A growing arsenal of new drugs that unleash the body’s immune system against tumors has captured the cancer treatment spotlight. Immunotherapy in different forms—checkpoint blockers, vaccines, and CAR T cells, for example—has had unprecedented success in halting or shrinking even advanced cancer in some patients, and prolonging lives in cancers such as melanoma.
In mid-2017, it was reported that 248 new immunotherapies and vaccines were in clinical trials, and trials testing combinations of immunotherapies with other treatments such as chemotherapy numbered 765.
Nevertheless, the sobering fact is that at present immunotherapies help only a minority of patients with a given cancer type, and in some types of cancer they have had little or no success. A major focus today is to discover why immunotherapies work or fail, and how they can be improved to reach their hoped-for potential as a broadly transformative treatment for cancer.
“This is what everybody wants to do now,” says Gordon Freeman, PhD, a Dana-Farber immunologist who made fundamental discoveries leading to checkpoint-blocking drugs. “The door is open, and now we want to expand the benefits.”
https://blog.dana-farber.org/insight/20 ... umors-hot/
Enhancing Immunotherapy: The Race to Make “Cold” Tumors “Hot”
Re: Enhancing Immunotherapy: The Race to Make “Cold” Tumors “Hot”
I believe this article provides a good early bases to how TKIs played a role in activating ( aiding our cold tumors to be inflamed -hot ) so as the immune system, in spite of being immune suppressived by the TKI and especially our chemo resistant alveolar soft part sarcoma immune system ,is able to begin to address our sarcoma.
The response when a patient is administered a TKI during the course of their reatment is a good indicator of where the immune system is at to address the eradication of the sarcoma, partially by the response seen on the scan. Too by the inflammatory response, the patient can benefit 2 fold by regulating the unregulated vascular system that is seen in ASPS tumors , and attracting the immune system to help create antigens for the future fight or current fight of mets.
Unfortunately the micro Mets are made more visible possibly , as well and possibly not treated because of our staging and the misunderstanding of our indolent sarcoma.
My opinion, as I'm not a doctor.
It was submitted for publication in 2007. :)
Immunostimulatory sequences in immunotherapy.
https://www.ncbi.nlm.nih.gov/m/pubmed/17620904/
The response when a patient is administered a TKI during the course of their reatment is a good indicator of where the immune system is at to address the eradication of the sarcoma, partially by the response seen on the scan. Too by the inflammatory response, the patient can benefit 2 fold by regulating the unregulated vascular system that is seen in ASPS tumors , and attracting the immune system to help create antigens for the future fight or current fight of mets.
Unfortunately the micro Mets are made more visible possibly , as well and possibly not treated because of our staging and the misunderstanding of our indolent sarcoma.
My opinion, as I'm not a doctor.
It was submitted for publication in 2007. :)
Immunostimulatory sequences in immunotherapy.
https://www.ncbi.nlm.nih.gov/m/pubmed/17620904/
Last edited by D.ap on Wed Sep 18, 2019 7:48 am, edited 4 times in total.
Debbie
Immunostimulatory sequences in immunotherapy.
Abstract
PURPOSE OF REVIEW: To review the current literature regarding immunostimulatory sequences of DNA for immunotherapy with respect to signaling mechanisms, cytokine profiles, structural characteristics and the applicability and success of this strategy to treat allergic disease.
RECENT FINDINGS: The binding of synthetic DNA-based immunotherapy agents composed of unmethylated cytosine-guanine dinucleotides (CpG ODN) to toll-like receptors have been found to be species-specific. CpG ODNs are capable of inducing a shift in the cytokine profile and immune response that favors the Th1 pathway and suppresses the Th2 pathway. This makes using CpG ODNs a promising candidate for the treatment of allergic diseases, which are known to be mediated by Th2-based response. Current CpG ODN studies have demonstrated prevention and reversal of acute allergen inflammation, airway hyper-reactivity and remodeling. Early animal and human trials of CpG ODNs have shown them to be both well tolerated and effective.
SUMMARY: The use of immunostimulatory sequences in immunotherapy, although still in the early stages of development, has thus far been shown to be both well tolerated and effective, and offers the potential for a better tolerated, more rapid, more efficacious and longer-lasting therapy over current immunotherapy protocols.
PURPOSE OF REVIEW: To review the current literature regarding immunostimulatory sequences of DNA for immunotherapy with respect to signaling mechanisms, cytokine profiles, structural characteristics and the applicability and success of this strategy to treat allergic disease.
RECENT FINDINGS: The binding of synthetic DNA-based immunotherapy agents composed of unmethylated cytosine-guanine dinucleotides (CpG ODN) to toll-like receptors have been found to be species-specific. CpG ODNs are capable of inducing a shift in the cytokine profile and immune response that favors the Th1 pathway and suppresses the Th2 pathway. This makes using CpG ODNs a promising candidate for the treatment of allergic diseases, which are known to be mediated by Th2-based response. Current CpG ODN studies have demonstrated prevention and reversal of acute allergen inflammation, airway hyper-reactivity and remodeling. Early animal and human trials of CpG ODNs have shown them to be both well tolerated and effective.
SUMMARY: The use of immunostimulatory sequences in immunotherapy, although still in the early stages of development, has thus far been shown to be both well tolerated and effective, and offers the potential for a better tolerated, more rapid, more efficacious and longer-lasting therapy over current immunotherapy protocols.
Debbie
Re: Enhancing Immunotherapy: The Race to Make “Cold” Tumors “Hot”
The right Timing, right combination, right sequence, and right delivery for Cancer immunotherapy
Abstract
This review will suggest a method to maximize the treatment efficiency of current CI.
Cancer immunotherapy (CI) represented by immune checkpoint inhibitors (ICIs) presents a new paradigm for cancer treatment. However, the types of cancer that attain a therapeutic benefit from ICIs are limited, and the efficacy of these treatments does not meet expectations. To date, research on ICIs has mainly focused on identifying biomarkers and patient characteristics that can enhance the therapeutic effect on tumors. However, studies on combinational strategies for CI are being actively conducted to overcome the resistance to ICI treatment. Moreover, it has been confirmed that dramatic anticancer effects are achieved through “neoadjuvant” immunotherapy with ICIs in treatment-naïve cancer patients; consequently, it has become necessary to consider how to best apply cancer immunotherapies for patients, even with respect to their tumor stages. In this review, we sought to discuss the right timing of ICI treatment in consideration of the progression of cancer with a changing tumor-immune microenvironment. Furthermore, we investigated which types of combinational treatments and their corresponding sequences of administration could optimize the therapeutic effect of ICIs to expand the applicable target of ICIs and increase their therapeutic efficacy. Finally, we discussed several delivery pathways and methods that can maximize the effect of ICIs.
https://www.sciencedirect.com/science/a ... 5921000183
Abstract
This review will suggest a method to maximize the treatment efficiency of current CI.
Cancer immunotherapy (CI) represented by immune checkpoint inhibitors (ICIs) presents a new paradigm for cancer treatment. However, the types of cancer that attain a therapeutic benefit from ICIs are limited, and the efficacy of these treatments does not meet expectations. To date, research on ICIs has mainly focused on identifying biomarkers and patient characteristics that can enhance the therapeutic effect on tumors. However, studies on combinational strategies for CI are being actively conducted to overcome the resistance to ICI treatment. Moreover, it has been confirmed that dramatic anticancer effects are achieved through “neoadjuvant” immunotherapy with ICIs in treatment-naïve cancer patients; consequently, it has become necessary to consider how to best apply cancer immunotherapies for patients, even with respect to their tumor stages. In this review, we sought to discuss the right timing of ICI treatment in consideration of the progression of cancer with a changing tumor-immune microenvironment. Furthermore, we investigated which types of combinational treatments and their corresponding sequences of administration could optimize the therapeutic effect of ICIs to expand the applicable target of ICIs and increase their therapeutic efficacy. Finally, we discussed several delivery pathways and methods that can maximize the effect of ICIs.
https://www.sciencedirect.com/science/a ... 5921000183
Neoadjuvant therapy refers to any treatment that is given for cancer before the main treatment, with the goal of making the main treatment more likely to be successful.
A person is considered to be "treatment-naive" if they have never undergone treatment for a particular illness.Feb 15, 2022
Debbie
T cell–inflamed versus non-T cell–inflamed tumors: a conceptual framework for cancer immunotherapy drug development and
T cell–inflamed versus non-T cell–inflamed tumors: a conceptual framework for cancer immunotherapy drug development and combination therapy selection
viewtopic.php?p=14567#p14567
Abstract
Immunotherapies such as checkpoint blocking antibodies and adoptive cell transfer are emerging as treatments for a growing number of cancers. Despite clinical activity of immunotherapies across a range of cancer types, the majority of patients fail to respond to these treatments and resistance mechanisms remain incompletely defined. Responses to immunotherapy preferentially occur in tumors with a pre-existing antitumor T-cell response that can most robustly be measured via expression of dendritic cell and CD8+ T cell–associated genes. The tumor subset with high expression of this signature has been described as the T cell–”inflamed” phenotype. Segregating tumors by expression of the inflamed signature may help predict immunotherapy responsiveness. Understanding mechanisms of resistance in both the T cell–inflamed and non-inflamed subsets of tumors will be critical in overcoming treatment failure and expanding the proportion of patients responding to current immunotherapies. To maximize the impact of immunotherapy drug development, pretreatment stratification of targets associated with either the T cell–inflamed or non-inflamed tumor microenvironment should be employed. Similarly, biomarkers predictive of responsiveness to specific immune-modulatory therapies should guide therapy selection in a growing landscape of treatment options. Combination strategies may ultimately require converting non-T cell–inflamed tumors into T cell–inflamed tumors as a means to sensitize tumors to therapies dependent on T-cell killing.
The immune system can detect and eradicate cancer cells. However, tumors acquire genetic mutations, induce immunosuppressive signaling pathways and undergo epigenetic changes that lead to resistant phenotypes. This resistance manifests as a capacity to avoid immune recognition or disable antitumor components of immunity. At baseline, spontaneous antitumor T-cell response occurs in a fraction of patients with solid tumors. Although cancer in these patients continues to progress, the beneficial effect of antitumor immune engagement may persist during tumor progression. The biological processes associated with this spontaneous, though inadequate, induction of antitumor immunity correlate with improved clinical outcomes and may predict responsiveness to immunotherapy (1–3).
Across cancer, the majority of tumors lack a robust T-cell infiltrate prior to treatment. It is not clear why T cells infiltrate some tumors and not others. Fundamental to answering this question is a more thorough understanding of the essential events leading to a spontaneous antitumor T-cell response (Figure 1). Innate immune recognition of incipient neoplasms and activation of type I interferon (IFN) signaling are among the most proximal events required to generate a de novo T-cell responses (4,5). One major mediator of type I IFN generation is the cGAS/STING (stimulator of interferon genes) pathway, which is activated by cytosolic tumor-derived DNA. Activation of STING mediates innate immune sensing of cancer cells by tumor-infiltrating antigen-presenting cells (APC) (6). STING pathway activation in the tumor microenvironment leads to downstream type I IFN production, resulting in the recruitment and activation of dendritic cells, including the Batf3 (basic leucine zipper transcription factor ATF-like 3)-driven subset (4,7). In turn, Batf3-lineage dendritic cells cross-present tumor-derived antigen to CD8+ T cells and regulate T-cell recruitment to tumors (4,8). To eradicate cancer cells, CD8+ T cells must become appropriately activated, traffic to tumor tissue, overcome local mechanisms of immune suppression, and maintain their effector function.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145135/
viewtopic.php?p=14567#p14567
Abstract
Immunotherapies such as checkpoint blocking antibodies and adoptive cell transfer are emerging as treatments for a growing number of cancers. Despite clinical activity of immunotherapies across a range of cancer types, the majority of patients fail to respond to these treatments and resistance mechanisms remain incompletely defined. Responses to immunotherapy preferentially occur in tumors with a pre-existing antitumor T-cell response that can most robustly be measured via expression of dendritic cell and CD8+ T cell–associated genes. The tumor subset with high expression of this signature has been described as the T cell–”inflamed” phenotype. Segregating tumors by expression of the inflamed signature may help predict immunotherapy responsiveness. Understanding mechanisms of resistance in both the T cell–inflamed and non-inflamed subsets of tumors will be critical in overcoming treatment failure and expanding the proportion of patients responding to current immunotherapies. To maximize the impact of immunotherapy drug development, pretreatment stratification of targets associated with either the T cell–inflamed or non-inflamed tumor microenvironment should be employed. Similarly, biomarkers predictive of responsiveness to specific immune-modulatory therapies should guide therapy selection in a growing landscape of treatment options. Combination strategies may ultimately require converting non-T cell–inflamed tumors into T cell–inflamed tumors as a means to sensitize tumors to therapies dependent on T-cell killing.
The immune system can detect and eradicate cancer cells. However, tumors acquire genetic mutations, induce immunosuppressive signaling pathways and undergo epigenetic changes that lead to resistant phenotypes. This resistance manifests as a capacity to avoid immune recognition or disable antitumor components of immunity. At baseline, spontaneous antitumor T-cell response occurs in a fraction of patients with solid tumors. Although cancer in these patients continues to progress, the beneficial effect of antitumor immune engagement may persist during tumor progression. The biological processes associated with this spontaneous, though inadequate, induction of antitumor immunity correlate with improved clinical outcomes and may predict responsiveness to immunotherapy (1–3).
Across cancer, the majority of tumors lack a robust T-cell infiltrate prior to treatment. It is not clear why T cells infiltrate some tumors and not others. Fundamental to answering this question is a more thorough understanding of the essential events leading to a spontaneous antitumor T-cell response (Figure 1). Innate immune recognition of incipient neoplasms and activation of type I interferon (IFN) signaling are among the most proximal events required to generate a de novo T-cell responses (4,5). One major mediator of type I IFN generation is the cGAS/STING (stimulator of interferon genes) pathway, which is activated by cytosolic tumor-derived DNA. Activation of STING mediates innate immune sensing of cancer cells by tumor-infiltrating antigen-presenting cells (APC) (6). STING pathway activation in the tumor microenvironment leads to downstream type I IFN production, resulting in the recruitment and activation of dendritic cells, including the Batf3 (basic leucine zipper transcription factor ATF-like 3)-driven subset (4,7). In turn, Batf3-lineage dendritic cells cross-present tumor-derived antigen to CD8+ T cells and regulate T-cell recruitment to tumors (4,8). To eradicate cancer cells, CD8+ T cells must become appropriately activated, traffic to tumor tissue, overcome local mechanisms of immune suppression, and maintain their effector function.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145135/
Debbie
Th1 and Th2 responses: what are they?
D.ap wrote: ↑Wed Sep 18, 2019 6:49 am Abstract
PURPOSE OF REVIEW: To review the current literature regarding immunostimulatory sequences of DNA for immunotherapy with respect to signaling mechanisms, cytokine profiles, structural characteristics and the applicability and success of this strategy to treat allergic disease.
RECENT FINDINGS: The binding of synthetic DNA-based immunotherapy agents composed of unmethylated cytosine-guanine dinucleotides (CpG ODN) to toll-like receptors have been found to be species-specific. CpG ODNs are capable of inducing a shift in the cytokine profile and immune response that favors the Th1 pathway and suppresses the Th2 pathway. This makes using CpG ODNs a promising candidate for the treatment of allergic diseases, which are known to be mediated by Th2-based response. Current CpG ODN studies have demonstrated prevention and reversal of acute allergen inflammation, airway hyper-reactivity and remodeling. Early animal and human trials of CpG ODNs have shown them to be both well tolerated and effective.
SUMMARY: The use of immunostimulatory sequences in immunotherapy, although still in the early stages of development, has thus far been shown to be both well tolerated and effective, and offers the potential for a better tolerated, more rapid, more efficacious and longer-lasting therapy over current immunotherapy protocols.
Th1 and Th2 responses: what are they?
Cytokines are the hormonal messengers responsible for most of the biological effects in the immune system, such as cell mediated immunity and allergic type responses. Although they are numerous, cytokines can be functionally divided into two groups: those that are proinflammatory and those that are essentially anti-inflammatory but that promote allergic responses.
T lymphocytes are a major source of cytokines. These cells bear antigen specific receptors on their cell surface to allow recognition of foreign pathogens. They can also recognise normal tissue during episodes of autoimmune diseases. There are two main subsets of T lymphocytes, distinguished by the presence of cell surface molecules known as CD4 and CD8. T lymphocytes expressing CD4 are also known as helper T cells, and these are regarded as being the most prolific cytokine producers. This subset can be further subdivided into Th1 and Th2, and the cytokines they produce are known as Th1-type cytokines and Th2-type cytokines.
Th1-type cytokines tend to produce the proinflammatory responses responsible for killing intracellular parasites and for perpetuating autoimmune responses. Interferon gamma is the main Th1 cytokine. Excessive proinflammatory responses can lead to uncontrolled tissue damage, so there needs to be a mechanism to counteract this. The Th2-type cytokines include interleukins 4, 5, and 13, which are associated with the promotion of IgE and eosinophilic responses in atopy, and also interleukin-10, which has more of an anti-inflammatory response. In excess, Th2 responses will counteract the Th1 mediated microbicidal action. The optimal scenario would therefore seem to be that humans should produce a well balanced Th1 and Th2 response, suited to the immune challenge.
Many researchers regard allergy as a Th2 weighted imbalance, and recently immunologists have been investigating ways to redirect allergic Th2 responses in favour of Th1 responses to try to reduce the incidence of atopy. Some groups have been looking at using high dose exposure to allergen to drive up the Th1 response in established disease,1 and other groups have been studying the use of mycobacterial vaccines in an attempt to drive a stronger Th1 response in early life.2
An additional strategy is being used to prevent the onset of disease; this involves the study of pregnancy and early postnatal life. Both of these states are chiefly viewed as Th2 phenomena (to reduce the risk of miscarriage, a strong Th2 response is necessary to modify the Th1 cellular response in utero). The fetus can switch on an immune response early in pregnancy, and because pregnancy is chiefly a Th2 situation, babies tend to be born with Th2 biased immune responses. These can be switched off rapidly postnatally under the influence of microbiological exposure or can be enhanced by early exposure to allergens. It is also hypothesised that those who go on to develop full blown allergies may be those who are born with a generally weaker Th1 response, although it is now apparent that babies with allergies produce weak Th1 and Th2 responses.
Some people have suggested that immunisation programmes (and the subsequent reduction in microbiological exposure) are responsible for the increasing incidence of atopy. There is, however, no evidence that immunisation causes atopy. Moreover, this is not an argument that we should be exposing children to potentially fatal diseases again. If experiencing native diseases reduces the incidence of atopy, then the task of immunologists must be to develop vaccines that mimic the positive effects of infection.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC27457/
Debbie
Re: Enhancing Immunotherapy: The Race to Make “Cold” Tumors “Hot”
An additional strategy is being used to prevent the onset of disease; this involves the study of pregnancy and early postnatal life. Both of these states are chiefly viewed as Th2 phenomena (to reduce the risk of miscarriage, a strong Th2 response is necessary to modify the Th1 cellular response in utero). The fetus can switch on an immune response early in pregnancy, and because pregnancy is chiefly a Th2 situation, babies tend to be born with Th2 biased immune responses. These can be switched off rapidly postnatally under the influence of microbiological exposure or can be enhanced by early exposure to allergens. It is also hypothesised that those who go on to develop full blown allergies may be those who are born with a generally weaker Th1 response, although it is now apparent that babies with allergies produce weak Th1 and Th2 responses.
Debbie
Re: Enhancing Immunotherapy: The Race to Make “Cold” Tumors “Hot”
The balance of Th1 and Th2 T cells is a key factor in the immune system's ability to respond to pathogens and maintain tolerance
Debbie
Re: Enhancing Immunotherapy: The Race to Make “Cold” Tumors “Hot”
“A "low mutational burden but lots of neoantigens" situation refers to a cancer where the overall number of genetic mutations in the tumor is relatively low, but the few mutations that are present still produce a significant amount of unique "neoantigens" that the immune system can potentially recognize as foreign and target, potentially leading to an immune response against the cancer cells even with a low mutation count; this can occur due to the specific nature of the mutations, their location within the protein, or the way they are presented to the immune system. “
“In the context of cancer, "indolent" means a tumor that grows very slowly and progresses minimally, often with few symptoms, while "low mutational" refers to a tumor with a low number of genetic mutations, which can also be associated with a slower growth rate and less aggressive behavior; essentially, an "indolent and low mutational" cancer is a slow-growing tumor with a relatively low number of genetic alterations making it less likely to spread rapidly”
“In the context of cancer, "indolent" means a tumor that grows very slowly and progresses minimally, often with few symptoms, while "low mutational" refers to a tumor with a low number of genetic mutations, which can also be associated with a slower growth rate and less aggressive behavior; essentially, an "indolent and low mutational" cancer is a slow-growing tumor with a relatively low number of genetic alterations making it less likely to spread rapidly”
Debbie