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.
The outlook for cancer treatment options is a promising one. Researchers and physicians are discovering new ways to identify the best care for patients through targeted treatments. With the large number of cancer types, a treatment plan that works well for one person may not be the best plan for another. Through collaboration, rapidly evolving technology, and research in genetics and the molecular profiling of tumors, researchers and physicians have made astounding strides in the development of personalized cancer care.
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
Background : During the conference of ASCO 2015, there was no consensus about TIL role in beast cancer and no recommendations concerning the microscopic assessment of TIL. In fact, the patients could be put on anti-PD1 drugs without the necessity of highlighting PD1 positive cells by using immunohistochemistry. Nevertheless, many questions about the prognostic impact of TIL, the methods of assessment, the type of TIL to count remain unresolved. Material and Methods : We performed a review of the literature on the sites : Pubmed and Cochrane. We used the key-words : �TIL in cancer�; �TIL in breast cancer� and �prognostic impact of TIL in breast cancer�. Results : According to our inclusion and exclusion criteria, thirty eight articles were retained. Our review of the literature showed that assessing TIL in high grade tumors seem unnecessary. They seem available in intermediate graded tumors. In neo-adjuvant and adjuvant conditions, CD3+ lymphocytes seem to be correlated to a good response to chemotherapy. After a chemotherapy, quantification T reg lymphocytes CD4 + FOXP3+ seems helpful because the decrease of their number is correlated to a good prognosis. Conclusion : The role of TIL in breast cancer is clearly established. The mechanisms of immune escape induced to discovery of immune therapy. The role of the microscopic examination and the subtyping of TIL using immunohistochemistry hasn�t been clearly established. Through this review of the literature, we tried to establish a diagram highlighting the different subtypes of TIL to evaluate and their prognostic impact.
The outlook for cancer treatment options is a promising one. Researchers and physicians are discovering new ways to identify the best care for patients through targeted treatments. With the large number of cancer types, a treatment plan that works well for one person may not be the best plan for another. Through collaboration, rapidly evolving technology, and research in genetics and the molecular profiling of tumors, researchers and physicians have made astounding strides in the development of personalized cancer care.
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
Background : During the conference of ASCO 2015, there was no consensus about TIL role in beast cancer and no recommendations concerning the microscopic assessment of TIL. In fact, the patients could be put on anti-PD1 drugs without the necessity of highlighting PD1 positive cells by using immunohistochemistry. Nevertheless, many questions about the prognostic impact of TIL, the methods of assessment, the type of TIL to count remain unresolved. Material and Methods : We performed a review of the literature on the sites : Pubmed and Cochrane. We used the key-words : �TIL in cancer�; �TIL in breast cancer� and �prognostic impact of TIL in breast cancer�. Results : According to our inclusion and exclusion criteria, thirty eight articles were retained. Our review of the literature showed that assessing TIL in high grade tumors seem unnecessary. They seem available in intermediate graded tumors. In neo-adjuvant and adjuvant conditions, CD3+ lymphocytes seem to be correlated to a good response to chemotherapy. After a chemotherapy, quantification T reg lymphocytes CD4 + FOXP3+ seems helpful because the decrease of their number is correlated to a good prognosis. Conclusion : The role of TIL in breast cancer is clearly established. The mechanisms of immune escape induced to discovery of immune therapy. The role of the microscopic examination and the subtyping of TIL using immunohistochemistry hasn�t been clearly established. Through this review of the literature, we tried to establish a diagram highlighting the different subtypes of TIL to evaluate and their prognostic impact.
Presentation focusing on what is cancer immunotherapy is, what are the potential challenges in the safety assessment of antibodies targeting immune system checkpoints, things to consider when designing and running your nonclinical safety programmes for immune checkpoint targets and measuring immunotoxicity / immunopharmacology. It also looks at what if your chosen therapeutic has no pharmacologically relevant non-clinical safety species.
Cancer testis antigens and NY-BR-1 expression in primary breast cancer: prog...Enrique Moreno Gonzalez
Cancer–testis antigens (CTA) comprise a family of proteins, which are physiologically expressed in adult human tissues solely in testicular germ cells and occasionally placenta. However, CTA expression has been reported in various malignancies. CTAs have been identified by their ability to elicit autologous cellular and or serological immune responses, and are considered potential targets for cancer immunotherapy. The breast differentiation antigen NY-BR-1, expressed specifically in normal and malignant breast tissue, has also immunogenic properties. Here we evaluated the expression patterns of CTAs and NY-BR-1 in breast cancer in correlation to clinico-pathological parameters in order to determine their possible impact as prognostic factors.
n overview of current immunotherapy therapies used to treat cancer. Also provides MOA of various medications, and updates on SITC guidelines for metastatice melanoma.
Acute myeloid leukemia (AML) is a hematopoietic malignancy with a dismal outcome in the majority of cases. A detailed understanding of the genetic alterations and gene expression changes that contribute to its pathogenesis is important to improve prognostication, disease monitoring, and therapy. In this context, leukemia-associated misexpression of microRNAs (miRNAs) has been studied, but no coherent picture has emerged yet, thus warranting further investigations.
Multicentric and multifocal versus unifocal breast cancer: differences in the...Enrique Moreno Gonzalez
The aim of this study was to evaluate the expression of the cell adhesion-related glycoproteins MUC-1, β-catenin and E-cadherin in multicentric/multifocal breast cancer in comparison to unifocal disease in order to identify potential differences in the biology of these tumor types.
Overexpression of YAP 1 contributes to progressive features and poor prognosi...Enrique Moreno Gonzalez
Yes-associated protein 1 (YAP 1), the nuclear effector of the Hippo pathway, is a key regulator of organ size and a candidate human oncogene in multiple tumors. However, the expression dynamics of YAP 1 in urothelial carcinoma of the bladder (UCB) and its clinical/prognostic significance are unclear.
Integrative Cancer - New theories and Advances in Treatment From Hippocrates ...Sheldon Stein
Professor Serge Jurasunsas' recent paper on Integrative Cancer, From Hippocrates to the Human Genome - posted on his behalf. Discusses testing, protocols and case discussion.
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.
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 based in reactivating the patient immune system specifically against the neoplasia, tumors have immunosuppression mechanisms that allow them to control and evade the immune response.
There are different immunotherapy approaches like tumor-targeting monoclonal antibodies, adoptive T cell transfer, anticancer vaccines, checkpoint inhibitors, most of these in important clinical trials in which the effects and toxicities are still evaluated. They are also beginning tested on a combination of immunotherapies and other non-immunological therapies in order to increase the survival of patients. Immunotherapy is still a young area and it needs to reach its peak, but it will surely be a great tool to treat and cure cancer.
Presentation focusing on what is cancer immunotherapy is, what are the potential challenges in the safety assessment of antibodies targeting immune system checkpoints, things to consider when designing and running your nonclinical safety programmes for immune checkpoint targets and measuring immunotoxicity / immunopharmacology. It also looks at what if your chosen therapeutic has no pharmacologically relevant non-clinical safety species.
Cancer testis antigens and NY-BR-1 expression in primary breast cancer: prog...Enrique Moreno Gonzalez
Cancer–testis antigens (CTA) comprise a family of proteins, which are physiologically expressed in adult human tissues solely in testicular germ cells and occasionally placenta. However, CTA expression has been reported in various malignancies. CTAs have been identified by their ability to elicit autologous cellular and or serological immune responses, and are considered potential targets for cancer immunotherapy. The breast differentiation antigen NY-BR-1, expressed specifically in normal and malignant breast tissue, has also immunogenic properties. Here we evaluated the expression patterns of CTAs and NY-BR-1 in breast cancer in correlation to clinico-pathological parameters in order to determine their possible impact as prognostic factors.
n overview of current immunotherapy therapies used to treat cancer. Also provides MOA of various medications, and updates on SITC guidelines for metastatice melanoma.
Acute myeloid leukemia (AML) is a hematopoietic malignancy with a dismal outcome in the majority of cases. A detailed understanding of the genetic alterations and gene expression changes that contribute to its pathogenesis is important to improve prognostication, disease monitoring, and therapy. In this context, leukemia-associated misexpression of microRNAs (miRNAs) has been studied, but no coherent picture has emerged yet, thus warranting further investigations.
Multicentric and multifocal versus unifocal breast cancer: differences in the...Enrique Moreno Gonzalez
The aim of this study was to evaluate the expression of the cell adhesion-related glycoproteins MUC-1, β-catenin and E-cadherin in multicentric/multifocal breast cancer in comparison to unifocal disease in order to identify potential differences in the biology of these tumor types.
Overexpression of YAP 1 contributes to progressive features and poor prognosi...Enrique Moreno Gonzalez
Yes-associated protein 1 (YAP 1), the nuclear effector of the Hippo pathway, is a key regulator of organ size and a candidate human oncogene in multiple tumors. However, the expression dynamics of YAP 1 in urothelial carcinoma of the bladder (UCB) and its clinical/prognostic significance are unclear.
Integrative Cancer - New theories and Advances in Treatment From Hippocrates ...Sheldon Stein
Professor Serge Jurasunsas' recent paper on Integrative Cancer, From Hippocrates to the Human Genome - posted on his behalf. Discusses testing, protocols and case discussion.
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.
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 based in reactivating the patient immune system specifically against the neoplasia, tumors have immunosuppression mechanisms that allow them to control and evade the immune response.
There are different immunotherapy approaches like tumor-targeting monoclonal antibodies, adoptive T cell transfer, anticancer vaccines, checkpoint inhibitors, most of these in important clinical trials in which the effects and toxicities are still evaluated. They are also beginning tested on a combination of immunotherapies and other non-immunological therapies in order to increase the survival of patients. Immunotherapy is still a young area and it needs to reach its peak, but it will surely be a great tool to treat and cure cancer.
This intro is geared towards interested novices who wish to find a resource that can serve as a starting point for further self-study. This is not meant to replace a doctor's advice. Please approach a medical professional for any health condition.
Immunotherapeutic drugs can be broadly classified into four types: checkpoint inhibitors, cytokines, monoclonal antibodies, and vaccines. However, immunotherapeutic drugs still have some problems, such as off-target side effects and poor pharmacokinetics.
Limitations of Immunotherapeutic Approaches for Cancer Treatment_Crimson Publ...CrimsonpublishersCancer
Of the multiple approaches to cancer therapy, few are as complex as those regimens that encompass immune-based agents. Immunotherapeutic approaches have been the central focus of medical investigators for the past several years. This advance in oncologic care is highlighted by the recognition of the Nobel commission in awarding the 2018 Nobel prize to Allison and Honjo [1]. Their seminal work concentrated on an immunotherapeutic approach to combatting cancers via immune checkpoint receptors’ enhancement of the adaptive immune system. A previous review emphasized the potential role of checkpoint inhibitors in the treatment and cure of HIV also through enhancement of adaptive immune function to counter this virus [2].
Hepatocellular carcinoma (HCC) has always been a difficult medical problem for the increasing mortality rate. According to the World Health Organization (WHO), hepatocellular carcinoma (HCC) is the fourth-leading cause of cancer related deaths worldwide [1] and is considered as a highly refractory cancer. Surgery is the most effective treatment to HCC, but HCC is resistant to conventional chemotherapy. In recent years, immunotherapy has been attracting growing attention as a promising therapeutic method to HCC. Immunotherapies to HCC including chimeric antigen receptor T cells (CAR-T), immune checkpoint inhibitor and oncolytic virus have become research hotspots.
Ultrasound Technology as a Novel Treatment Strategy in Pancreatic Cancer_Crim...CrimsonpublishersCancer
Adenocarcinoma of the pancreas (PDAC) accounts for 2.4% of all cancers diagnosed and is the fourth leading cause of cancer death, with almost equal rates of incidence and mortality [1]. By 2030, pancreatic cancer is projected to be the second leading cause of cancer-related death [2], surpassing breast, prostate and colorectal cancer. The overall survival at 5 years of around 7.2% as the majority of patients present with advanced disease at diagnosis. Patients with localized disease are treated with surgery, with or without neoadjuvant chemotherapy/ radiotherapy, followed by adjuvant chemotherapy. The majority (around 80%) of patients are treated only with chemotherapy as they have an advanced disease. Patients are treated in the first line with gemcitabine-abraxane or Folfirinox and with Naliri plus 5FU in the second line. There have been few clinical advances in PDAC treatment over the last 20 years and chemotherapy is the only treatment option available for the majority of patients. These tumours are also resistant to many targeted therapies such as anti-EGFR therapy like cetuximab [3] due to the presence of a KRAS mutation in the majority of primary tumors. Personalized medicine strategies have not yet been established in pancreatic cancer as in other more common tumour types. Thus, novel anti-tumour strategies are an important clinical need in order to improve survival rates.
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 “Can the Addition of Immunotherapy to Multimodal Management of Stage I-III NSCLC Help Break the Stalled Cycle of Poor Outcomes?” For the full presentation, downloadable Practice Aids, and complete CME/MOC information, and to apply for credit, please visit us at https://bit.ly/3m1OV2m. CME/MOC credit will be available until February 27, 2023.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
Acute scrotum is a general term referring to an emergency condition affecting the contents or the wall of the scrotum.
There are a number of conditions that present acutely, predominantly with pain and/or swelling
A careful and detailed history and examination, and in some cases, investigations allow differentiation between these diagnoses. A prompt diagnosis is essential as the patient may require urgent surgical intervention
Testicular torsion refers to twisting of the spermatic cord, causing ischaemia of the testicle.
Testicular torsion results from inadequate fixation of the testis to the tunica vaginalis producing ischemia from reduced arterial inflow and venous outflow obstruction.
The prevalence of testicular torsion in adult patients hospitalized with acute scrotal pain is approximately 25 to 50 percent
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
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Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...
Pham2018
1. REVIEW ARTICLE – TRANSLATIONAL RESEARCH AND BIOMARKERS
An Update on Immunotherapy for Solid Tumors: A Review
Toan Pham, MBBS, BMedSc, PGDipSurgAnat, FRACS1,2,3,4
, Sara Roth, BSc, MSc, PhD1
,
Joseph Kong, MBChB, MS, PhD, FRACS1,2,3,4
, Glen Guerra, MBBS, PGDipSurgAnat, FRACS1,2,3,4
,
Vignesh Narasimhan, MBChB, FRACS1,2,3,4
, Lloyd Pereira, BSc (Hons), PhD1
, Jayesh Desai, MBBS, FRACP3
,
Alexander Heriot, MB, BChir, MA, MD, MBA, FRACS, FRCS (Gen.), FRCSEd, FACS, GAICD1,2,3,4
,
and Robert Ramsay, BSc (Hons), PhD1,5
1
Divisions of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; 2
Cancer Surgery, Melbourne,
VIC, Australia; 3
Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia;
4
Department of Surgery, University of Melbourne, Melbourne, VIC, Australia; 5
Department of Pathology, University of
Melbourne, Melbourne, VIC, Australia
ABSTRACT In recent years, it has been demonstrated
that immunotherapy is an effective strategy for the man-
agement of solid tumors. The origins of immunotherapy
can be traced back to the work of William Coley, who
elicited an immune response against sarcoma by injecting
patients with a mixture of dead bacteria. Significant pro-
gress has been made since, with immune markers within
the tumor now being used as predictors of cancer prognosis
and manipulated to improve patient survival. While surgery
remains central to the management of most patients with
solid malignancies, it is important that surgeons consider
the different immunotherapy strategies that can be
employed to manage disease. Here, we highlight how the
immune system influences tumorigenesis and bring atten-
tion to how current and future immunotherapies can serve
as an adjunct to surgery.
Cancer is the leading cause of mortality worldwide,
being responsible for 8.8 million deaths in 2015.1
Despite
advances in prevention, screening, and diagnosis of cancer,
the landscape of cancer treatment has been altered by the
advent of immunotherapy, offering improved survival in
several solid cancers and establishing itself as a new
therapeutic modality.2
The concept of exploiting the host immune system to
eradicate cancer was first conceived by William Coley. In
pioneering work, a mixture of attenuated bacteria was
injected into patients in order to elicit an immune-mediated
response against sarcoma.3,4
However, significant advances
in cancer immunology have only been achieved in recent
years, with immunotherapy demonstrating clear efficacy in
clinical trials, and a synergistic effect when used in
combination.5,6
In this review, we delineate the relationship between
cancer and the immune response and discuss how this has
been used as a basis for immunotherapy. As personalized
medicine begins to enter the domain of all oncology spe-
cialties, an awareness of available therapies is important,
allowing surgeons to provide the most up-to-date care for
their patients.
THE IMMUNE SYSTEM AND PROGNOSIS:
A NOVEL STAGING SYSTEM
Our immune system continuously protects us against
environmental pathogens and malignant cells (Fig. 1).
However, malignant cells can acquire the capacity to evade
the action of the immune system and form cancer7
.
A seminal publication by Galon et al.8
demonstrated that
low infiltrating cytotoxic (CD8?
) and memory (CD45RO?
)
lymphocytes predict early relapse in colon cancer (CC). This
led to a new scoring system called Immunoscore (IS),9–11
which has been evaluated in 1336 stage I–III CC patients
and further validated in 2681 patients by an international
Toan Pham and Sara Roth have contributed equally to this study and
are co-first authors.
Ó Society of Surgical Oncology 2018
First Received: 27 February 2018
T. Pham, MBBS, BMedSc, PGDipSurgAnat, FRACS
e-mail: toan.pham@petermac.org
Ann Surg Oncol
https://doi.org/10.1245/s10434-018-6658-4
2. consortium. Both studies concluded that high IS is associ-
ated with longer recurrence-free survival.11,12
Moreover, IS
was able to identify high-risk patients (low IS) within
American Joint Committee on Cancer (AJCC) stage II CC,
thus making IS a powerful biomarker tool to stratify patients
to adjuvant chemotherapy. IS was translated to other tumor
types including gastric cancer13,14
and melanoma,15
in
which patients within the same tumor–node–metastasis
(TNM) stage could be stratified with enhanced accuracy to
predict long-term outcomes. Hence, IS is expected to
become a new component of the AJCC TNM system.
CANCER IMMUNOTHERAPY STRATEGIES
In cancer immunotherapy, the host immune system is
used to target and eradicate cancer cells.3,16
Tumors
express neoantigens that can be recognized as foreign by
the immune system and increase the level of T-lympho-
cytes infiltrating the tumor (TILs). This relationship can be
further described by the concept of immunoediting, which
forms the basis of modern cancer immunology research.17
In this paradigm, elimination, equilibrium, and escape are
key components. Elimination is the recognition and
destruction of tumor cells by the immune system. Subse-
quently, through immunoediting [e.g., expression of
immune checkpoints, loss of major histocompatibility
complex (MHC) expression, and/or upregulation of
T-regulatory cells], tumors create a sanctuary against the
immune system, thereby establishing an equilibrium
between tumor growth and immune destruction. In this
context, tumors escape immune control when the degree of
immunoediting allows for unchecked proliferation. This
model is underpinned by the close interaction between the
immune system and cancer cells, thus our understanding of
this relationship is an important component in the devel-
opment and considered use of immunotherapy. An outline
of the main classes of immunotherapy is shown in Fig. 2
and further described under each subheading below.
Immune Checkpoint Inhibitors: Reactivation of Tumor-
Infiltrating T-Cells
Immune checkpoints are the body’s natural brakes to
dampen the immune response and prevent autoimmunity.
Tumor cells can exploit this avenue to escape the immune
system by expressing complementary molecules that
interact with T-cells, rendering them incapable of killing.
Hence, these immune checkpoints [e.g., programmed cell
death (PD)-1, PD-L1, cytotoxic T lymphocyte-associated
antigen (CTLA)-4] form therapeutic targets.
The first immune checkpoint inhibitor (ICI) discovered
was ipilimumab (Bristol-Myers Squibb), an anti-CTLA-4
Innate Immune System
Microbes
Complement
system
Dendritic cell B cells Antibodies
T cells
Effector T cells
Blood vessel
NK cell
Infected/
transformed cell
Infected/
transformed cell
Granulocytes Monocytes/
Macrophages
Skin barrier
Hours Days
Adaptive Immune System
FIG. 1 Overview of the immune system: the immune system is
divided into the innate and adaptive arms. The innate system responds
rapidly to a conserved repertoire of pathogenic antigens, whereas the
adaptive system mounts a specific and memory response that initially
requires 4–7 days to develop
T. Pham et al.
3. antibody.18
It was first approved for the treatment of
unresectable metastatic melanoma, and the results were
encouraging with median overall survival of 10.1 months
versus 6.4 months in the control group.18
This equated to
improved 1- and 2-year survival rates of 46 versus 25 %
and 24 versus 14 %, respectively.18
Despite its promising
therapeutic efficacy, there were significant side effects,
including diarrhea (41.4%), colitis (15.9%), and endocrine
disorders (37.6%), and five on-trial mortalities.19
As such,
ipilimumab is now used as second-line therapy or in
combination with another ICI.
Pembrolizumab (Merck & Co.) and nivolumab (Bristol-
Myers Squibb) are the first two Food and Drug Adminis-
tration (FDA)-approved ICIs that block the interaction
between PD-1 (expressed by T-cells) and its ligands PD-L1
and PD-L2 (expressed by tumor and myeloid cells).20
These therapies have similar efficacy and long-term out-
comes to anti-CTLA-4 therapy but without significant side
effects,21
thus gaining FDA approval following landmark
clinical trials for melanoma (KEYNOTE-002),22
non-small
cell lung cancer (KEYNOTE-010),23
microsatellite unsta-
ble/mismatch repair gene deficient colorectal cancer,24
and
gastric cancer (KEYNOTE-059).25
Recently, combination anti-PD-1 and anti-CTLA-4
therapies in treatment-naı̈ve metastatic melanoma
(CHECKMATE-067)5
have demonstrated a synergistic
survival advantage over either monotherapy.5
Conse-
quently, pembrolizumab is now being tested with a variety
of other drugs, including molecular targeted therapies, such
as dabrafenib and trametinib, in BRAF-mutant advanced
melanoma (KEYNOTE-022).26
Expanding an Existing Immune Response: Adoptive
Cellular Therapy
Another emerging immunotherapy is adoptive cellular
therapy (ACT), where tumor-specific lymphocytes are
extracted from peripheral blood or resected tumors and
expanded ex vivo. These lymphocytes are then reintroduced
into the patient with or without systemic lymphodepletion
therapy. The Surgery Branch of the National Cancer Insti-
tute, led by Steven Rosenberg, has been at the forefront of
this therapy, with first successes in melanoma27,28
and cur-
rent clinical trials targeting other malignancies including
head and neck,29,30
renal cell,31
and gynecological can-
cers.32,33
Recent trials have explored the combination of
ACT with BRAF inhibitor34
and PD-1 ICI.35
ACT has even
led to an additional indication for metastasectomy which was
once considered futile, now a potential source for tumor-
specific lymphocytes used in ACT.36
a b
Dying
tumor cell
Granzyme
& perforin
Cytotoxic
T-cell
Cytotoxic
T-cell
Cytotoxic
T-cell
Cytotoxic
T-cell
Cytotoxic
T-cell
NK cell
CAR T -cell
CAR T -cell
Antigen
presenting cell
Oncolytic
virus
Radiation
Neoantigen induced
cytotoxic T-cell
Cytotoxic
T-cell
MDSC
Treg
MHC class I
presentation
Resistant
tumor cell
Tumor
surface protein
Immune
checkpoint
receptor/
ligand
interaction
Immune
checkpoint
inhibitor
Vaccine induced
cytotoxic T-cell
Recognition and Elimination
Of Malignant Cell
Radiation or Oncolytic Virus
induced Tumor Neoantigen
Adoptive CAR T-cell therapy
or Cancer Vaccination
Administration of Immune
Checkpoint Blockers
Adoptive CAR T-cell or NK cell
therapy
Depletion or Suppression of
MDSC and Tregs
Low Immunogenicity of
presented Antigen
Expression of Immune
Checkpoints
Downregulation of MHC
Class I Expression
Suppression by MDSC or
Tregs
c
NORMAL
IMMUNOSUPPRESION
THERAPY
OPTONS
FIG. 2 Tumor ‘‘escape’’ mechanisms (pink) and associated
immunotherapy counterstrategies (green): a normal recognition of
transformed cells by MHC class I presentation of tumor-associated
antigen and subsequent destruction by specific cytotoxic T-cells
(blue); b malignant cells escape immune recognition by low
immunogenicity of the presented antigen, expression of immune
checkpoints, downregulation of MHC class I, and generation of an
immunosuppressive microenvironment; c current immunotherapies
counteracting these evasion mechanisms via increasing the tumor-
specific antigens (radiation, vaccination, oncolytic viruses), immune
checkpoint blockade, CAR T-cells, and NK cell therapies, and
elimination of immunosuppressive microenvironment
Immunotherapy for Solid Tumors: A Review
4. Enhancing the Immunological Profile of Solid Tumors
Tumors with sparse TILs typically have low mutational
burden and consequently low neoantigen load. In order to
address this subset of challenging cancers, immune-based
strategies such as radiotherapy, oncolytic viruses, and
cancer vaccines have been developed to enhance the
immune recognition of these tumors.
Radiotherapy Radiotherapy can induce antigen expression
through tumor cell death and upregulation of MHC class I on
surviving tumor cells, both increasing their susceptibility to
cytotoxic T-cell killing.37
Single high-dose (5–10 Gy) or
hypofractionated (3 9 8 Gy) radiotherapy induces a
proinflammatory response that may result in an abscopal
effect,38
which is most pronounced in immunogenic tumors
including renal cell carcinoma (RCC), melanoma, and
hepatocellular carcinoma (HCC).39
Several clinical trials
are now investigating the combination of radiotherapy and
immune checkpoint inhibitors,40
because radiation has been
associated with PD-L1 upregulation.41
Oncolytic Viruses Oncolytic viruses (OV) are genetically
engineered or naturally occurring viruses that selectively
replicate in and kill cancer cells without collateral damage
to normal tissues. The release of antigens from the lysed
cancer cell enhances immune recognition and triggers
further immune-mediated destruction.42
The tumor
specificity of OV can be attributed to multiple factors
including the virus’s tropism for specific tissue type,
downregulation of the antiviral response of cancer cells,
and/or engineered enhancements to the virus to exploit the
different intracellular milieu of cancer cells.43
OV can also
be ‘‘armed’’ with genes encoding for immunodulators such
as granulocyte-macrophage colony-stimulating factor
(GM-CSF) or tumor-associated antigens to further
enhance their function.43
The first OV approved by the FDA was T-Vec, an
oncolytic herpes simplex virus type 1 armed with GM-
CSF, for the treatment of advanced melanoma.44
Further
oncolytic viruses such as Pexa-Vec against hepatocellular
carcinoma, G47D against glioblastoma and prostate cancer,
and CG0070 against bladder cancer show promising
results.43,45
The main disadvantage of OV is the acquired specific
immunity against the virus that effectively neutralizes any
repeat therapy. However, even partial responses leading to
downstaging may facilitate surgical resection and ICI
therapy.
Cancer Vaccines Cancer vaccines represent a different
approach of generating tumor-specific T-cells in poorly
immunogenic tumors, against either neoantigens or
differentially overexpressed self-antigens. Most cancer
vaccines to date have demonstrated limited clinical
benefit,46
which can be attributed to immune-suppressive
mechanisms within the tumor microenvironment (TME) if
administered as monotherapy. The success of ICI has led to
a renaissance of combination therapy cancer vaccine
clinical trials, with promising results.47,48
A few
encouraging examples include the FDA-approved
Sipuleucel-T (dendritic cell vaccine) for castrate-resistant
prostate cancer,49
TG01 (mutant K-ras peptide vaccine) for
pancreatic cancer,50
and two personalized neoantigen
vaccines for melanoma.47,48
The TetMYB vaccine, a
DNA plasmid encoding a modified MYB oncoprotein
fused with tetanus antigen to break self-tolerance, is being
tested against advanced colorectal and adenoid cystic
carcinoma (NCT03287427).51
NK Cell and CAR T-Cell Therapy: Lifting the Cloak
of Invisibility
Another immune evasion technique employed by tumor
cells is downregulation of MHC class I molecules, thus
rendering the tumor invisible to cytotoxic T-cells.52,53
This
adaptation has been observed in patients treated with ICI
and cancer vaccines,48,54
and may be countered by natural
killer (NK) and chimeric antigen receptor (CAR) T-cell
therapies, as these two immune cells do not rely on MHC
class I presentation for tumor recognition.
In early-phase clinical trials, NK cell therapy has proven
to be safe and well tolerated, albeit with limited success, in
non-small cell lung,55,56
gastrointestinal,57
breast, ovar-
ian,58
and renal cell cancers, and melanoma.59
The intrinsic
lack of tumor infiltration by NK cells is often attributed to
suppressive TME. This can be mitigated by nanoparticles
that attract and expand NK cells within the tumor60
or
genetically modified NK cells.61
CAR T-cells are autologous T-cells that have undergone
ex vivo genetic modification to express a tumor-specific
hybrid receptor. Prominent successes have been achieved
in hematological malignancies, including the use of anti-
CD19 CAR T-cells in non-Hodgkin’s B cell lymphoma and
lymphoblastic leukemia, which gained FDA approval in
2017.62–64
Current target antigens include epidermal
growth factor receptor (EGFR), human epidermal growth
factor receptor 2 (HER-2), mesothelin, and carcinoembry-
onic antigen (CEA)65
on solid tumors.
Early-phase trials have shown CAR T-cells to be safe
and feasible in a variety of solid tumors, including non-
small cell lung cancer,66
neurological malignancies,67–69
breast,70
pancreatic,71,72
and metastatic colon cancer,73
and
sarcoma.74,75
Furthermore, enhanced efficacy in combina-
tion with ICI has been observed against melanoma,
Hodgkin’s lymphoma, and non-small cell lung cancers.76
T. Pham et al.
5. T-Regulatory and Myeloid-Derived Suppressor Cells:
Antisuppressor Therapy
T-regulatory (Treg) and myeloid-derived suppressor
cells (MDSCs) are partly responsible for the immunosup-
pressive TME,77
thus representing a potential avenue in
cancer immunotherapy.
FoxP3-expressing Treg cells induce self-tolerance and
prevent autoimmunity. Tumors can exploit Tregs to their
advantage, and current therapeutic strategies are focusing
on depleting these cells.78
Two such therapies are dacli-
zumab (IL-2 receptor blocking antibody) and denileukin
diftitox (IL-2:diptheria toxin fusion peptide), which have
demonstrated robust clinical outcomes79
in metastatic
breast cancer80,81
and chemo/immuno-naı̈ve stage IV
melanoma.82
Additionally, the checkpoint inhibitor ipili-
mumab has been reported to deplete tumor-infiltrating
Tregs via antibody-dependent cell-mediated cytotoxicity
(ADCC) in melanoma patients.83
MDSCs are immature myeloid cells that suppress
cytotoxic T-cell function and modulate the activation and
expansion of Tregs by immunosuppressive cytokines,
arginase-1, and reactive oxygen species (ROS) and nitric
oxide (NO).77
Treatments targeting MDSCs were
serendipitously discovered as a by-effect of other cancer
treatments.84
Ipilimumab and vemurafenib (BRAF inhibitor) have
been shown to reverse the immunosuppressive effect of
MDSCs in melanoma.85,86
Sunitinib (tyrosine kinase inhi-
bitor) decreases MDSC levels by reducing the expansion of
monocytic MDSCs and inducing apoptosis of granulocytic
MDSCs,87
being the first-line therapy for metastatic RCC.
All-trans retinoic acid (ATRA) and vitamin D3 promote
differentiation of MDSCs into mature nonsuppressive cells
and have shown benefit in metastatic RCC88
and head and
neck squamous cell carcinoma (SCC),89
respectively.
Sildenafil, tadalafil, and vardenafil (PDE5 inhibitors) have
been shown to inhibit arginase-1 and NO expression and
significantly reduce disease burden in myeloma patients90
and circulating MDSCs in head and neck SCC.91
Addi-
tionally, conventional chemotherapeutic drugs, namely
gemcitabine and 5-fluorouracil, have been found to
decrease MDSC and to improve antitumor immune
responses.92,93
Other Barriers Against Immunotherapy
In addition to the immune-evasive mechanism men-
tioned above, further parts of the TME can adversely affect
immune cell function.
Some tumors create a hostile TME for TILs by depleting
nutrients and oxygen and releasing acidic94
and toxic
metabolites.95
Others promote an immunosuppressive cell
infiltrate by altering the inflammatory cytokine milieu.96
Lastly, modifications of the tumor vasculature such as
downregulation of intercellular adhesion molecule 1
(ICAM-1)97
and altering the tumor stroma98,99
to retard
T-cell migration have been described.
Research into counteracting some of these mechanisms
is currently being done, however there are no clinical trials
to date.
THE RISE OF IMMUNOTHERAPY CLINICAL
TRIALS
An enquiry of the ClinicalTrials.gov database revealed
that, of the 60,903 cancer trials in the entire database, the
search string ‘‘Cancer AND Immunotherapy’’ returned
1994 (* 3%) interventional studies, and of these, 313
(* 16%) have been completed (Table 1). Recent years
have seen a rapid increase in the number of immunotherapy
trials (Fig. 3). Although earlier trials were disappointing,
more recent trials featuring combination therapies have
shown promising results. Thus, there is a need for further
evaluation of upcoming therapies as well as the potential
synergistic effects of existing therapies.
INTEGRATION WITH SURGICAL PRACTICE
Local/Regional Control
The success of treating primary solid malignancies is
highly dependent on the disease stage. Surgery has tradi-
tionally played a role in this setting, with early-stage
disease often cured with a margin-negative resection. In
contrast, in many locally advanced solid tumors, neoadju-
vant therapies such as radiotherapy and/or chemotherapy
have shown benefit in downstaging cancers to enable
resection. This is exemplified in breast cancer, where
5-year survival for stage III patients was similar between
mastectomy (96.3%) and chemoradiotherapy combined
with breast-conserving surgery (90.9%, p = 0.669).100
More recently, chemoimmunotherapy has been used suc-
cessfully to downstage prostate cancer.101
Distant/Metastatic Disease
The presence of metastatic disease has classically
implied an incurable state for patients. Surgery has tradi-
tionally had a limited role, often reserved for control of
symptoms. Chemotherapy and radiotherapy can extend
overall survival in this cohort; however, this requires bal-
anced consideration given the impact on quality of life and
treatment-related morbidity.
Harnessing what immunotherapy promises to offer, we
have the potential to turn advanced cancer into a chronic
Immunotherapy for Solid Tumors: A Review
6. disease, or state of equilibrium.17
This has been demon-
strated in subgroups of the CheckMate-066 and -067
melanoma trials, where clinical benefit from nivolumab is
seen beyond disease progression for advanced mela-
noma.102
Furthermore, improvement in survival has been
achieved with dual checkpoint inhibition.5
TABLE 1 Phase and modality of completed immunotherapy clinical trials against solid malignancies (compiled from ClinicalTrials.gov;
5/15/2018)
Solid cancer
type
Phase of
clinical trial
(number of
trials*)
Immunotherapy modality (number of trials*)
I II III Cancer
vaccine
Checkpoint
inhibition
Adoptive
cellular
therapy
CAR
T-cell
Oncolytic virus,
gene therapy
Anti-Treg,
anti-MDSC
Cytokine,
targeted therapy
Prostate 17 27 7 39 4 2 3 3
Melanoma 39 41 5 40 6 19 1 2 1 16
Lung 18 30 3 35 5 1 10
Head and neck 11 8 10 2 1 1 5
Neurological 26 20 3 24 1 8 4 3 9
Gynecological 12 15 1 16 3 1 8
Anal 3 2 1 1 1 2
Penile 3 1 1 1 2
Sarcoma 10 8 8 1 4 1 4
Urothelial 7 14 4 9 1 4 1 1 9
Breast 18 18 23 1 6 6
Hepatobiliary 9 4 2 6 4 2 3
Colorectal 10 13 1 17 1 2 1 3
Esophagogastric 6 4 5 1 4
Pancreas 13 11 2 20 1 1 1 3
Total 202 216 28 254 21 58 12 10 4 87
*Where a trial involves more than one therapy, it is counted in duplicate according to the number of immunotherapy modalities used
0
5
10
15
20
25
30
1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015
Number
of
Trials
Year of Trial Commencement
The Rise of Cancer Immunotherapy Trials
FIG. 3 Trend showing the rapid
increase in number of started
cancer immunotherapy trials from
1995–2015 (compiled from
ClinicalTrials.gov; 5/15/2018)
T. Pham et al.
7. When examining published data, there is a changing role
for surgery. Current immunotherapeutic agents are most
effective when there is low to moderate tumor burden given
the limited immunosuppressive factors. Therefore, surgery’s
role is still foremost to achieve cure in early-stage disease,
however what was once considered futile/palliative surgery
now has the potential to offer cure when combined with
immunotherapy. This not only includes resecting tumors
after downstaging, but also removing tumors in some can-
cers, including metastatic deposits, in order to understand the
immune profile of the resistant clone, and for the expansion
of TILs. Both of these methods allow a personalized treat-
ment algorithm to be developed and modified throughout the
patient’s journey, so that the best outcomes can be achieved.
CONCLUSIONS
Immunotherapy is a promising therapeutic avenue that is
rapidly shifting the paradigm of cancer management. This
review is intended to raise awareness about the current
immunotherapeutic strategies. Immunotherapy can provide
an important adjunct to current available therapies to
improve long-term outcomes in previously resistant or
incurable cancers. With its growing use, it is important for
surgeons and surgical oncologists to embrace it, thereby
providing immunotherapy as a treatment options for their
patients.
ACKNOWLEDGMENT Not applicable.
DISCLOSURE All authors are involved in the MYPHISMO clin-
ical trial (NCT03287427).
REFERENCES
1. World Health Organization Cancer Factsheet. 2018; http://www.
who.int/mediacentre/factsheets/fs297/en/. Accessed 18 Feb
2018.
2. Weber JS, O’Day S, Urba W, et al. Phase I/II study of ipili-
mumab for patients with metastatic melanoma. J Clin Oncol.
2008;26(36):5950–56.
3. Coley WB. The treatment of inoperable sarcoma by bacterial
toxins (the mixed toxins of the Streptococcus erysipelas and the
Bacillus prodigiosus). Proc R Soc Med. 1910;3:1–48.
4. Coley WB. The treatment of malignant tumors by repeated
inoculations of erysipelas. With a report of ten original cases.
1893. Clin Orthop Relat Res. 1991(262):3–11.
5. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall
survival with combined nivolumab and ipilimumab in advanced
melanoma. N Engl J Med. 2017;377(14):1345–56.
6. Ott PA, Hodi FS, Kaufman HL, Wigginton JM, Wolchok JD.
Combination immunotherapy: a road map. J Immunother Can-
cer. 2017;5:16.
7. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer
immunoediting: from immunosurveillance to tumor escape. Nat
Immunol. 2002;3(11):991–8.
8. Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and
location of immune cells within human colorectal tumors predict
clinical outcome. Science. 2006;313(5795):1960–4.
9. Mlecnik B, Tosolini M, Kirilovsky A, et al. Histopathologic-
based prognostic factors of colorectal cancers are associated
with the state of the local immune reaction. J Clin Oncol.
2011;29(6):610–8.
10. Galon J, Mlecnik B, Bindea G, et al. Towards the introduction of
the ‘Immunoscore’ in the classification of malignant tumours. J
Pathol. 2014;232:199–209.
11. Galon J, Mlecnik B, Marliot F, et al. Validation of the Immu-
noscore (IM) as a prognostic marker in stage I/II/III colon
cancer: Results of a worldwide consortium-based analysis of
1,336 patients. J Clin Oncol. 2016;34(15):3500–3500.
12. Pages F, Mlecnik B, Marliot F, et al. International validation of
the consensus Immunoscore for the classification of colon can-
cer: a prognostic and accuracy study. Lancet.
2018;391(10135):2128–39.
13. Fujitani K, Ando M, Sakamaki K, et al. A prospective multi-
center observational study of surgical palliation examining
postoperative quality of life in patients treated for malignant
gastric outlet obstruction caused by incurable advanced gastric
cancer. J Clin Oncol. 2017;35(4):6-6.
14. Qi X, Jiang Y, Zhang Q, et al. Prognostic and predictive value of
immunoscore signature in gastric cancer. J Clin Oncol.
2017;35(15):e15594-e15594.
15. Galon J, Fox BA, Bifulco CB, et al. Immunoscore and
immunoprofiling in cancer: an update from the melanoma and
immunotherapy bridge 2015. J Transl Med. 2016;14(1):273.
16. Pilch YH, Myers GH, Sparks FC, Golub SH. Prospects for the
immunotherapy of cancer. Part I: basic concepts of tumor
immunologyProspects for the immunotherapy of cancer. Part I:
basic concepts of tumor immunology. Curr Probl Surg.
1975;12(1):1–46.
17. Dunn GP, Old LJ, Schreiber RD. The three Es of cancer
immunoediting. Annu Rev Immunol. 2004;22:329–60.
18. Lipson EJ, Drake CG. Ipilimumab: an anti-CTLA-4 antibody for
metastatic melanoma. Clin Cancer Res. 2011;17(22):6958–62.
19. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival
with ipilimumab in patients with metastatic melanoma. N Engl J
Med. 19 2010;363(8):711–23.
20. Ribas A. Tumor immunotherapy directed at PD-1. N Engl J
Med. 2012;366(26):2517–9.
21. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus
ipilimumab in advanced melanoma. N Engl J Med.
2015;372(26):2521–32.
22. Ribas A, Puzanov I, Dummer R, et al. Pembrolizumab versus
investigator-choice chemotherapy for ipilimumab-refractory
melanoma (KEYNOTE-002): a randomised, controlled, phase 2
trial. Lancet Oncol. 2015;16(8):908–18.
23. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus
docetaxel for previously treated, PD-L1-positive, advanced non-
small-cell lung cancer (KEYNOTE-010): a randomised con-
trolled trial. Lancet. 2016;387(10027):1540–50.
24. Le DT, Uram JN, Wang H, et al. PD-1 Blockade in tumors with
mismatch-repair deficiency. N Engl J Med.
2015;372(26):2509–20.
25. Fuchs CS, Doi T, Jang RW-J, et al. KEYNOTE-059 cohort 1:
Efficacy and safety of pembrolizumab (pembro) monotherapy in
patients with previously treated advanced gastric cancer. J Clin
Oncol. 2017;35(15):4003-4003.
26. Ribas A, Hodi FS, Lawrence D, et al. 1216OKEYNOTE-022
update: phase 1 study of first-line pembrolizumab (pembro) plus
dabrafenib (D) and trametinib (T) for BRAF-mutant advanced
melanoma. Vol 282017.
Immunotherapy for Solid Tumors: A Review
8. 27. Dudley ME, Wunderlich J, Nishimura MI, et al. Adoptive
transfer of cloned melanoma-reactive T lymphocytes for the
treatment of patients with metastatic melanoma. J Immunother.
2001;24(4):363–73.
28. Dudley ME, Wunderlich JR, Yang JC, et al. A phase I study of
nonmyeloablative chemotherapy and adoptive transfer of
autologous tumor antigen-specific T lymphocytes in patients
with metastatic melanoma. J Immunother. 2002;25(3):243–51.
29. Zhou P, Tian S, Li J, et al. Paradoxes in thyroid carcinoma
treatment: analysis of the SEER database 2010–2013. Onco-
target. 2017;8(1):345–53.
30. Ostrom QT, Gittleman H, Kruchko C, et al. Completeness of
required site-specific factors for brain and CNS tumors in the
Surveillance, Epidemiology and End Results (SEER) 18 data-
base (2004–2012, varying). J Neurooncol. 2016;130(1):31–42.
31. Liao Z, Rodrigues MC, Poynter JN, Amatruda JF, Rodriguez-
Galindo C, Frazier AL. Risk of second malignant neoplasms in
women and girls with germ cell tumors. Ann Oncol.
2017;28(2):329–32.
32. Yao N, Alcala HE, Anderson R, Balkrishnan R. Cancer dis-
parities in rural Appalachia: incidence, early detection, and
survivorship. J Rural Health. 2017;33(4):375–81.
33. Shah BK, Kandel P, Khanal A. Second primary malignancies in
hepatocellular cancer - A US population-based study. Anti-
cancer Res. 2016;36(7):3511–4.
34. Deniger DC, Kwong ML, Pasetto A, et al. A pilot trial of the
combination of vemurafenib with adoptive cell therapy in
patients with metastatic melanoma. Clin Cancer Res.
2017;23(2):351–62.
35. Bista A, Sharma S, Shah BK. Disparities in receipt of radio-
therapy and survival by age, sex, and ethnicity among patient
with stage I follicular lymphoma. Front Oncol. 2016;6:101.
36. Crompton JG, Klemen N, Kammula US. Metastasectomy for
tumor-infiltrating lymphocytes: an emerging operative indica-
tion in surgical oncology. Ann Surg Oncol. 2018;25(2):565–72.
37. Reits EA, Hodge JW, Herberts CA, et al. Radiation modulates
the peptide repertoire, enhances MHC class I expression, and
induces successful antitumor immunotherapy. J Exp Med.
2006;203(5):1259–71.
38. Haikerwal SJ, Hagekyriakou J, MacManus M, Martin OA,
Haynes NM. Building immunity to cancer with radiation ther-
apy. Cancer Lett. 2015;368(2):198–208.
39. Reynders K, Illidge T, Siva S, Chang JY, De Ruysscher D. The
abscopal effect of local radiotherapy: using immunotherapy to
make a rare event clinically relevant. Cancer Treat Rev.
2015;41(6):503–10.
40. Ko EC, Formenti SC. Radiotherapy and checkpoint inhibitors: a
winning new combination? Ther Adv Med Oncol.
2018;10:1758835918768240.
41. Dovedi SJ, Illidge TM. The antitumor immune response gen-
erated by fractionated radiation therapy may be limited by tumor
cell adaptive resistance and can be circumvented by PD-L1
blockade. Oncoimmunology. 2015;4(7):e1016709.
42. Lawler SE, Speranza MC, Cho CF, Chiocca EA. Oncolytic
viruses in cancer treatment: a review. JAMA Oncol.
2017;3(6):841–9.
43. Fukuhara H, Ino Y, Todo T. Oncolytic virus therapy: A new era
of cancer treatment at dawn. Cancer Sci. 2016;107(10):1373–9.
44. Kaufman HL, Bines SD. OPTIM trial: a Phase III trial of an
oncolytic herpes virus encoding GM-CSF for unresectable stage
III or IV melanoma. Future Oncol. Jun 2010;6(6):941–9.
45. Breitbach CJ, Moon A, Burke J, Hwang TH, Kirn DH. A phase
2, open-label, randomized study of Pexa-Vec (JX-594) admin-
istered by intratumoral injection in patients with
unresectable primary hepatocellular carcinoma. Methods Mol
Biol. 2015;1317:343–57.
46. Dalgleish AG, Whelan MA. Cancer vaccines as a therapeutic
modality: The long trek. Cancer Immunol Immunother.
2006;55(8):1025–32.
47. Ott PA, Hu Z, Keskin DB, et al. An immunogenic personal
neoantigen vaccine for patients with melanoma. Nature.
2017;547(7662):217–21.
48. Sahin U, Derhovanessian E, Miller M, et al. Personalized RNA
mutanome vaccines mobilize poly-specific therapeutic immunity
against cancer. Nature. 2017;547(7662):222–6.
49. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T
immunotherapy for castration-resistant prostate cancer. N Engl J
Med. 2010;363(5):411–22.
50. Weden S, Klemp M, Gladhaug IP, et al. Long-term follow-up of
patients with resected pancreatic cancer following vaccination
against mutant K-ras. Int J Cancer. 2011;128(5):1120–8.
51. MYPHISMO: MYB and PD-1 Immunotherapies against multi-
ple oncologies trial. https://ClinicalTrials.gov/show/
NCT03287427.
52. Garrido F, Perea F, Bernal M, Sanchez-Palencia A, Aptsiauri N,
Ruiz-Cabello F. The escape of cancer from T cell-mediated
immune surveillance: HLA class I loss and tumor tissue archi-
tecture. Vaccines (Basel). 2017;5(1):7.
53. Garrido F, Ruiz-Cabello F, Aptsiauri N. Rejection versus
escape: the tumor MHC dilemma. Cancer Immunol Immunother.
2017;66(2):259–71.
54. Zaretsky JM, Garcia-Diaz A, Shin DS, et al. Mutations associ-
ated with acquired resistance to PD-1 blockade in melanoma. N
Engl J Med. 2016;375(9):819–29.
55. Tonn T, Schwabe D, Klingemann HG, et al. Treatment of
patients with advanced cancer with the natural killer cell line
NK-92. Cytotherapy. 2013;15(12):1563–70.
56. Yang YJ, Park JC, Kim HK, Kang JH, Park SY. A trial of
autologous ex vivo-expanded NK cell-enriched lymphocytes
with docetaxel in patients with advanced non-small cell lung
cancer as second- or third-line treatment: phase IIa study. An-
ticancer Res. 2013;33(5):2115–22.
57. Sakamoto N, Ishikawa T, Kokura S, et al. Phase I clinical trial of
autologous NK cell therapy using novel expansion method in
patients with advanced digestive cancer. J Transl Med.
2015;13:277.
58. Geller MA, Cooley S, Judson PL, et al. A phase II study of
allogeneic natural killer cell therapy to treat patients with
recurrent ovarian and breast cancer. Cytotherapy.
2011;13(1):98–107.
59. Arai S, Meagher R, Swearingen M, et al. Infusion of the allo-
geneic cell line NK-92 in patients with advanced renal cell
cancer or melanoma: a phase I trial. Cytotherapy.
2008;10(6):625–32.
60. Ammam M. Immunotherapy based on natural killer cells may
soon begin clinical studies. In: M. Nace (Ed) Immuno-Oncology
News. Dallas, TX: BioNews Services, LLC; 2017.
61. Rezvani K, Rouce R, Liu E, Shpall E. Engineering natural killer
cells for cancer immunotherapy. Mol Ther. 2017;25(8):1769–81.
62. Porter DL, Kalos M, Zheng Z, Levine B, June C. Chimeric
antigen receptor therapy for B-cell malignancies. J Cancer.
2011;2:331–2.
63. Porter DL, Hwang WT, Frey NV, et al. Chimeric antigen
receptor T cells persist and induce sustained remissions in
relapsed refractory chronic lymphocytic leukemia. Sci Transl
Med. 2015;7(303):303ra139.
64. FDA US. FDA approval brings first gene therapy to the United
States. CAR T-cell therapy approved to treat certain children
and young adults with B-cell acute lymphoblastic leukemia:
FDA, USA; 2017.
65. Yu S, Li A, Liu Q, et al. Chimeric antigen receptor T cells: a
novel therapy for solid tumors. J Hematol Oncol. 2017;10(1):78.
T. Pham et al.
9. 66. Feng K, Guo Y, Dai H, et al. Chimeric antigen receptor-modi-
fied T cells for the immunotherapy of patients with EGFR-
expressing advanced relapsed/refractory non-small cell lung
cancer. Sci China Life Sci. 2016;59(5):468–79.
67. A phase I trial of T cells expressing an anti-GD2 chimeric
antigen receptor in children and young adults with GD2?
solid
tumors. https://ClinicalTrials.gov/show/NCT02107963.
68. CMV-specific cytotoxic T lymphocytes expressing CAR tar-
geting HER2 in patients with gbm. https://ClinicalTrials.gov/sh
ow/NCT01109095.
69. Pilot study of autologous anti-EGFRvIII CAR T cells in recur-
rent glioblastoma multiforme. https://ClinicalTrials.gov/show/
NCT02844062.
70. Kawalec P, Paszulewicz A, Holko P, Pilc A. Sipuleucel-T
immunotherapy for castration-resistant prostate cancer. A sys-
tematic review and meta-analysis. Arch Med Sci.
2012;8(5):767–75.
71. A study of mesothelin redirected autologous T cells for
advanced pancreatic carcinoma. https://ClinicalTrials.gov/show/
NCT02706782.
72. Pilot study of autologous T-cells in patients with metastatic
pancreatic cancer. https://ClinicalTrials.gov/show/
NCT02465983.
73. Katz SC, Burga RA, McCormack E, et al. Phase I hepatic
immunotherapy for metastases study of intra-arterial chimeric
antigen receptor-modified T-cell therapy for CEA?
liver
metastases. Clin Cancer Res. 2015;21(14):3149–59.
74. Ahmed N, Brawley VS, Hegde M, et al. Human epidermal
growth factor receptor 2 (HER2)-specific chimeric antigen
receptor-modified T cells for the immunotherapy of HER2-
positive sarcoma. J Clin Oncol. 2015;33(15):1688–96.
75. Her2 chimeric antigen receptor expressing T cells in advanced
sarcoma. https://ClinicalTrials.gov/show/NCT00902044.
76. Hegde UP, Mukherji B. Current status of chimeric antigen
receptor engineered T cell-based and immune checkpoint
blockade-based cancer immunotherapies. Cancer Immunol
Immunother. 2017;66(9):1113–21.
77. Lindau D, Gielen P, Kroesen M, Wesseling P, Adema GJ. The
immunosuppressive tumour network: myeloid-derived suppres-
sor cells, regulatory T cells and natural killer T cells.
Immunology. 2013;138(2):105–15.
78. Tanaka A, Sakaguchi S. Regulatory T cells in cancer
immunotherapy. Cell Res. 2017;27(1):109–18.
79. Liu C, Workman CJ, Vignali DA. Targeting regulatory T cells in
tumors. FEBS J. 2016;283(14):2731–48.
80. Rech AJ, Vonderheide RH. Clinical use of anti-CD25 antibody
daclizumab to enhance immune responses to tumor antigen
vaccination by targeting regulatory T cells. Ann N Y Acad Sci.
2009;1174:99–106.
81. Rech AJ, Mick R, Martin S, et al. CD25 blockade depletes and
selectively reprograms regulatory T cells in concert with
immunotherapy in cancer patients. Sci Transl Med.
2012;4(134):134–62.
82. Telang S, Rasku MA, Clem AL, et al. Phase II trial of the
regulatory T cell-depleting agent, denileukin diftitox, in patients
with unresectable stage IV melanoma. BMC Cancer.
2011;11:515.
83. Romano E, Kusio-Kobialka M, Foukas PG, et al. Ipilimumab-
dependent cell-mediated cytotoxicity of regulatory T cells
ex vivo by nonclassical monocytes in melanoma patients. Proc
Natl Acad Sci U S A. 2015;112(19):6140–5.
84. Tobin RP, Davis D, Jordan KR, McCarter MD. The clinical
evidence for targeting human myeloid-derived suppressor cells
in cancer patients. J Leukoc Biol. 2017;102(2):381–91.
85. Schilling B, Sucker A, Griewank K, et al. Vemurafenib reverses
immunosuppression by myeloid derived suppressor cells. Int J
Cancer. 2013;133(7):1653–63.
86. de Coana YP, Wolodarski M, Poschke I, et al. Ipilimumab
treatment decreases monocytic MDSCs and increases CD8
effector memory T cells in long-term survivors with advanced
melanoma. Oncotarget. 2017;8(13):21539–53.
87. Ko JS, Rayman P, Ireland J, et al. Direct and differential sup-
pression of myeloid-derived suppressor cell subsets by sunitinib
is compartmentally constrained. Cancer Res.
2010;70(9):3526–36.
88. Mirza N, Fishman M, Fricke I, et al. All-trans-retinoic acid
improves differentiation of myeloid cells and immune response
in cancer patients. Cancer Res. 2006;66(18):9299–307.
89. Lathers DM, Clark JI, Achille NJ, Young MR. Phase 1B study to
improve immune responses in head and neck cancer patients
using escalating doses of 25-hydroxyvitamin D3. Cancer
Immunol Immunother. 2004;53(5):422–30.
90. Noonan KA, Ghosh N, Rudraraju L, Bui M, Borrello I. Tar-
geting immune suppression with PDE5 inhibition in end-stage
multiple myeloma. Cancer Immunol Res. 2014;2(8):725–31.
91. Weed DT, Vella JL, Reis IM, et al. Tadalafil reduces myeloid-
derived suppressor cells and regulatory T cells and promotes
tumor immunity in patients with head and neck squamous cell
carcinoma. Clin Cancer Res. 2015;21(1):39–48.
92. Annels NE, Shaw VE, Gabitass RF, et al. The effects of gem-
citabine and capecitabine combination chemotherapy and of
low-dose adjuvant GM-CSF on the levels of myeloid-derived
suppressor cells in patients with advanced pancreatic cancer.
Cancer Immunol Immunother. 2014;63(2):175–83.
93. Kanterman J, Sade-Feldman M, Biton M, et al. Adverse
immunoregulatory effects of 5FU and CPT11 chemotherapy on
myeloid-derived suppressor cells and colorectal cancer out-
comes. Cancer Res. 2014;74(21):6022–35.
94. Fischer K, Hoffmann P, Voelkl S, et al. Inhibitory effect of
tumor cell-derived lactic acid on human T cells. Blood.
2007;109(9):3812–9.
95. Chang CH, Qiu J, O’Sullivan D, et al. Metabolic competition in
the tumor microenvironment is a driver of cancer progression.
Cell. 2015;162(6):1229–41.
96. Allavena P, Germano G, Marchesi F, Mantovani A. Chemokines
in cancer related inflammation. Exp Cell Res.
2011;317(5):664–73.
97. Griffioen AW, Damen CA, Martinotti S, Blijham GH, Groe-
newegen G. Endothelial intercellular adhesion molecule-1
expression is suppressed in human malignancies: the role of
angiogenic factors. Cancer Res. 1996;56(5):1111–7.
98. Lider O, Mekori YA, Miller T, et al. Inhibition of T lymphocyte
heparanase by heparin prevents T cell migration and T cell-
mediated immunity. Eur J Immunol. 1990;20(3):493–9.
99. Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer.
2006;6(5):392–401.
100. Shin HC, Han W, Moon HG, et al. Breast-conserving surgery
after tumor downstaging by neoadjuvant chemotherapy is
oncologically safe for stage III breast cancer patients. Ann Surg
Oncol. 2013;20(8):2582–9.
101. Vuky J, Corman JM, Porter C, Olgac S, Auerbach E, Dahl K.
Phase II trial of neoadjuvant docetaxel and CG1940/CG8711
followed by radical prostatectomy in patients with high-risk
clinically localized prostate cancer. Oncologist.
2013;18(6):687–8.
102. Long GV, Weber JS, Larkin J, et al. Nivolumab for patients with
advanced melanoma treated beyond progression: analysis of 2
phase 3 clinical trials. JAMA Oncol. 2017;3(11):1511–19.
Immunotherapy for Solid Tumors: A Review