1) Adoptive T-cell immunotherapy (ACT) involves extracting a patient's T-cells, modifying them to better recognize cancer cells, and reintroducing them to attack the cancer. Two main types are tumor-infiltrating lymphocytes (TILs) and engineered T-cells.
2) While promising, ACT faces challenges including T-cell inhibition by the immune system and cancer, toxicity from off-target autoimmunity, and short longevity of the modified T-cells. Additional research is needed to address these issues before ACT can become widely used.
3) The lengthy and resource-intensive cell culture and testing required for each patient also makes ACT costly currently, limiting its application to rare cancers
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.
Assessing the clinical utility of cancer genomic and proteomic data across tu...Gul Muneer
This document summarizes a study that used machine learning to predict cancer patient survival based on integrating multiple types of molecular and clinical data from The Cancer Genome Atlas. The study found that combining molecular data like gene expression, methylation, and mutations with clinical data significantly improved survival prediction for kidney, ovarian, and lung cancers compared to using single data types alone. Analyzing the models provided biological insights into molecular subtypes and markers correlated with survival outcomes. The results suggest that more comprehensive molecular profiling of tumors could help stratify patients and identify targets for personalized cancer treatment.
Osteoblasts remotely supply lung tumors with cancer-promoting SiglecFhigh neu...Gul Muneer
Osteoblasts remotely supply lung tumors with cancer-promoting SiglecFhigh neutrophils. Lung tumors disrupt bone homeostasis and increase osteoblast activity and bone formation. Osteoblasts amplify tumor-associated SiglecFhigh neutrophils that promote tumor growth through angiogenesis, immunosuppression and other mechanisms. Serum from tumor-bearing mice increases osteoblast activity through elevated sRAGE, which stimulates neutrophil maturation. SiglecFhigh neutrophils correlate with poor survival in lung cancer patients. Therefore, lung tumors communicate with bone through factors like sRAGE to modulate osteoblasts and promote neutrophil-driven tumor progression.
Cancer Precision Medicine Physiological Function of C MYC as Targeted Moleculeijtsrd
The genome represents a design for creating the body, with each one being different. In cancer genomic medicine, many genes are simultaneously examined using mainly cancer tissues the oncogene panel test , and gene mutations are revealed. Cancer treatments are then initiated according to each individual's constitution and medical condition based on gene mutations. A system for cancer genome medical treatment is currently being developed. In the treatment of several cancer types, the "oncogene test with an oncogene companion diagnosis" is already being performed as a standard test using cancer tissue to detect one or several gene mutations. Precision Medicine discovering unique therapies that treat an individual's cancer based on the specific abnormalities, i.e. germline or somatic mutations of their tumors. In this paper, we will explain the biological role of C MYC and emphasize the importance of C MYC as a target factor in cancer precision medicine. The functional activated C MYC for cell proliferation and tumorigenesis is potential candidate as anti oncogenic molecule. Takuma Hayashi | Ikuo Konishi "Cancer Precision Medicine: Physiological Function of C-MYC as Targeted Molecule" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-3 | Issue-5 , August 2019, URL: https://www.ijtsrd.com/papers/ijtsrd28030.pdfPaper URL: https://www.ijtsrd.com/medicine/other/28030/cancer-precision-medicine-physiological-function-of-c-myc-as-targeted-molecule/takuma-hayashi
Sipuleucel-T (Provenge) is an autologous cellular immunotherapy for asymptomatic metastatic prostate cancer. It consists of autologous dendritic cells activated ex vivo with a recombinant fusion protein and infused back to the patient to stimulate an immune response against prostate cancer cells. Clinical trials demonstrated a significant survival benefit for patients treated with Sipuleucel-T compared to placebo. Dendreon is preparing for the commercial launch of Provenge in the US and EU, which will require a major manufacturing and logistics effort to process and deliver the personalized immunotherapy to thousands of patients.
1. Sipuleucel-T (Provenge) is an autologous cellular immunotherapy for asymptomatic metastatic prostate cancer that works by activating antigen-presenting cells and T-cells against prostatic acid phosphatase.
2. Clinical trials showed Provenge improved overall survival in metastatic castration-resistant prostate cancer patients.
3. Manufacturing and delivering Provenge presents logistical challenges due to its personalized nature that Dendreon aims to address through an advanced planning system and partnerships.
Dendreon is a biotechnology company focused on developing immunotherapies for cancer treatment. Their first product, Provenge, received FDA approval in 2010 for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer. Provenge involves extracting a patient's antigen-presenting cells and combining them with a recombinant prostate antigen to stimulate an immune response against prostate cancer cells. Dendreon is working to expand Provenge's market and develop new immunotherapy treatments targeting antigens like HER2/neu, CA-9, and CEA expressed on other cancer types. They face challenges in scaling up manufacturing and achieving reimbursement to fully commercialize Provenge in the US and expand into Europe.
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.
Assessing the clinical utility of cancer genomic and proteomic data across tu...Gul Muneer
This document summarizes a study that used machine learning to predict cancer patient survival based on integrating multiple types of molecular and clinical data from The Cancer Genome Atlas. The study found that combining molecular data like gene expression, methylation, and mutations with clinical data significantly improved survival prediction for kidney, ovarian, and lung cancers compared to using single data types alone. Analyzing the models provided biological insights into molecular subtypes and markers correlated with survival outcomes. The results suggest that more comprehensive molecular profiling of tumors could help stratify patients and identify targets for personalized cancer treatment.
Osteoblasts remotely supply lung tumors with cancer-promoting SiglecFhigh neu...Gul Muneer
Osteoblasts remotely supply lung tumors with cancer-promoting SiglecFhigh neutrophils. Lung tumors disrupt bone homeostasis and increase osteoblast activity and bone formation. Osteoblasts amplify tumor-associated SiglecFhigh neutrophils that promote tumor growth through angiogenesis, immunosuppression and other mechanisms. Serum from tumor-bearing mice increases osteoblast activity through elevated sRAGE, which stimulates neutrophil maturation. SiglecFhigh neutrophils correlate with poor survival in lung cancer patients. Therefore, lung tumors communicate with bone through factors like sRAGE to modulate osteoblasts and promote neutrophil-driven tumor progression.
Cancer Precision Medicine Physiological Function of C MYC as Targeted Moleculeijtsrd
The genome represents a design for creating the body, with each one being different. In cancer genomic medicine, many genes are simultaneously examined using mainly cancer tissues the oncogene panel test , and gene mutations are revealed. Cancer treatments are then initiated according to each individual's constitution and medical condition based on gene mutations. A system for cancer genome medical treatment is currently being developed. In the treatment of several cancer types, the "oncogene test with an oncogene companion diagnosis" is already being performed as a standard test using cancer tissue to detect one or several gene mutations. Precision Medicine discovering unique therapies that treat an individual's cancer based on the specific abnormalities, i.e. germline or somatic mutations of their tumors. In this paper, we will explain the biological role of C MYC and emphasize the importance of C MYC as a target factor in cancer precision medicine. The functional activated C MYC for cell proliferation and tumorigenesis is potential candidate as anti oncogenic molecule. Takuma Hayashi | Ikuo Konishi "Cancer Precision Medicine: Physiological Function of C-MYC as Targeted Molecule" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-3 | Issue-5 , August 2019, URL: https://www.ijtsrd.com/papers/ijtsrd28030.pdfPaper URL: https://www.ijtsrd.com/medicine/other/28030/cancer-precision-medicine-physiological-function-of-c-myc-as-targeted-molecule/takuma-hayashi
Sipuleucel-T (Provenge) is an autologous cellular immunotherapy for asymptomatic metastatic prostate cancer. It consists of autologous dendritic cells activated ex vivo with a recombinant fusion protein and infused back to the patient to stimulate an immune response against prostate cancer cells. Clinical trials demonstrated a significant survival benefit for patients treated with Sipuleucel-T compared to placebo. Dendreon is preparing for the commercial launch of Provenge in the US and EU, which will require a major manufacturing and logistics effort to process and deliver the personalized immunotherapy to thousands of patients.
1. Sipuleucel-T (Provenge) is an autologous cellular immunotherapy for asymptomatic metastatic prostate cancer that works by activating antigen-presenting cells and T-cells against prostatic acid phosphatase.
2. Clinical trials showed Provenge improved overall survival in metastatic castration-resistant prostate cancer patients.
3. Manufacturing and delivering Provenge presents logistical challenges due to its personalized nature that Dendreon aims to address through an advanced planning system and partnerships.
Dendreon is a biotechnology company focused on developing immunotherapies for cancer treatment. Their first product, Provenge, received FDA approval in 2010 for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer. Provenge involves extracting a patient's antigen-presenting cells and combining them with a recombinant prostate antigen to stimulate an immune response against prostate cancer cells. Dendreon is working to expand Provenge's market and develop new immunotherapy treatments targeting antigens like HER2/neu, CA-9, and CEA expressed on other cancer types. They face challenges in scaling up manufacturing and achieving reimbursement to fully commercialize Provenge in the US and expand into Europe.
Nigella sativa bioactives against Non-Small Cell Lung Cancer & Breast CancerYusuf Asad
This document summarizes a study on targeting the ERK and AKT pathways in non-small cell lung cancer and triple-negative breast cancer cells with bioactives from Nigella sativa. The study found that thymoquinone (TQ) and thymol (THY) from N. sativa exhibited cytotoxic effects on cancer cells in a dose-dependent manner. Combining THY and TQ showed greater inhibition of cell viability than either component alone. Treatment with the combination also significantly downregulated expression of the AKT and ERK genes involved in proliferation. The findings suggest TQ may improve the efficacy of THY as an adjuvant therapy for lung and breast cancers.
The document summarizes immunotherapy approaches for treating cancer patients, including therapeutic vaccines, passive immunotherapy using monoclonal antibodies, and adoptive cell transfer therapy. It discusses antigens targeted by vaccines, types of vaccines like whole cell, peptide, and dendritic cell vaccines, and adjuvants used to stimulate immune responses. It also notes challenges faced by immunotherapy like tumor evasion mechanisms and the need for clinical efficacy data.
Content Cytotoxicity Studies of Colorectal Carcinoma Cells Using Printed Impe...journalBEEI
Monitoring the effectiveness of drugs on cancer cells is crucial for chemotherapeutics studies. In-vitro cell-based biosensors can be used as an alternative for characteristic studies of cells’ response to drugs. Cell-based sensors provide real-time measurements and require smaller sample volumes compared to conventional T-flask measurement methods. This paper presents a biosensor that detects in real-time, impedance variations of human colon cancer, HCT-116 cells when treated with anti-cancer agent, 5-Fluorouracil (5-FU). Two different extracellular matrix (ECM); polyaniline and gelatin were tested and evaluated in terms of attachment quality. Polyaniline was found to provide the best attachment for HCT-116 cells and was used for cytotoxicity studies. Cytokinetic behavior indicated that 5-FU inhibited HCT-116 cells at IC50 of 6.8 µg/mL. Trypan blue exclusion method for testing cell viability was used to validate the impedance measurements, where the cancer cell concentrations were reduced to ~35% when treated with 2.5 µg/mL, and 50% when treated with 6.8 µg/mL. The results generated by the microfabricated impedance biosensor are comparable to the Trypan blue method since both gave similar cell growth trend. It can be concluded that the impedance biosensor has potential to be used as an alternative method in drug testing applications.
Cancer is one of the most challenging diseases and up until now. One of the most challenging things about cancer treatment is not the cure itself but the differentiation between the tumor cells and the normal cells. Most of the medical treatments of the cancer today cannot differentiate between the cancer cells and the normal one as well as it damages the hall tissue and it is still considered as a low-effect treatment to be applied in cancer. One of the most popular treatments of this kind is chemotherapy which is known for damaging the hall cells, cancer, and normal ones. Our research is focusing on generating a new therapy that can target the cancer cell itself so it will give us more efficiency ratio to stop cancer and will keep the other cells without any damage. We will use an antibody body for the protein antigen ErbB-2 which is located rabidly in the lung cancer cells' membrane surface. These antibodies will be produced by the immune system so it will target the tumor cells especially and stop the cell growth and damage it in some cases.
This document provides an overview of principles of cancer immunotherapy. It discusses anti-cancer immunity mechanisms like antigen presentation and T cell activation. It also examines how cancers can evade the immune system through strategies like low MHC expression and immunosuppressive factors. The document then reviews clinical applications of immunotherapy including cytokines, monoclonal antibodies, adoptive cell transfer, vaccines, and checkpoint inhibitors. Combination therapies are showing promise for enhancing anti-tumor responses.
University of Missouri - Columbia, POSH Inhibitor-Based Cancer Therapykphodel
This document summarizes research into developing a non-toxic cancer treatment by inhibiting POSH and JNK1/JNK2. The treatment shows promise in killing various leukemia and lymphoma cell lines as well as drug-resistant cancer cells in mice. It may also have applications for autoimmune diseases and viral infections by selectively eliminating T-cells and reducing HIV viral release. Next steps include further testing in mice and canines along with developing targeted delivery methods before potential human trials. The researchers are seeking partners for licensing, sponsored research, and collaboration.
Sipuleucel_T Immunotherapy for Metastatic Prostate Cancer after Failing Hormo...mjavan2001
This PowerPoint presentation demonstrates findings on a clinical trial of sipuleucel-T in HRPC patients to evaluate overall survival in this group. The FDA approval of Provenge was based on the results of IMPACT study.
Global cancer immunotherapy market outlook 2020KuicK Research
The document provides an overview of the global cancer immunotherapy market outlook for 2020. It discusses how cancer immunotherapies work by modulating the immune system to treat cancer. The market has seen significant growth with many approved and pipeline immunotherapies across classes like monoclonal antibodies, cytokines, vaccines, and immune checkpoint inhibitors. The market is expected to continue growing in coming years due to increased research and funding leading to new treatment modalities and biomarkers to expand the use of immunotherapies for additional cancer types.
1) The document discusses tumor immunology and mechanisms of tumor immune evasion. It describes how tumors can downregulate MHC expression, secrete immunosuppressive factors, inhibit T cell function through checkpoint pathways like PD-1/PD-L1, and recruit immunosuppressive cells like Tregs.
2) Checkpoint pathways like CTLA-4 and PD-1 normally regulate T cell activation, but tumors can exploit these pathways to evade immune destruction by overexpressing ligands that bind these inhibitory receptors.
3) Several immunotherapies targeting CTLA-4 and PD-1/PD-L1 have been developed including ipilimumab, nivolumab, pembrol
This document discusses various animal models that can be used for cancer drug development and evaluation. It describes several types of models including spontaneous tumor models, virus-induced models, radiation-induced models, chemically-induced models, and transplantable tumor models. Transplantable tumor models involve transplanting cancer cell lines or tissues into mice or rats, which can be done either heterotopically or orthotopically. These models provide advantages such as being easy to control and having many tumor types available, but they do not fully recapitulate human cancer development and progression. The document emphasizes that the appropriate selection of an animal model is crucial for properly evaluating new drug candidates.
This document provides an overview of immunotherapy for cancer treatment. It discusses how the immune system normally protects the body from cancer but can fail to control cancer cells. Various immunotherapy strategies are described to harness the immune system against cancer, including improving antigen presentation to prime more immune cells. The history and types of cancer immunotherapy are reviewed, as well as how immunotherapy works, common approaches, effectiveness, and potential risks. Current research focuses on continuing to develop more effective immunotherapy treatments for cancer.
This document discusses cancer gene therapy. It explains that gene therapy involves introducing genetic material into cells to replace missing or defective genes that may cause cancer. There are two main approaches - ex vivo gene therapy, where genes are introduced into cells removed from the body and cultured before being returned, and in vivo gene therapy where genes are directly delivered to target cells and tissues in the body. Various gene delivery methods and vector systems are described. Examples of specific cancer types and genes targeted for therapy are provided, such as introducing the Hs-tk gene for ovarian cancer treatment. The goals and applications of cancer gene therapy are to alter the immunogenicity of tumors, genetically modify immune cells, introduce suicide or sensitivity genes, and replace tumor suppressor
This document summarizes the effects of malignancies and cancer treatments on the human immune system. It discusses how both cancers and therapies can impair the innate and adaptive immune responses. Barriers like mucositis increase infection risk. Therapies can decrease natural killer cells, phagocytes, and dendritic cells. They also impact regulatory T cells and suppress T cell and humoral immune functions. Maintaining immune defenses is important for fighting infection and potentially enhancing cancer immunotherapy approaches.
The document discusses cancer immunotherapy and biomarkers. It provides diagrams of immune checkpoint blockade showing how CTLA-4 and PD-1 inhibitors work. It lists FDA-approved immune checkpoint inhibitors across different cancer types. Emerging immunotherapy targets and combinations are discussed, as well as current and emerging biomarkers like PD-L1 expression, MSI/MMR status, and tumor mutational burden that can help identify patients most likely to respond to immunotherapy. Practice aids provide more details on mechanisms, targets, and biomarker testing.
1. The document discusses new targeted cancer therapies that inhibit specific deregulated proteins, which could enable individualized treatment approaches.
2. It describes RPPA (Reverse Phase Protein Microarray) technology, which can quantitatively measure proteins from tumor tissues and may help reliably screen for new therapeutic targets and biomarkers.
3. Several examples of currently used targeted cancer drugs are provided along with their tumor types and protein targets, which are detected using methods like IHC, FISH, and mutational analysis. The integration of DNA, RNA, and protein profiling is said to provide a comprehensive tumor description to select patients for individualized targeted therapies.
This document summarizes Keiya Ozawa's research on CD19-targeted CAR T-cell therapy for B-cell lymphoma. It describes the design of CARs to target the CD19 antigen on B-cells, experimental data showing CD19-CAR T-cells effectively killed CD19-positive lymphoma cells in vitro and in mouse models, and outlines Ozawa's ongoing clinical trial testing CD19-CAR T-cell therapy in patients with relapsed/refractory B-cell lymphoma. The clinical trial uses lymphodepletion prior to infusing autologous T-cells engineered to express an anti-CD19 CAR to determine the maximum tolerated dose.
1. Aberrations in sphingolipid metabolism are implicated in promoting glioblastoma multiforme (GBM) aggressiveness. GBM exhibits lower levels of ceramide and higher levels of sphingosine-1-phosphate (S1P) compared to normal brain tissue.
2. GBM manipulates sphingolipid pathways to shift the balance towards higher S1P and lower ceramide. Mechanisms include upregulating S1P-producing enzymes and downregulating ceramide-producing enzymes and phosphatases.
3. Receptors for the bioactive sphingolipid S1P are also upregulated in GBM, suggesting S1P signaling contributes to GBM
This document discusses the immunobiology of cancer. It begins with an outline and then covers cancer causes including genetic factors and carcinogens. It describes the innate and adaptive immune system, including mechanisms of immunosurveillance and immunoediting that allow tumors to evade detection. As an example, it examines hepatocellular carcinoma and the failure of immune responses against it. The document concludes by discussing immunotherapy approaches like passive monoclonal antibody therapy and active vaccination strategies that aim to harness the immune system against cancer.
This presentation was made for Journal club session about 2017 article from Journal of cancer immunotherapy. It reveals a new method of chemokine receptor gene modification on NK cells to improve their migration into tumor site. Such modification helps us to "cheat" tumor by changing the pattern of immune cells homing.
Chimeric Antigen Receptors (paper with corresponding power point)Kevin B Hugins
Gene therapy was first conceptualized to alter debilitating fates of genetic diseases. Gene therapy technology can help introduce new functional DNA to replace mutated genes. The idea first arose in 1972 when Friedmann and Roblin authored a paper, “Gene therapy for human genetic disease?”, demonstrating that exogenous DNA can be taken up by mammalian cells (1). They proposed that the same procedure could be done on humans to correct genetic defects by introducing therapeutic DNA. Currently, genetic modification of T lymphocytes has been the major area of research for treating malignant tumors. This technique seeks to create chimeric antigen receptor (CAR) in T cells by genetically modifying them in vitro and reintroduce them back into blood circulation. The T cells are unique to every patient and the chimeric antigen receptors are unique to the tumor that it is targeting.
Engineered T Cell Therapy for
Gynecologic Malignancies
Challenges and Opportu...RudrikaChandra1
This document discusses engineered T cell therapy for gynecologic malignancies. It begins by introducing common gynecologic cancers and recent successes of adoptive T cell therapy using engineered T cells for other cancers. The document then summarizes two main types of engineered T cells - T cell receptor modified T cells (TCR-Ts) and chimeric antigen receptor T cells (CAR-Ts) - and their mechanisms of action. Finally, it explores opportunities to apply these engineered T cell therapies to treat gynecologic cancers based on preclinical research and early clinical trials.
Nigella sativa bioactives against Non-Small Cell Lung Cancer & Breast CancerYusuf Asad
This document summarizes a study on targeting the ERK and AKT pathways in non-small cell lung cancer and triple-negative breast cancer cells with bioactives from Nigella sativa. The study found that thymoquinone (TQ) and thymol (THY) from N. sativa exhibited cytotoxic effects on cancer cells in a dose-dependent manner. Combining THY and TQ showed greater inhibition of cell viability than either component alone. Treatment with the combination also significantly downregulated expression of the AKT and ERK genes involved in proliferation. The findings suggest TQ may improve the efficacy of THY as an adjuvant therapy for lung and breast cancers.
The document summarizes immunotherapy approaches for treating cancer patients, including therapeutic vaccines, passive immunotherapy using monoclonal antibodies, and adoptive cell transfer therapy. It discusses antigens targeted by vaccines, types of vaccines like whole cell, peptide, and dendritic cell vaccines, and adjuvants used to stimulate immune responses. It also notes challenges faced by immunotherapy like tumor evasion mechanisms and the need for clinical efficacy data.
Content Cytotoxicity Studies of Colorectal Carcinoma Cells Using Printed Impe...journalBEEI
Monitoring the effectiveness of drugs on cancer cells is crucial for chemotherapeutics studies. In-vitro cell-based biosensors can be used as an alternative for characteristic studies of cells’ response to drugs. Cell-based sensors provide real-time measurements and require smaller sample volumes compared to conventional T-flask measurement methods. This paper presents a biosensor that detects in real-time, impedance variations of human colon cancer, HCT-116 cells when treated with anti-cancer agent, 5-Fluorouracil (5-FU). Two different extracellular matrix (ECM); polyaniline and gelatin were tested and evaluated in terms of attachment quality. Polyaniline was found to provide the best attachment for HCT-116 cells and was used for cytotoxicity studies. Cytokinetic behavior indicated that 5-FU inhibited HCT-116 cells at IC50 of 6.8 µg/mL. Trypan blue exclusion method for testing cell viability was used to validate the impedance measurements, where the cancer cell concentrations were reduced to ~35% when treated with 2.5 µg/mL, and 50% when treated with 6.8 µg/mL. The results generated by the microfabricated impedance biosensor are comparable to the Trypan blue method since both gave similar cell growth trend. It can be concluded that the impedance biosensor has potential to be used as an alternative method in drug testing applications.
Cancer is one of the most challenging diseases and up until now. One of the most challenging things about cancer treatment is not the cure itself but the differentiation between the tumor cells and the normal cells. Most of the medical treatments of the cancer today cannot differentiate between the cancer cells and the normal one as well as it damages the hall tissue and it is still considered as a low-effect treatment to be applied in cancer. One of the most popular treatments of this kind is chemotherapy which is known for damaging the hall cells, cancer, and normal ones. Our research is focusing on generating a new therapy that can target the cancer cell itself so it will give us more efficiency ratio to stop cancer and will keep the other cells without any damage. We will use an antibody body for the protein antigen ErbB-2 which is located rabidly in the lung cancer cells' membrane surface. These antibodies will be produced by the immune system so it will target the tumor cells especially and stop the cell growth and damage it in some cases.
This document provides an overview of principles of cancer immunotherapy. It discusses anti-cancer immunity mechanisms like antigen presentation and T cell activation. It also examines how cancers can evade the immune system through strategies like low MHC expression and immunosuppressive factors. The document then reviews clinical applications of immunotherapy including cytokines, monoclonal antibodies, adoptive cell transfer, vaccines, and checkpoint inhibitors. Combination therapies are showing promise for enhancing anti-tumor responses.
University of Missouri - Columbia, POSH Inhibitor-Based Cancer Therapykphodel
This document summarizes research into developing a non-toxic cancer treatment by inhibiting POSH and JNK1/JNK2. The treatment shows promise in killing various leukemia and lymphoma cell lines as well as drug-resistant cancer cells in mice. It may also have applications for autoimmune diseases and viral infections by selectively eliminating T-cells and reducing HIV viral release. Next steps include further testing in mice and canines along with developing targeted delivery methods before potential human trials. The researchers are seeking partners for licensing, sponsored research, and collaboration.
Sipuleucel_T Immunotherapy for Metastatic Prostate Cancer after Failing Hormo...mjavan2001
This PowerPoint presentation demonstrates findings on a clinical trial of sipuleucel-T in HRPC patients to evaluate overall survival in this group. The FDA approval of Provenge was based on the results of IMPACT study.
Global cancer immunotherapy market outlook 2020KuicK Research
The document provides an overview of the global cancer immunotherapy market outlook for 2020. It discusses how cancer immunotherapies work by modulating the immune system to treat cancer. The market has seen significant growth with many approved and pipeline immunotherapies across classes like monoclonal antibodies, cytokines, vaccines, and immune checkpoint inhibitors. The market is expected to continue growing in coming years due to increased research and funding leading to new treatment modalities and biomarkers to expand the use of immunotherapies for additional cancer types.
1) The document discusses tumor immunology and mechanisms of tumor immune evasion. It describes how tumors can downregulate MHC expression, secrete immunosuppressive factors, inhibit T cell function through checkpoint pathways like PD-1/PD-L1, and recruit immunosuppressive cells like Tregs.
2) Checkpoint pathways like CTLA-4 and PD-1 normally regulate T cell activation, but tumors can exploit these pathways to evade immune destruction by overexpressing ligands that bind these inhibitory receptors.
3) Several immunotherapies targeting CTLA-4 and PD-1/PD-L1 have been developed including ipilimumab, nivolumab, pembrol
This document discusses various animal models that can be used for cancer drug development and evaluation. It describes several types of models including spontaneous tumor models, virus-induced models, radiation-induced models, chemically-induced models, and transplantable tumor models. Transplantable tumor models involve transplanting cancer cell lines or tissues into mice or rats, which can be done either heterotopically or orthotopically. These models provide advantages such as being easy to control and having many tumor types available, but they do not fully recapitulate human cancer development and progression. The document emphasizes that the appropriate selection of an animal model is crucial for properly evaluating new drug candidates.
This document provides an overview of immunotherapy for cancer treatment. It discusses how the immune system normally protects the body from cancer but can fail to control cancer cells. Various immunotherapy strategies are described to harness the immune system against cancer, including improving antigen presentation to prime more immune cells. The history and types of cancer immunotherapy are reviewed, as well as how immunotherapy works, common approaches, effectiveness, and potential risks. Current research focuses on continuing to develop more effective immunotherapy treatments for cancer.
This document discusses cancer gene therapy. It explains that gene therapy involves introducing genetic material into cells to replace missing or defective genes that may cause cancer. There are two main approaches - ex vivo gene therapy, where genes are introduced into cells removed from the body and cultured before being returned, and in vivo gene therapy where genes are directly delivered to target cells and tissues in the body. Various gene delivery methods and vector systems are described. Examples of specific cancer types and genes targeted for therapy are provided, such as introducing the Hs-tk gene for ovarian cancer treatment. The goals and applications of cancer gene therapy are to alter the immunogenicity of tumors, genetically modify immune cells, introduce suicide or sensitivity genes, and replace tumor suppressor
This document summarizes the effects of malignancies and cancer treatments on the human immune system. It discusses how both cancers and therapies can impair the innate and adaptive immune responses. Barriers like mucositis increase infection risk. Therapies can decrease natural killer cells, phagocytes, and dendritic cells. They also impact regulatory T cells and suppress T cell and humoral immune functions. Maintaining immune defenses is important for fighting infection and potentially enhancing cancer immunotherapy approaches.
The document discusses cancer immunotherapy and biomarkers. It provides diagrams of immune checkpoint blockade showing how CTLA-4 and PD-1 inhibitors work. It lists FDA-approved immune checkpoint inhibitors across different cancer types. Emerging immunotherapy targets and combinations are discussed, as well as current and emerging biomarkers like PD-L1 expression, MSI/MMR status, and tumor mutational burden that can help identify patients most likely to respond to immunotherapy. Practice aids provide more details on mechanisms, targets, and biomarker testing.
1. The document discusses new targeted cancer therapies that inhibit specific deregulated proteins, which could enable individualized treatment approaches.
2. It describes RPPA (Reverse Phase Protein Microarray) technology, which can quantitatively measure proteins from tumor tissues and may help reliably screen for new therapeutic targets and biomarkers.
3. Several examples of currently used targeted cancer drugs are provided along with their tumor types and protein targets, which are detected using methods like IHC, FISH, and mutational analysis. The integration of DNA, RNA, and protein profiling is said to provide a comprehensive tumor description to select patients for individualized targeted therapies.
This document summarizes Keiya Ozawa's research on CD19-targeted CAR T-cell therapy for B-cell lymphoma. It describes the design of CARs to target the CD19 antigen on B-cells, experimental data showing CD19-CAR T-cells effectively killed CD19-positive lymphoma cells in vitro and in mouse models, and outlines Ozawa's ongoing clinical trial testing CD19-CAR T-cell therapy in patients with relapsed/refractory B-cell lymphoma. The clinical trial uses lymphodepletion prior to infusing autologous T-cells engineered to express an anti-CD19 CAR to determine the maximum tolerated dose.
1. Aberrations in sphingolipid metabolism are implicated in promoting glioblastoma multiforme (GBM) aggressiveness. GBM exhibits lower levels of ceramide and higher levels of sphingosine-1-phosphate (S1P) compared to normal brain tissue.
2. GBM manipulates sphingolipid pathways to shift the balance towards higher S1P and lower ceramide. Mechanisms include upregulating S1P-producing enzymes and downregulating ceramide-producing enzymes and phosphatases.
3. Receptors for the bioactive sphingolipid S1P are also upregulated in GBM, suggesting S1P signaling contributes to GBM
This document discusses the immunobiology of cancer. It begins with an outline and then covers cancer causes including genetic factors and carcinogens. It describes the innate and adaptive immune system, including mechanisms of immunosurveillance and immunoediting that allow tumors to evade detection. As an example, it examines hepatocellular carcinoma and the failure of immune responses against it. The document concludes by discussing immunotherapy approaches like passive monoclonal antibody therapy and active vaccination strategies that aim to harness the immune system against cancer.
This presentation was made for Journal club session about 2017 article from Journal of cancer immunotherapy. It reveals a new method of chemokine receptor gene modification on NK cells to improve their migration into tumor site. Such modification helps us to "cheat" tumor by changing the pattern of immune cells homing.
Chimeric Antigen Receptors (paper with corresponding power point)Kevin B Hugins
Gene therapy was first conceptualized to alter debilitating fates of genetic diseases. Gene therapy technology can help introduce new functional DNA to replace mutated genes. The idea first arose in 1972 when Friedmann and Roblin authored a paper, “Gene therapy for human genetic disease?”, demonstrating that exogenous DNA can be taken up by mammalian cells (1). They proposed that the same procedure could be done on humans to correct genetic defects by introducing therapeutic DNA. Currently, genetic modification of T lymphocytes has been the major area of research for treating malignant tumors. This technique seeks to create chimeric antigen receptor (CAR) in T cells by genetically modifying them in vitro and reintroduce them back into blood circulation. The T cells are unique to every patient and the chimeric antigen receptors are unique to the tumor that it is targeting.
Engineered T Cell Therapy for
Gynecologic Malignancies
Challenges and Opportu...RudrikaChandra1
This document discusses engineered T cell therapy for gynecologic malignancies. It begins by introducing common gynecologic cancers and recent successes of adoptive T cell therapy using engineered T cells for other cancers. The document then summarizes two main types of engineered T cells - T cell receptor modified T cells (TCR-Ts) and chimeric antigen receptor T cells (CAR-Ts) - and their mechanisms of action. Finally, it explores opportunities to apply these engineered T cell therapies to treat gynecologic cancers based on preclinical research and early clinical trials.
The document discusses several clinical trials involving TIL therapy for melanoma:
1) A 1986 NIH clinical protocol treating advanced melanoma with TIL showed a 35-40% response rate, even in patients who did not respond to other therapies including IL-2 alone.
2) However, the procedure was expensive and difficult due to the large numbers of TILs and high doses of IL-2 required. Only a subset of the heterogeneous TIL population appeared to be effective in vivo.
3) The protocol has since been optimized by Dr. Rosenberg's group at NIH, achieving a 72% response rate using pre-conditioning lymphodepletion.
4) Data from patient samples pre-
Cancer stem cells (CSCs) are a subset of cells found in tumors that can self-renew and differentiate, leading to tumor growth, recurrence, and metastasis. In contrast to normal stem cells, CSCs have mutations that allow uncontrolled growth and resistance to chemotherapy and radiation. Immunocellular Therapeutics' dendritic cell-based vaccine ICT-107 targets multiple CSC antigens to activate the immune system against brain cancer cells. Phase I/II trials showed ICT-107 increased survival rates and time to tumor progression compared to standard treatments.
Chemosensitivity Testing of Circulating Epithelial Tumor Cells (CETC) in Vitr...Peter Pachmann
ABSTRACT
Background: Chemotherapy is a mainstay of tumor therapy, however, it is predominantly applied according to empiri- cally developed recommendations derived from statistical relapse rates occurring years after the treatment in the adju- vant situation and from progression-free interval data in the metastatic situation, without any possibility of individually determining the efficacy in the adjuvant situation and with loss of time and quality of life in the metastatic situation if the drugs chosen are not effective. Here, we present a method to determine the efficiency of chemotherapeutic drugs using tumor cells circulating in blood as the part of the tumor actually available in the patient’s body for chemosensitiv- ity testing. Methodology/Principal Findings: After only red blood cell lysis, omitting any enrichment (analogous to other blood cell enumeration methods, including rare CD34 cells), the white cells comprising the circulating epithelial tumor cells (CETC) are exposed to the drugs in question in different concentrations and for different periods of time. Staining with a fluorescence-labeled anti-epithelial antibody detects both vital and dying tumor cells, distinguishing vital from dying cells through membrane permeability and nuclear staining with propidium iodide. Increasing percent- ages of dying tumor cells are observed dependent on time and concentration. The sensitivity can vary during therapy and was correlated with decrease or increase in CETC and clinical outcome. Conclusions/Significance: Thus, we are able to show that chemosensitivity testing of circulating tumor cells provides real-time information about the sensitivity of the tumor present in the patient, even at different times during therapy, and correlates with treatment success.
T cells genetically engineered to express chimeric antigen receptors (CAR) have proven an impressive therapeutic activity in patients with certain subtypes of B cell leukaemia or lymphoma, with promising efficacy also demonstrated in patients with multiple myeloma. However, in patients with solid tumors, objective responses to CAR-T cell therapy remain sporadic and transient. Key challenges relating to CAR T cells include the lack of tumor exclusive target, restricted CAR-T cell trafficking to tumor sites, antigen escape and heterogeneity as well as a highly immunosuppressive microenvironment. In this report, we review the current state of the CAR-T technologies as a clinical treatment in solid tumor and we highlight the preclinical innovative designs of novel CAR T cell products that are being developed to increase and expand the clinical benefits of these treatments in patients with solid malignancies.
Gene therapy involves inserting genetic material into cells to give them a new or restore a missing function. It can be used to treat cancer by modifying cancer cells at the molecular level, such as replacing a defective tumor suppressor gene like p53 to stop uncontrolled cell growth or induce cell death. Several approaches for gene therapy for cancer have shown promise in preclinical studies, including restoring tumor suppressor gene function, blocking oncogenes, and introducing "suicide genes" to selectively kill cancer cells. However, challenges remain to effectively target all cancer cells, including metastases.
This proposal outlines a thesis project to investigate the role of chemokines CCL19b and CCL25b in recruiting T cells into melanoma tumors. The student hypothesizes that inducing expression of these chemokines in melanoma cell lines transplanted into an animal model will increase T cell recruitment and reduce tumor burden. The proposal provides background on melanoma, the immune system response to tumors, and current immunotherapy strategies including adoptive T cell transfer and immune checkpoint inhibitors. If successful, the research could provide a new treatment option or complement existing therapies to improve patient survival rates.
Chemotherapy Friends or Foe to Cancer Immunotherapy by Prof. Mohamed L. SalemProf. Mohamed Labib Salem
This talk is presented by Mohamed Labib Salem, Ph.D.; Prof. of Immunology; Director, Center of Excellence in Cancer Research, Tanta University, Egypt
at the 15TH INTERNATIONAL CONFERENCE ON CHEMISTRY AND ITS ROLE IN DEVELOPMENT (15TH ICCRD), August 9, 2021
Faculty of Science, Mansoura University, Egypt
The document discusses a potential "magic bullet" combinatorial therapy for melanoma. It would involve a sequence of drugs: 1) that make the tumor more susceptible to chemotherapy by shedding tumor antigens, 2) that suppress regulatory T cells and activate immune cells, and 3) that keep cytotoxic T cells activated long-term. Achieving an immune response requires not just T cells but various immune system components and the tumor microenvironment. The therapy aims to first generate tumor antigens via radiation or chemotherapy, then activate T cells using drugs like anti-CTLA-4 and anti-PD-1 to overcome regulatory T cell suppression, in order to induce a robust and sustained immune response against the tumor.
This document summarizes recent advances in immunotherapy for solid tumors. It discusses how immunotherapy has established itself as an effective treatment strategy, building on William Coley's pioneering work in the late 1800s using bacteria to elicit anti-tumor immune responses. The document outlines several key immunotherapy approaches, including immune checkpoint inhibitors, adoptive cellular therapy, strategies to enhance tumor immunogenicity like radiotherapy and oncolytic viruses, and cancer vaccines. It also discusses how tumor-infiltrating lymphocytes and immunoscore can help predict cancer prognosis and how the immune system interacts with tumors.
Co-Chairs, Nasser Altorki, MD, and Jonathan D. Spicer, MD, PhD, FRCSC, prepared useful Practice Aids pertaining to NSCLC for this CME/MOC activity titled “How to Integrate Perioperative Immunotherapy Into Multimodal Treatment Plans to Improve Outcomes in Resectable NSCLC.” For the full presentation, downloadable Practice Aids, and complete CME/MOC information, and to apply for credit, please visit us at https://bit.ly/3xb6WS1. CME/MOC credit will be available until June 14, 2023.
Gastroenterology Medicine & Research-Crimson Publishers: Can we Optimize Immu...CrimsonGastroenterology
Immunotherapy is revolutionizing oncology, with a simple guiding principle: the host immune system has the potential to eradicate cancer, treatment consisting in optimizing immune actors' functions. Although significant results were demonstrated in patients with melanoma or lung cancer, objective response rate (ORR) is only 20% in digestive oncology. However, we can improve this situation by a better knowledge of anti-tumor immunity. For example, ORR is multiplied by two to three in case of PD-L1 (programmed death-ligand 1) overexpression or microsatellite instability (MSI). In a near future, we will certainly be able to take into account other biomarkers for building composite scores for assigning to each patient with digestive cancer an 'immune identity card' able to strongly predict immunotherapy efficacy.
Chair & Moderator, Prof. Solange Peters, MD, PhD, Mark M. Awad, MD, PhD, and Jonathan D. Spicer, MD, PhD, FRCSC, prepared useful Practice Aids pertaining to Cancer Immunotherapy for this CME/MOC/CC activity titled “Parsing the Practicalities of Pathologic Response Assessment After Neoadjuvant Immunotherapy to Facilitate Progress in Early-Stage Cancers.” For the full presentation, downloadable Practice Aids, and complete CME/MOC/CC information, and to apply for credit, please visit us at https://bit.ly/3uRHyjk. CME/MOC/CC credit will be available until May 9, 2023.
CAR-T cells are T cells that are genetically engineered to express chimeric antigen receptors (CARs) that target specific antigens on tumor cells. The first CAR-T cell therapy, Kymriah, was approved in 2017 for treating B-cell acute lymphoblastic leukemia. It showed high rates of complete remission. While effective, CAR-T cells can cause cytokine release syndrome and neurotoxicity as side effects. Ongoing research aims to expand CAR-T cell use in solid tumors and improve their safety profile.
Cytokine Immunotherapy: A Forthcoming Visible Feature in Cancer TherapeuticsSachin K. S. Chauhan
The document discusses cytokine immunotherapy as a promising approach for cancer treatment. It notes that cytokines can stimulate the immune system to fight tumors, but that mono-cytokine therapy has limitations. Combined cytokine therapy or cytokine therapy combined with other treatments may be more effective by creating a specific immune response. The document advocates focusing research on combination therapies to help overcome drawbacks of traditional cancer treatments.
This white paper discusses improving the clinical development of cancer immunotherapies. It outlines the current immunotherapy landscape including checkpoint inhibitors, adoptive T cell therapies, cancer vaccines, and biomarkers. The paper emphasizes that while immunotherapy has promising results for some patients and cancer types, more research is needed to understand which patients will benefit most from which approaches and how to best leverage various immune system components in the fight against cancer. Operational considerations and cautions for clinical development are also discussed.
Similar to Review of Adoptive T-Cell Immunotherapy (20)
1. Luke Brennan
4/21/2015
Review of Adoptive T-Cell Immunotherapy
INTRODUCTION
One of the ‘hallmarks’ of cancer is its ability to evade detection and destruction by the body’s
immune system by essentially hiding in plain sight1
. Cancer is also inherently derived from the body’s
own tissue, and harbors many of the signals that identify it as ‘self,’ which contributes to its
camoflauge1
. These two factors have made cancer so difficult to treat, because the immune system is
insufficient and man-made chemicals and radiation therapy used to attack cancer inevitably targets
unintended healthy tissue.
These issues and more prompted the development of immunotherapy for cancer treatment.
Much like how a vaccination conditions the adaptive immune system to respond to a certain pathogen,
immunotherapy would allow the immune system to sense and destroy cancer, though it uses different
means. This is often referred to as the cancer immunosurveillance hypothesis, and it gained significant
support after the verification of human tumor-associated antigens (TAAs) which are identifiers unique to
cancer, and can be exploited to discern cancer from healthy tissue2
.
Although immunotherapy is used to treat cancer in many ways, the scope of this paper will be
limited to Adoptive T-Cell Therapy (ACT). T-cells are lymphocytes, or white blood cells, which are present
throughout the body and attack pathogens and cells marked for apoptosis. T cells usually destroy cells
that would become cancerous before they even become a problem, when these mutated cells aren’t
destroyed and proliferate in an uncontrolled way they become cancers. ACT is the process by which T-
cells (originally extracted from the body, in most cases and for the purposes of this paper) with cancer-
recognizing properties are introduced into the patient to combat cancer.
Harnessing the power of these cancer sensitive T cells for use against cancer has great potential
for many reasons:
“1) T cell responses are specific, and can thus potentially distinguish between healthy
and cancerous tissue;
2) T cells responses are robust, undergoing up to 1,000-fold clonal expansion after activation;
3) T cell response can traffic to the site of antigen, suggesting a mechanism for eradication of
distant metastases;
4) T cell responses have memory, maintaining therapeutic effect for many years after initial
treatment.”2
As elegant a solution as immunotherapy may seem for the above reasons, many challenges
must be overcome before this becomes a viable treatment for mainstream cancer patients, as discussed
later in this review. Regardless, the following sections describe two main types of ACT based on the anti-
tumor activity of the lymphocytes collected from the patient.
ACT USING TUMOR-INFILTRATING LYMPHOCYTES
This type of ACT is dependent on the collection of lymphocytes with anti-tumor cytotoxic
activity, called tumor-infiltrating lymphocytes (TILs), against the cancer in question2
. Fortunately, such T-
cells have been identified in the tumor samples of up to 80% of melanoma patients, with admittedly
lower frequency in other forms of cancer5
. In fact, though not universal, lymphocyte infiltration of tumor
tissue has in fact become a hallmark of cancer1
. In the cases where such cells are detected and can be
extracted, these TILs can be cultured and grown ex vivo.
2. This process begins with the TILs from a “micro culture derived from a single tumor fragment or
106
viable cells derived from a single-cell enzymatic digestion [of a resected tumor specimen]”29
. These
cells are grown and cultures split as needed for two weeks with high dose interleukin 2, after which
point each culture is kept at 0.8-1.6x106
mL-1
in flasks and generates roughly 5x107
cells (the required
minimum being 3x107
cells) from each culture after 3-5 weeks29
. The cultures are then tested for activity
and specificity by an immunosorbent assay after stimulation with tumor cells, and cultures deemed
active undergo a rapid expansion phase for 2 weeks with donor feeder cells, anti-CD3 OKT-3 monoclonal
antibody, and high dose interleukin 2 to promote expansion 29
. In total, the entire manufacture process
takes roughly 6-8 weeks31
. The expanded colonies of TILs are then reintroduced to the body to attack
the cancer with greater numbers than before. This approach capitalizes on the ‘strength in numbers’
strategy, but with the added benefit of more specific TILs from the testing and selection processes
performed ex-vivo29
. This type of ACT would be considered the most feasible, but it sacrifices efficacy.
ACTs using TILs are limited in a few ways. First, this treatment is simply not an option for any
patient in whom TILs cannot be identified or extracted. Even for those patients from whom TILs can be
extracted, there is growing concern that these TILs may have little to no effect on tumor progression
despite their presence in areas of tumor inhibition2
. Further, to avoid unintended autoimmune attack,
these TILs generally have low affinity to the self-antigens and germline antigens that are usually
overexpressed by cancerous tissues (but are shared by healthy body tissues)6
. While this is still the most
effective method of ACT to date, these limitations have encouraged development of the second type of
ACT.
ACT USING ENGINEERED T CELLS
This method of ACT makes use of the T-cells’ time ex vivo (as described in the methods section)
to enhance T-cell function by changing receptors to give the cells improved affinity to self-antigens or
novel specificity, and/or by improving their proliferative capacity through alterations in signaling
functions7
. Because the cells are being engineered, the T-cells do not necessarily need to be TILs or even
from the tumor region, and can be collected from peripheral blood samples which are much easier to
collect, and are present in every patient8
. This higher affinity and novel specificity is largely achieved
through expression of heterodimeric T-cell receptors (TCRs) in T-cells which can allow tighter binding to
the self-antigens overexpressed on cancer, or neo-antigens, which are epitopes that are only present in
cells with cancerous mutations9
. To achieve this, a gene corresponding to the engineered TCR is
introduced into the T cells by a retroviral vector32
. The TCR then “combines TCR-alpha and TCR-beta
genes” and undergoes MHC restriction, a process that ensures it only recognizes peptide antigens when
they are presented on the body’s MHC molecule10
. Another method to enhance affinity is to reduce N-
glycosylation on TCR chains11
. Surprisingly, self-antigens (specifically genes of the cancer testis family*for
more info look at 12
) rather than neoantigens, are more often the targets of such engineered TCRs12
.
Some of the first trials of this type have been for the NY ESO-1-specific and HLA-A2-restricted
TCR for use in melanoma, myeloma, and synovial cell sarcoma13
. These studies have been making great
progress and have not shown toxicity. Toxicity is a large concern in these trials, after all these cells are
being engineered to attack self-antigens that are present on healthy body tissue. In fact in another study
a TCR engineered for enhanced MAGE 3 affinity and HLA-A1-restriction had off target recognition of the
muscle protein Titin, resulting in lethal cardiac toxicity for both patients14,15
. This will be discussed
further along in the paper. Another problem of ACT with genetically engineered T-cells is that, due to a
multitude of factors known and unknown, it has been less successful than ACT with TILs16,17
. This being
said, ACT remains relevant because of how much it can improve with better protocols, and because it
3. greatly expands the range of ACT to cancers like neuroblastoma, synovial cell carcinoma, and colorectal
carcinoma (among others) where TILs cannot be extracted18,19, 20
.
The synthesis of these genetically engineered T-cells begins with T-cells from ficoll-purified
PMBCs, which are activated with OKT-3 antibodies29
. They are then transduced with a retroviral vector
that encodes the desired antigen-specific TCR, cultured for 2 weeks, and transduced and expanded
under cGMP 32,33
. These activated T-cells are then transduced again with retroviral vectors in
RetroNectin-coated cell bags, inoculated in a WAVE bioreactor for two days, and expanded with a
continuous perfusion regime29
. After this, the beads (from cGMP treatment) are removed and the cells
are formulated for infusion29
.
This total process takes about 2 weeks and is of a large enough scale to support multiple clinical
trials29
.
CAR T-Cells
One other noteworthy category of genetically engineered T-cells for use in ACT is the CAR-
modified T-cell. This modification exploits the fact that “the cytoplasmic tail of the TCR CD3zeta chain
[can] activate T-cells without the rest of the receptor complex”21
. Despite disappointing results from first
generation CARs22
, second and third generation CARs have shown antitumor effects and have remained
in patients for up to a decade (but also as little as a month)*for more information about the modifications of second and third
CARs go to 23
. What is promising is that response rates are generally encouraging, over 50% of patients
achieving some kind of remission in studies at the University of Pennsylvania, and that this response is
correlated with CAR T-cell proliferation, indicating that the remission is related to the presence or
activities of the CAR T-cells10
.
CAR modification represent a valuable alternative to TCR modification because only CAR-
modified T-cells can recognize a cancer cell that has lost MHC expression, a condition which applies to
many cancers24,25
. Also, CAR-modified T-cells are sometimes able to remain in the body and fight cancer
much longer than TCR-modified T-cells, though the longevity of each varies substantally26,27
. This being
said, TCR-modification has its place, as it is “able to sense the entire intracellular proteome that is
presented by MHC molecules” and accordingly can attack a wider range of molecules in the cancer
cells10
. It also requires about 10x less target antigen expression (sometimes less than 10 ligands) to
induce cytolosys28
.
DISCUSSION
ACT involving any type of T-cell is not yet ready for the standard treatment of cancers on a large
scale. This is because of several factors both biological and practical.
T-cell Inhibition
First, both the cancer and the immune system itself have several methods of inhibiting an
immune response to cancer tissue. As T-cells are maturing in the thymus, they are tested for recognition
to self-antigens, and those that are particularly reactive are deleted to avoid autoimmunity34
. These
especially active T-cells that the body stops from maturing are needed to recognize the over-expressed
self-antigens on the surface of cancer cells, so this limits the effectiveness of any TIL related ACT10
. T-
cells are also inhibited from attacking cancer in maturity by peripheral tolerance mechanisms, which
consists of 3 categories2
:
1. Inhibition from the T-cell itself or its nature, like low activity around inflammation*for more information
see 35
4. 2. Inhibition from the Tumor, like the expression of checkpoint molecules*for more information go to 36, this is
an area of relatively high development after trials in melanoma (37,38).
3. Inhibition from regulatory T-cells and myeloid derived suppressor cells*for more information see 39
.
The first two sources of inhibition are difficult to handle, as they are meant to stop autoimmune
attack on one’s own body tissues2
. Simply turning these inhibitory mechanisms off could cause severe
autoimmune disease.
Toxicity
Toxicity is another huge concern, with off-target autoimmunity having lethal ramifications in
both TCR-modified T-cell ACT studies (see above) and CAR-modified T-cells which can cause B-cell
aplasia, lysis syndrome, and cytokine release syndrome22,40,41,10
. To make matters works, the toxicity
from these ACTs can target the brain or heart, and cannot always be managed with corticosteroids10
.
The problem here is that T-cells are being engineered to have greater recognition of self-antigens, and
while this allows them to detect the overexpressed self-antigens on cancer cells, it is difficult to
eliminate all off target effects since almost every cell in the body has these self-antigens. It goes without
saying that work is being done to stop this off target autoimmunity, and one noteworthy idea is to add
inducible mechanisms for T-cell apoptosis when engineering the T-cells ex-vivo so that they could be
stopped quickly and easily if toxicity were to become an issue10
.
Longevity
The final biological issue with ACT is response and longevity, specifically for engineered T-cells.
As noted above, most TCR-modified T-cells can often last for only a few months, and CAR-modified T-
cells aren’t much better. This is only counting the patients who respond well to the treatment. For ACT
to become a mainstream treatment, researchers need to find ways to allow the engineered cells to have
antitumor effects in a larger proportion of patients, and to have longer lasting effects in each patient.
One way of prolonging the effects of T cells is by immunodepletion of the regulatory immune
system, which can be achieved by total body irradiation and lymphodepleting chemotherapy2
.
Lymphodepletion before ACT can allow better proliferation of the reactive T cells by lowering the
numbers of regulatory T cells and myeloid-derived suppressor cells, enhancing innate immunity, and by
increasing cytokines42
. This lymphodepletion has improved results in mouse models of B16 melanoma43
.
Also, for stage IV melanoma response rates were 49% with 1x lymphodepletion and 72% with 3x
lymphodepletion44
. Finally, checkpoint inhibitors are proving to be a great way to assist cancer
therapy*for more information see 37, 38
.
Culturing
The practical problems of ACT are the time and resources necessary to culture and test these T-
cells for the 6-8 weeks31
, and a minimum of 2 extra weeks to incorporate any genetically engineered
changes required for TCR or CAR modification29
. This must be done over for every single patient (the
epitome of individualized medicine) as each cancer is different, presents unique markers, and
accordingly requires T-cells with unique receptors2
. This delay of at least 6-10 weeks makes this therapy
somewhat sluggish, and the weeks of cell culture requires hours of work for a researcher. Using current
methods, it would be unfeasible to run these ACT protocols for the general population in all but very
rare cancers.
Cost
5. All the time and resources necessary to culture these T-cells inherently makes this a costly
process. The hospital stay required to have the cells injected is also costly, as it is essentially a form of
transplant2
. It is nearly impossible to even estimate a cost seeing as the protocols change rapidly as
development of this field proceeds, and as costs are not always publicly reported in clinical trials2
. For a
very rough estimate, sipuleucel-T, a cancer vaccine used to treat prostate cancer, requires the isolation
of immune cells from each patient, in-vitro culturing, and infusion back into the patient, all just like ACT,
and it costs $93,000 all told44
.
THE FUTURE FOR ACT
ACT is certainly still a treatment under development. Its simple premise inspires hope for
success in the future, but the long list of limitations admittedly casts doubt. What will likely determine if
ACT becomes a widely used therapy in the near future is how the cost-to-benefit ratio changes in
relation to other therapies like chemotherapy and radiation. Unless the process of T-cell culture and
engineering can be majorly streamlined and automated, it seems unlikely that ACT will be able to
compete with chemotherapy and radiation therapy for most cancers.
Of course, the cost-to-benefit ratio goes hand in hand with the biological effectiveness of ACT.
Many versions of this therapy pose a toxicity risk to the patient, which is often quite severe. While this
may be quite difficult or even impossible to eliminate completely given the need for enhanced affinity to
self-antigens, there needs to be a way of minimizing the potential harm to the patient. This could come
in the form of an inducible apoptosis mechanism for the modified T cells, or by focusing efforts on
neoantigens as receptor targets rather than self-antigens. These engineered T cells must also last longer
in the host in order to produce significant anti-tumor effects, so these cells need to proliferate better
and avoid degradation. Finally, better receptors need to be engineered for use in TCR and CARs, though
given the transformation between first and third generation CARs there seems to be little doubt that
these improvements will come with time.
To its credit, ACT could eventually enable patients to attack even aggressive, metastatic, and
heterogeneous cancers with very limited toxicity or side effects. Perhaps this dream will propel the
research needed to bring this form of therapy to fruition.
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