methods. Anti-EGFR therapies like cetuximab show promise for colorectal cancer, but EGFR expression levels alone do not predict response to treatment. EGFR gene amplification analysis is also an uncertain prognostic indicator due to varying definitions and guidelines. Overall the role of EGFR in colorectal cancer requires further standardized research.
Management of hormonal resistant breast cancer Ahmed Allam
The document discusses endocrine therapy for breast cancer and mechanisms of resistance. It notes that around 60% of ER-positive breast cancer patients benefit from endocrine therapy like tamoxifen. Later studies found aromatase inhibitors and mTOR inhibitors can help overcome resistance. One study showed everolimus plus tamoxifen extended time to progression compared to tamoxifen alone in metastatic breast cancer patients previously treated with aromatase inhibitors.
1. Management of Immune-
related adverse events and
kinetic of response with
Targeted Therapy
Ahmed Allam A.H. Mohammed.
Ass. Lecturer, Clinical oncology and Nuclear med. Depart. Assiut
University Hospitals
2. Targeted Therapy ?*
normal cells, the pathways that control cell growth, death, and differentiation are regulated by
In
communication within the cell, called signal transduction, and by signals that pass from one cell to
another.
cancer cell, these regulatory mechanisms are bypassed, so the cells avoid cell death and demonstrate
In
uncontrolled growth and impaired differentiation.
Growing tumors associated with neovascularization and evading the immune system
Targeted therapy refers to a growing class of agents that target molecular pathways that are known to be
altered in cancer cells and micor-enviroment.
Chabner BA, Barnes J, Neal J, et al. Targeted therapies: tyrosine kinase inhibitors, monoclonal antibodies, and cytokines. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman &
Gilman's The Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw-Hill; 2011:1731-1753.
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Unlike chemotherapy, which often destroys both normal and cancer cells,
targeted therapy selectively inhibits the pathways cancer cells rely on to grow
and survive and may kill or arrest the growth of cancerous cells while sparing
most normal cells.
5. Main Categories of Targeted Therapy
( cont’d).
2- Monoclonal antibodies
I-according to type of mAb
• Murine mAb: (suffix-momab) highly immunogenic Example:
Ibritumomab.
• Chimeric mAb: (suffix-ximab) murine variable region fused onto constant
human constant region → 65% human. Example: Rituximab.
• Humanized mAb: (suffix-zumab) murine hypervariable fused into human
antibody→95% human. Example: Bevacizuman.
• Human mAb: (suffix-mumab) transfer the human Ig genes into murine
genome, then the mouse is vacinated against the desire antigen→full
human in vitro Ab. Example: Panitumumab.
6. Main Categories of Targeted Therapy
( cont’d).
2- Monoclonal antibodies (cont’d)
II- according to the target
• Target tumor (suffix-tu**mab) Example Cetuximab.
• Target cardiovascular system (suffix-ci**mab) Example:
Bevacizuman.
• Target immune system (suffix-li**mab) Example Ipilimumab,
Termelimumab
7. Ipilimumab* and Tremelimumab
Both are anti CTLA-4 antibodies.
CTLA-4 is one of two homologous proteins present within T-
cells that are exported to the cell surface after immune cell
activation and counterbalance each other in the stimulation
and inhibition of T cell proliferation and activation.
CTLA-4, which has a much greater binding affinity for the B7
surface molecules found on the antigen-presenting cell (APC)
than CD28, effectively induces T cell anergy and inhibits cell
proliferation and secretion of IL-2.
In contrast, its counterpart, CD28, is a costimulator of T cell
proliferation and the production of IL-2
*Ipilimumab: controversies in its development, utility and autoimmune adverse events. Weber J, Cancer Immunol Immunother (2009) 58:823–830 DOI
10.1007/s00262-008-0653-8
8. Ipilimumab and Tremelimumab (cont’d)
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*Management of Immune-Related Adverse Events and Kinetics of Response With Ipilimumab, Jeffrey S. Weber, Katharina C. Ka¨hler, and Axel
Hauschild VOLUME JULY 20 2012
9. Ipilimumab (Yervoy™)
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10. Ipilimumab (Yervoy™)
A total of 676 patients with unresectable stage III or IV
melanoma, were randomly assigned, in a 3:1:1 ratio, to
receive ipilimumab plus gp100 (403 patients),
ipilimumab alone (137), or gp100 alone (136).
Ipilimumab, at a dose of 3 mg per kilogram of body
weight, was administered with or without gp100 every 3
weeks for up to four treatments (induction). Eligible
patients could receive reinduction therapy. The primary
end point was overall survival.*
*Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. F. Stephen Hodi, M.D.,et al., n engl j med 363;8 august 19,
2010.
11. Ipilimumab (Yervoy) cont’d
• Overall survival rate at 1 year was 46% (95% CI: 37.0, 54.1) in the Ipilimumab arm vs
25% (95% CI: 18.1, 32.9) in the gp100 arm.*
• Overall survival rate at 2 years was 24% (95% CI: 16.0, 31.5) in the Ipilimumab arm
vs 14% (95% CI: 8.0, 20.0) in the gp100 arm.*
• Median overall survival in the Ipilimumab + gp100 arm was 10 months (95% CI: 8.5,
11.5), 6 months (95% CI: 5.5, 8.7) in the gp100 arm, and 10 months (95% CI: 8.0, 13.8)
in the Ipilimumab arm.*
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*Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. F. Stephen Hodi, M.D.,et al., n engl j med 363;8 august 19, 2010.
12. Ipilimumab (Yervoy) cont’d
Associated with unique side effects of the
drug called ‘‘immune-related adverse
events’’ irAEs.
Unique kinetic of response.
13. Immune-related Adverse Events “irAEs”
Early in ipilimumab’s development, it became clear that it induced dose-related, immune-
related, or inflammatory side effects.*
The most common systems affected were the skin, gut, liver, and pituitary. *
Immunohistochemistry of affected skin and gut revealed infiltration by CD4 and CD8 T- cells,
and highly activated effector cells correlated with side effect intensity.*
Elevated inflammatory cytokines in the sera, as well as rapid resolution of some irAE
symptoms with use of the tumor necrosis factor-alpha antibody infliximab, suggested that
cytokine release by activated T cells was associated with irAEs*
Drug-related overall adverse events were observed in 84.6% of patients, of which immune-
related adverse events of any grade accounted for 72.3%.**
*Hodi FS, Mihm MC, Soiffer RJ, et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and
ovarian carcinoma patients. Proc Natl Acad Sci U S A. 2003;100:4712-4717.
**Lebbe´ C, ODay S, Chiarion Sileni V, et al. Analysis of the onset and resolution of immune-related adverse events during treatment with ipilimumab in patients with
metastatic melanoma. Presented at Perspectives in Melanoma XII, The Hague, Netherlands, October 2-4, 2008.
14. Immune-related Adverse Events “irAEs”
(cont’d)
Dermatologic Toxicity:
A diffuse, erythematous maculopapular rash that can be intensely pruritic was observed
in 47% to 68% of patients, starting an average of 3 to 4 weeks after ipilimumab.*
In 4% of patients, it was severe.*
Rare cases of toxic epidermal necrolysis, as well as Stevens-Johnson syndrome, both in
less than 1% of patients, have been reported with ipilimumab, and several patients with
those conditions have died *
Microscopic examination shows a perivascular lymphocytic infiltrate that extends deep
into the dermis in most cases.**
Immunohistochemical staining showed that CD4-positive and Melan-A-specific CD8-
positive T cells were in close proximity to apoptotic melanocytes, suggesting that an
immune response was directed against melanocytes, This is consistent with a reported
11% rate of vitiligo with ipilimumab.**
*Weber J. Ipilimumab: Controversies in its development, utility, and autoimmune adverse events. Cancer Immunol Immunother. 2009;58:823-830.
**Hodi FS, Mihm MC, Soiffer RJ, et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and
ovarian carcinoma patients. Proc Natl Acad Sci U S A. 2003;100:4712-4717.
15. Dermatologic Toxicity (cont’d):*
Topical glucocorticosteroids (e.g., betamethasone 0.1% cream) or urea-
containing creams in combination with oral antipruritics (e.g.,
diphenhydramine HCl or hydroxyzine HCl) are recommended for G1-2.
For G 3 dermatologic irAEs, one should hold a dose and treat with a 3 to
4-week tapering course of oral steroids, starting at 1 mg/kg prednisone
or dexamethasone 4 mg four times orally daily.
Ipilimumab can be held for moderate to severe skin toxicity but should
be permanently discontinued for severe, life-threatening skin toxicity
and steroids initiated at 1 to 2 mg/kg prednisone orally or its equivalent
tapering over not less than 30 days.
*Management of Immune-Related Adverse Events and Kinetics of Response With Ipilimumab, Jeffrey S. Weber, Katharina C. Ka¨hler, and Axel Hauschild VOLUME JULY 20
2012
16. Immune-related Adverse Events “irAEs”
(cont’d)
Diarrhea/Colitis
GI and hepatic adverse events began to occur within 6 to 7 weeks
Diarrhea occurs in up to 44% of patients receiving Ipilimumab at dose of
10 mg/kg.*
Severe diarrhea (grade 3 or 4; at least six diarrheal bowel movements
above baseline in 24 hours) was reported in approximately 18% of
patients.*
Diarrhea can also be associated with signs and symptoms of colitis,
which can lead to obstruction and bowel perforation, potentially
requiring colostomy. The rate of bowel perforation is less than 1%.*
IrAE-related colitis involves the descending colon more often than the
sigmoid colon, ascending colon, or rectum.**
*Robert C, Thomas L, Bondarenko I, et al: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517-
2525, 2011
** Wolchok JD, Neyns B, Linette G, et al: Ipilimumab monotherapy in patients with pretreated advanced melanoma: A randomised, double-
blind, multicentre, phase 2, dose-ranging study. Lancet Oncol 11:155-164, 2010
17. Diarrhea/Colitis (con’d):*
Low-grade diarrhea (grade 1, an increase of 2 over baseline in 24
hours) should be treated symptomatically using loperamide, oral
hydration, and electrolyte substitution.
With persistent or higher-grade diarrhea, bacterial or parasitic
infection, viral gastroenteritis, or the first manifestation of an IBD
must be ruled out by examination for stool leukocytes, stool cultures,
and a Clostridium difficile titer.
Grade 2 diarrhea can be treated with the addition of oral
diphenoxylate hydrochloride and atropine sulfate four times daily.
Endoscopy is recommended to confirm or rule out colitis with
persistent grade 2 diarrhea or grades 1 to 2 diarrhea with bleeding.
*Management of Immune-Related Adverse Events and Kinetics of Response With Ipilimumab, Jeffrey S. Weber, Katharina C. Ka¨hler, and Axel Hauschild VOLUME JULY 20
2012
18. Diarrhea/Colitis (con’d):*
For grade 3 or 4 diarrhea (7 or more increase over baseline in 24 hours),
treatment with ipilimumab should be permanently discontinued and
intravenous steroids and replenishment of fluid and electrolytes
intravenously should be instituted.
Intravenous methylprednisolone 125 mg should be given. Oral
dexamethasone 4 mg every four hours or prednisone 1 to 2 mg/kg/daily can
be given thereafter, followed by a taper and discontinuation over the next 6
weeks.
If intravenous steroids followed by high-dose oral steroids does not decrease
symptoms within 48 to 72 hours,treatment with infliximab at 5 mg/kg every
2 weeks is an alternative.
Once relief of symptoms is achieved, which can be very rapid and dramatic,
it should be discontinued and a prolonged steroid taper over 45 to 60 days
should be instituted.
*Management of Immune-Related Adverse Events and Kinetics of Response With Ipilimumab, Jeffrey S. Weber, Katharina C. Ka¨hler, and Axel Hauschild VOLUME JULY 20
2012
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71-year-old woman receiving ipilimumab for treatment of metastatic melanoma.
Axial CT image of pelvis shows mural thickening of sigmoid colon with adjacent fat
stranding and mesenteric hypervascularity. Colonic biopsy revealed moderate-to-
severe active inflammation, consistent with ipilimumab-induced colitis.
Radiologic Aspects of Immune- Related Tumor Response Criteria and Patterns of Immune-Related Adverse Events in Patients Undergoing Ipilimumab Therapy, AJR 2011; 197:W241–
W246
20. Immune-related Adverse Events “irAEs”
(cont’d)
Hepatotoxicity:
Immune-related hepatotoxicity was observed in 3% to 9% of
patients receiving anti-CTLA-4 antibodies.*’**
It usually presents as an asymptomatic increase of transaminases
and bilirubin, although some patients also have fevers and malaise.
Liver biopsies have shown a diffuse T-cell infiltrate consistent with
immune-related hepatitis.
This must be differentiated from progressive metastases in the liver,
as well as other etiologies such as viral hepatitis or another drug-
specific toxic reactions.
*Hodi FS, O’Day SJ, McDermott DF, et al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711-723, 2010
** Robert C, Thomas L, Bondarenko I, et al: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517-2525,
2011
21. Hepatotoxicity (cont’d):*
One should perform a standard workup to rule out viral hepatitis, disease
progression, and other drug-related causes for abnormal liver functions.
The current algorithm for the management of a hepatotoxicity irAE
contains the recommendation that for grades 3 to 5 toxicity, one should
use high-dose intravenous glucocorticosteroids for 24 to 48 hours,
followed by an oral steroid taper with dexamethasone in a dosage of 4 mg
every 4 hours or prednisone at 1 to 2 mg/kg tapered over not less than 30
days.
If serum transaminase levels do not decrease 48 hours after initiation of
systemic steroids, consideration should be given to the use of oral
mycophenolate mofetil 500 mg every 12 hours
Infliximab—because of its potential for hepatotoxicity—should be
avoided in this setting.
*Management of Immune-Related Adverse Events and Kinetics of Response With Ipilimumab, Jeffrey S. Weber, Katharina C. Ka¨hler, and Axel
Hauschild VOLUME JULY 20 2012
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59-year-old man with metastatic melanoma undergoing treatment with
ipilimumab. A, Baseline CT image obtained before treatment shows normal
appearance of liver. B, Repeat CT image obtained 8 weeks after commencing
treatment because of elevated liver function test levels shows diffusely decreased
attenuation of hepatic parenchyma and new periportal edema (arrow). Liver
biopsy showed severe active hepatitis consistent with drug-induced cause.
Radiologic Aspects of Immune- Related Tumor Response Criteria and Patterns of Immune-Related Adverse Events in Patients Undergoing Ipilimumab Therapy, AJR 2011; 197:W241–
W246
23. Immune-related Adverse Events “irAEs”
(cont’d)
Hypophysitis :*
Immune-related hypophysitis occurs in 1% to 6% of patients
treated with 3 or 10 mg/kg ipilimumab.
Headache, nausea, vertigo, behavior change, visual
disturbances such as diplopia, and weakness occur at an
average of 6 weeks after initiation of therapy.
The most important differential diagnosis is the new
occurrence of brain metastases. Magnetic resonance imaging
scans with gadolinium and selective cuts of the pituitary can
show enlargement or heterogeneity and confirm the diagnosis
* Blansfield JA, Beck KE, Tran K, et al: Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with
metastatic melanoma and renal cancer. J Immunother 28:593-598, 2005
24. Hypophysitis (cont’d):*
Before treatment, a blood sample should be taken to
determine pituitary, thyroid, adrenal, and gonadal
status (serum morning cortisol, adrenocorticotropic
hormone [ACTH], free triiodothyronine [T3], free
thyroxine [T4], thyroid-stimulating hormone [TSH]
and,in addition, testosterone in males and follicle
stimulating hormone, luteinizing hormone, and
prolactin in females).
Typically, low levels of thyroid, adrenal, and gonadal
hormones are found, but they may all be reduced,
only one axis may be decreased, or one may be spared.
*Management of Immune-Related Adverse Events and Kinetics of Response With Ipilimumab, Jeffrey S. Weber, Katharina C. Ka¨hler, and Axel
Hauschild VOLUME JULY 20 2012
25. Hypophysitis (cont’d): *
For symptomatic pan-hypopituitarism and for any grade 3 to 4
endocrinopathy, the ipilimumab dose should be held,
initial dose of methylprednisolone 1 to 2 mg/kg intravenously should
An
be given. This should be followed by prednisone 1 to 2 mg/kg, orally once
per day with gradual tapering over 4 weeks and replacement of
appropriate hormones as the steroid dose is tapered. Usually, after a few
days, symptoms improve, and a reduction of the swelling and
heterogeneity of the pituitary gland can be observed radiologically.
Consultation with an endocrinologist is appropriate for further
management.
*Management of Immune-Related Adverse Events and Kinetics of Response With Ipilimumab, Jeffrey S. Weber, Katharina C. Ka¨hler, and Axel
Hauschild , JCO, VOLUME JULY 20 2012
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Pituitary enlargement. (A) Magnetic resonance imaging scan of the brain with
pituitary cuts performed pretreatment on June 30, 2004; (B) same cut after
development of hypopituitarism with an enlarged and inhomogeneous
pituitary on December 3, 2004.
* Blansfield JA, Beck KE, Tran K, et al: Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with
metastatic melanoma and renal cancer. J Immunother 28:593-598, 2005
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Kinetics of appearance of Immune-Related Adverse Events*
*Management of Immune-Related Adverse Events and Kinetics of Response With Ipilimumab, Jeffrey S. Weber, Katharina C. Ka¨hler, and Axel
Hauschild , JCO, VOLUME JULY 20 2012
28. Immune-related Adverse Events “irAEs”
(cont’d)
Pancreatitis: *
Immune-related pancreatitis has been reported in less than 1.5% of
patients receiving anti-CTLA-4 antibodies. This generally
manifested as an asymptomatic increase of amylase and lipase,
although some patients also had accompanying fevers and malaise.
Nausea and vomiting were rare, although abdominal pain was
frequent, often low grade, and out proportion to the degree of
increase in the results of blood tests.
An oral steroid taper with prednisone or dexamethasone was
indicated, but often this had minimal immediate effects on the
biochemical abnormalities that resolve slowly.
*Management of Immune-Related Adverse Events and Kinetics of Response With Ipilimumab, Jeffrey S. Weber, Katharina C. Ka¨hler, and Axel
Hauschild , JCO, VOLUME JULY 20 2012
29. Immune-related Adverse Events “irAEs”
(cont’d)
Neuropathies:*
Transient peripheral neuropathies, both sensory and motor, have been reported in less
than 1% of patients. In some cases, they were minor and simply resolved spontaneously.
One can hold a dose of ipilimumab in patients with persistent grade 2 neuropathy that is
not interfering with daily activities. Persisting and worsening neuropathies should be
treated with an oral steroid taper with prednisone or dexamethasone of 3 to 4 weeks.
For severe (grade 3 and 4) neuropathies, ipilimumab should be permanently discontinued,
and one should initiate systemic corticosteroids at a dose of prednisone or equivalent 1 to 2
mg/kg once per day, including tapering over at least 30 days
*Management of Immune-Related Adverse Events and Kinetics of Response With Ipilimumab, Jeffrey S. Weber, Katharina C. Ka¨hler, and Axel
Hauschild , JCO, VOLUME JULY 20 2012
30. Unique Kinetic of Response.
The first response criteria for solid tumors were developed approximately 30 years ago by the
World Health Organization (WHO).*
More recently, these criteria have been superseded by the Response Evaluation Criteria in
Solid Tumors (RECIST) published in 2000**, and updated in 2009 (RECIST 1.1)***.
Using the latter criteria, early increases in tumor size or the appearance of new lesions is
classified as “progressive disease,” a term now synonymous with treatment failure***.
Frequency of tumour re-evaluation while on treatment should be protocol specific and
adapted to the type and schedule of treatment. However, in the context of phase II studies
where the beneficial effect of therapy is not known, follow-up every 6–8 weeks***.
*Reporting results of cancer treatment. Miller AB, Hoogstraten B, Staquet M, Winkler A.. Cancer 1981; 47:207–214
**New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of
the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92: 205–216
***New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1), EUROPEAN JOURNAL OF CANCER 4 5 ( 2 0 0 9 ) 2 2 8 –2 4 7
31. Unique Kinetic of Response (con’d)
Hamid et al.* undertook a review and analysis of five studies on 269 patients
with stage III or IV melanoma to determine the kinetics and duration of
response with ipilimumab.
An objective response was observed in 41 patients (15%). Some patients had a
late onset CR or PR occurring, at 10–106 weeks and 5–62 weeks after treatment
initiation, respectively.
In 28 patients, onset of response occurred after more than 12 weeks of
treatment, and in 4 patients, PD preceded a response without additional
therapy. In some patients, PD was followed by SD, and ultimately, PR.
The duration of response has been considerable as well, with the overall
response duration ranging from 6 to 187 weeks.
Late-onset response was not associated with dose, regimen or concomitant
therapy.
*Hamid O, Urba WJ, Yellin M et al (2007) Kinetics of response to ipilimumab (MDX-010) in patients with stage III/IV melanoma. J Clin Oncol suppl 25: abstr 8525
32. Unique Kinetic of Response (con’d)
Immune-related response criteria were proposed by a
collaborative group of approximately 200 oncologists,
immunotherapists, and regulatory experts who
convened in 2004 and 2005 to devise these criteria on
the basis of clinical observations*.
These criteria were validated using a series of large
multinational studies including 487 patients treated
with ipilimumab*.
*Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria.
Clin Cancer Res 2009; 15:7412–7420
33. Patterns of Tumor Response to Ipilimumab*:
Response to treatment with ipilimumab can be complete (immune-
related complete response) or partial (immune-related partial
response).
Four distinct patterns of tumor response to ipilimumab have been
described :
1. type A, reduction in size of baseline lesions with no new lesions;
2. type B, stable disease with no significant change in the sizeof the
baseline lesions that may or may not be followed by a slow, steady
decline in tumor size;
3. type C, initial increase in tumor burden followed by response; and
4. type D, reduction in total tumor burden in spite of the appearance of
new lesions.
*Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria.
Clin Cancer Res 2009; 15:7412–7420
34. Patterns of Tumor Response to Ipilimumab:
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Type A response to ipilimumab therapy in 55-year-old man with metastatic
melanoma to right thigh and lung. A and B, Baseline CT images obtained before
treatment show large mass in anterior compartment of right thigh (arrow, A) and right
lower lobe pulmonary nodule (arrow, B). C and D, CT images obtained 12 weeks
after commencing treatment with ipilimumab show significant reduction in size of
right thigh mass (arrow, C) and interval resolution of right lung nodule.
Radiologic Aspects of Immune- Related Tumor Response Criteria and Patterns of Immune-Related Adverse Events in Patients Undergoing Ipilimumab Therapy, AJR 2011; 197:W241–
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Type B response to ipilimumab therapy in 71-year-old woman with metastatic
melanoma to lung. A, Baseline CT image obtained before treatment shows
lobulated nodule (arrow) in right middle lobe. B, Repeat CT image obtained 12
weeks after commencing ipilimumab therapy shows no significant change in size of
nodule (arrow), indicating stable disease
Radiologic Aspects of Immune- Related Tumor Response Criteria and Patterns of Immune-Related Adverse Events in Patients Undergoing Ipilimumab Therapy, AJR 2011; 197:W241–
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Type C response to ipilimumab therapy in 56-year-old woman with metastatic
melanoma to both lower extremities. A, Lower extremity coronal reformatted CT
image shows multiple bilateral masses in medial compartments of both thighs (arrow
and arrowhead). B, Repeat CT image obtained 12 weeks after commencing
ipilimumab therapy shows interval enlargement of masses (arrow and arrowhead). C,
Repeat CT image at 24 weeks shows significant response. Arrow and arrowhead
point to areas where masses shown in A and B were.
Radiologic Aspects of Immune- Related Tumor Response Criteria and Patterns of Immune-Related Adverse Events in Patients Undergoing Ipilimumab Therapy, AJR 2011; 197:W241–
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Type D response to ipilimumab therapy in 56-year-old woman with metastatic
melanoma. A and B, CT images obtained at baseline (A) and 12 weeks after
commencing ipilimumab therapy (B) show new subcutaneous nodule in
left gluteal region (arrow, B), considered suspicious for new melanoma deposit;
other new subcutaneous nodules were also seen. C, Repeat CT image obtained
at 24 weeks shows complete resolution of nodule. Other target lesions in
same patient also showed response to treatment.
Radiologic Aspects of Immune- Related Tumor Response Criteria and Patterns of Immune-Related Adverse Events in Patients Undergoing Ipilimumab Therapy, AJR 2011; 197:W241–
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40. Science and Charity
one of the major works from Picasso’s early years. At just 15, Picasso felt mature enough to take on
large ambitious compositions as the culmination of his academic studies in Barcelona School of Fine
Arts that were led by his father Jose Ruiz Picasso, who was the model for the doctor in this painting.
Editor's Notes
diphenoxylate hydrochloride :is an opioid agonist used for the treatment of diarrhea that acts by slowing intestinal contractions and peristalsis allowing the body to consolidate intestinal contents and prolong transit time, thus allowing the intestines to draw moisture out of them at a normal or higher rate and therefore stop the formation of loose and liquid stools. It is the main active ingredient in the anti- peristaltic medication Lomotil , which also contains atropine as noted below. and atropine sulfate
mycophenolate mofetil: Mycophenolate mofetil (MMF) (brand names CellCept, Myfortic) is an immunosuppressant and prodrug of mycophenolic acid , used extensively in transplant medicine. It is a reversible inhibitor of inosine monophosphate dehydrogenase [1] (IMPDH) in purine biosynthesis (specifically guanine synthesis) which is necessary for the growth of T cells and B cells . Other cells are able to recover purines via a separate, scavenger, pathway and are, thus, able to escape the effect. MMF is a less toxic alternative to azathioprine . (wikipedia).