Tag: Antigen

City of Hope cures oldest person of blood cancer and achieves HIV remission
[ad_1]
City of Hope^®, one of the largest cancer research and treatment organizations in the United States, treated the oldest person to be cured of a blood cancer and then achieve remission for HIV after receiving a blood stem cell transplant from a donor with a rare genetic mutation. Research published in NEJM today demonstrates that older adults with blood cancers who receive reduced intensity chemotherapy before a stem cell transplant with donor cells that are resistant to HIV may be cured of HIV infection.

Paul Edmonds, 68, of Desert Springs, California, is the fifth person in the world to achieve remission for acute myelogenous leukemia and HIV after receiving stem cells with a rare genetic mutation, homozygous CCR5 Delta 32. That mutation makes people who have it resistant to acquiring HIV. Edmonds is also the person who had HIV the longest -; for over 31 years -; among these five patients.

Known as the “City of Hope patient” among these five patients, Edmonds received a transplant at City of Hope on Feb. 6, 2019, and is now considered to be cured of leukemia. Edmonds stopped taking antiretroviral therapies for HIV nearly three years ago and will be considered cured of HIV after he has stopped taking antiretrovirals for five years.

“City of Hope’s case demonstrates that it is possible to achieve remission from HIV even at an older age and after living with HIV for many years,” said Jana K. Dickter, M.D., a clinical professor in City of Hope’s Division of Infectious Diseases, who led the study. “Furthermore, remission can be achieved with a lower-intensity regimen than the therapy received by the four other patients who went into remission for HIV and cancer. As people with HIV continue to live longer, there will be more opportunities for personalized treatments for their blood cancers.”

For Edmonds’ medical team, this meant they would need to tailor his treatment to address his age and the duration of his HIV. City of Hope’s decades-long expertise treating older adults with cancer and HIV -; efforts led by John A. Zaia, M.D., director of City of Hope’s Center for Gene Therapy and Aaron D. Miller and Edith Miller Chair for Gene Therapy, and other doctors -; proved to be invaluable in treating Edmonds and helping him go into remission for both leukemia and HIV.

Under the care of City of Hope hematologist Ahmed Aribi, M.D., assistant professor in the Division of Leukemia and a study author, Edmonds received three different therapies to get him into remission before receiving a transplant. The therapy is needed to help the patient achieve remission, and the patient can then proceed with a transplant with the goal of curing the cancer.

Edmonds received a chemotherapy-based, reduced-intensity transplant regimen prior to his transplant that was developed by City of Hope and other transplant programs for treatment of older patients with blood cancers. Reduced-intensity chemotherapy makes the transplant more tolerable for older patients and reduces the potential for transplant-related complications from the procedure.

For the transplant, Aribi and his team worked with City of Hope’s Unrelated Donor Bone Marrow Transplant Program -; directed by Monzr M. Al Malki, M.D. -; to find a donor who was a perfect match for the patient and had the rare genetic mutation, which is found in just 1-2% of the general population.

The mutation makes people who have it resistant to acquiring HIV. CCR5 is a receptor on CD4+ immune cells, and HIV uses that receptor to enter and attack the immune system. But the CCR5 mutation blocks that pathway, which stops HIV from replicating.

Edmonds had mild to moderate side effects caused by graft-versus-host disease, which occurs when the donor’s T lymphocytes, a type of white blood cell that fights infections, attack the patient’s cells.

Edmonds also achieved “full chimerism,” meaning that all of his bone marrow and blood stem cells originated from the donor.

Stephen J. Forman, M.D., director of City of Hope’s Hematologic Malignancies Research Institute and a professor in the Department of Hematology & Hematopoietic Cell Transplantation, noted a confluence of several research initiatives by City of Hope over the years helped lead the institution to this moment.

City of Hope and other institutions started performing successful stem cell transplants in older adults a decade ago, an intensive and high-risk procedure in this population that was unheard of prior to then. We have treated patients who are in their 80s with transplants and that is due to City of Hope’s emphasis on expanding therapies to more patients, as well as our compassionate, top-notch care of even the most vulnerable populations.”

Stephen J. Forman, M.D., Director of City of Hope’s Hematologic Malignancies Research Institute

“City of Hope is not stopping there. Our researchers are working on creating stem cells that have the genetic mutation that makes them naturally resistant to HIV, among other research initiatives,” he added.

These milestones include:
- City of Hope was one of the first institutions in the United States to perform a reduced intensity regimen for older patients with myelodysplasia, a blood disease that can evolve into leukemia and that Edmonds had prior to acute myelogenous leukemia.
- Ryotaro Nakamura, M.D., director of City of Hope’s Center for Stem Cell Transplantation and Jan & Mace Siegel Professor in Hematology & Hematopoietic Cell Transplantation, led the national trial that demonstrated a transplant could become standard of care for older people with myelodysplastic syndromes, which led to Medicare approving the therapy in older populations.
- City of Hope was one of the first centers in the United States to perform effective, curative autologous transplants, which use a person’s own stem cells, for patients with HIV-related lymphoma. When many centers still treated patients with low-intensity, noncurative treatment approaches, City of Hope -; led by Forman and Amrita Krishnan, M.D., executive medical director of hematology, City of Hope Orange County – challenged that paradigm by demonstrating that autologous transplants could be used to cure patients with HIV-related lymphomas who would otherwise die.
- City of Hope was also a primary national co-leader in two National Cancer Institute-sponsored trials for autologous as well as allogeneic stem cell transplantation, which use a donor’s stem cells, for patients with HIV and blood cancers. Led by Joseph Alvarnas, M.D., City of Hope’s vice president of government affairs and a hematology professor, these trials led to a change in the national standards of care on how best to manage this vulnerable patient population.
City of Hope’s blood stem cell and bone marrow transplant (BMT) program has performed nearly 19,000 transplants, making it one of the largest programs in the nation. City of Hope has exceptional transplant outcomes year after year, according to the Center for International Blood & Marrow Transplant Research.

Building on its BMT expertise, City of Hope is also a pioneer in the development of chimeric antigen receptor (CAR) T cells to treat blood cancers and solid tumors. More than 1,200 patients have been treated with CAR T cell therapy at City of Hope.

Leveraging their expertise in cellular immunotherapy, City of Hope scientists have also developed chimeric antigen receptor CAR T cells that can target and kill HIV-infected cells and control HIV in preclinical research. A City of Hope clinical trial using CAR T cell therapy, which has the potential to provide HIV patients with a lifelong viral suppression without antiretroviral therapies, is expected to open later this year.

Angelo Cardoso, M.D., Ph.D., City of Hope director of the Laboratory of Cellular Medicine, is also a study author and performed many of the experiments that confirmed Edmonds’ HIV remission.

Source:

Journal reference:

Dickter, J. K., et al. (2024). HIV-1 Remission after Allogeneic Hematopoietic-Cell Transplantation. The New England Journal of Medicine. doi.org/10.1056/nejmc2312556.
[ad_2]

Source link
February 16, 2024
Smoking, infection, and BMI found to significantly sway immune response, study shows

[ad_1]

In a recent study published in the journal Nature, researchers explored the factors influencing cytokine release, a critical component of the host immunological response.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic emphasized the wide variation in immunological responses between populations, with age, sex, and genetic variables all playing vital roles. However, therapy and vaccine development often disregard immunological diversity. The Milieu Intérieur research project has contributed to understanding immune homeostasis by quantitatively evaluating the impacts of age, gender, cellular composition, and genetics on immune-related gene transcript levels and those of age, gender, smoking, and cytomegalovirus (CMV) infections on leukocyte distribution in blood. Further study might help us better understand the elements that influence immune responses and how they affect clinical outcomes.

Study: Smoking changes adaptive immunity with persistent effects. Image Credit: NeydtStock / Shutterstock

About the study

In the present study, researchers investigated environmental variables associated with cytokine responsiveness to immunological activation.

The team measured the levels of several cytokines [C‐X‐C motif chemokine ligand 5 (CXCL5), colony-stimulating factor 2 (CSF2), interferon-gamma (IFNγ), interleukin-1 beta (IL-1β), IL-2, 6, 8, 10, 12p70, 13, 17, 23, and tumor necrosis factor (TNF)] after 22 hours of whole-blood stimulations with 11 immunological agonists for 1,000 Milieu Intérieur project donors and in an unstimulated (control) condition. They categorized the stimulations as microbial, viral, T-lymphocyte activated, and cytokines.

Heat maps and principal component analyses (PCA) of 13 cytokine molecules investigated in 12 immunological stimulations revealed the individual cytokines generated by every independent condition. The team performed hierarchical clustering evaluations of log mean variations in cytokine levels to identify groups corresponding to stimulation types.

The researchers compiled 136 environmental, socio-demographic, nutritional, and clinical variables from the digital case report forms and tested for their relationships with cytokines induced in every stimulation using likelihood ratio tests (LRTs) with age, experimental batch, and gender as covariates. They also investigated human leukocyte antigen (HLA) as a predictor of immune response variability, particularly in antigen-specific responses. The team investigated whether smoking-cytokine correlations continued when particular subsets of circulating immune cells were included in their models, as these cells are related to cytokine elevations. They evaluated the biological impact of smoking on cytokine production, calculating the effect sizes for the smoking variables in the linear models and assessing the influence of 326 soluble proteins in sera obtained from 400 donors.

The researchers investigated whether epigenetic pathways contribute to the impact of smoking on adaptive immune responses. They analyzed deoxyribonucleic acid (DNA) methylation at more than 850,000 CpG sites and investigated whether the levels may explain the association between smoking and cytokine levels following SEB stimulation. The study was especially well-suited to identifying response protein quantitative trait loci (pQTLs) since it tested 5,699,237 high-quality imputed single nucleotide polymorphisms (SNPs) for relationships with the cytokines elicited by each stimulation.

Results

The team identified smoking, CMV latent infection, and body mass index (BMI) as the most significant drivers of cytokine response variability. Smoking impacts innate and adaptive immune responses, with the influence on innate responses diminishing after quitting and associated with serum carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) levels. However, the impact on adaptive responses lasts long after smoking cessation and is associated with epigenetic memory.

The study highlighted eleven factors related to one or more cytokines in the immune stimulations, with BMI being the most prevalent. Smoking-related factors were related to interleukin-2 and interleukin-13 (adaptive immunity) in Staphylococcus aureus enterotoxin B superantigen (SEB), anti-cluster of differentiation 3 (anti-CD3) and anti-CD28 immune stimulations, and CXCL5 following Escherichia coli infections or innate immunological stimulations. The findings indicate that smoking causes inflammation and reduces immunity against bacterial infections.

Cytomegalovirus latent infection was associated with TNF, CSF2, and IFNγ cytokines secreted by adaptive immune cells. BMI-related factors were related to CXCL5 following Bacillus Calmette-Guérin (BCG) immune stimulation, and interleukin-2 following SEB stimulation demonstrated obesity dysregulation. The team found no significant association between major histocompatibility complex (MH) class II, DQ beta 1, and HLA.DBQ1.1P, and IL-6 in the control condition.

The study found 2,416 CpG locations related to smoking in the Milieu Intérieur sample, with 129 significantly associated with IL-2 in SEB stimulation. However, 11 CpGs abolished the relationship between smoking and IL-2 and IL-13. Current smokers had lower DNA methylation than non-smokers, but former smokers had an intermediate methylation level. The number of years smoked, total cigarettes smoked, and IL-2 levels in SEB stimulation were adversely linked with DNA methylation, although the number of years after smoking typically correlated positively.

Overall, the study findings identified three novel factors, i.e., smoking status, CMV latent infection, and BMI, associated with variability in cytokine secretion following immunological stimulation. These characteristics may have clinical consequences for the risk of contracting infections, cancer, or autoimmune diseases. Smokers have a heightened inflammatory response after bacterial activation, which promptly decreases after quitting. However, the impacts on adaptive immunity last for years after stopping. The link between smoking and long-lived B and T cell subsets and DNA methylation offers a potential for long-term consequences in the adaptive response.

[ad_2]

Source link

February 14, 2024
Advanced melanoma survival rates improve significantly from 2013 to 2019, Dutch study finds

[ad_1]

In a recent study published in EClinicalMedicine, a group of researchers assessed the change in overall survival (OS) among advanced melanoma patients diagnosed between 2013 and 2021.

Study: Improving survival in advanced melanoma patients: a trend analysis from 2013 to 2021. Image Credit: Africa Studio/Shutterstock.com

Background

The outlook for advanced melanoma, encompassing unresolvable stage III and IV cases, has markedly improved due to the advent of novel treatments.

Starting with the Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) blocking antibody ipilimumab in 2012, the treatment landscape expanded to include B-Raf proto-oncogene, serine/threonine kinase (BRAF) inhibitors for patients with BRAF-mutant melanoma in 2012, anti-Programmed Cell Death (PD)-1 antibodies in 2015, and combinations of BRAF inhibitors with Mitogen-Activated Protein Kinase (MEK) inhibitors and ipilimumab with nivolumab in 2016.

Recent advancements also introduced therapies such as Lymphocyte-Activation Gene 3 (LAG-3) antibodies and Tumor-Infiltrating Lymphocyte (TIL) therapy. In the Netherlands, survival rates have risen following these innovations, even outside clinical trials.

Further research is needed to understand the factors driving the recent decline in survival rates and to develop strategies to improve outcomes for advanced melanoma patients, particularly in the coronavirus disease 2019 (COVID-19) pandemic and evolving treatment modalities.

About the study

The data for the present study was sourced from the Dutch Melanoma Treatment Registry (DMTR). They involved patients aged 18 and over diagnosed with advanced melanoma from 2013 to 2021, specifically focusing on those who received systemic treatment.

These patients were categorized based on the year their melanoma was diagnosed as unresectable.

Those who progressed to unresectable disease following neoadjuvant or adjuvant treatments were included from the point they commenced treatment for their unresectable condition. Exclusions were made for patients with uveal or mucosal melanoma.

Patient demographics and tumor characteristics at the point of advanced disease diagnosis – including age, gender, performance status, lactate dehydrogenase levels (LDH) levels, melanoma location and type, thickness, ulceration presence, liver and brain metastases, number of metastatic organ sites, American Joint Committee on Cancer (AJCC) 8th edition staging, and mutation status were carefully recorded. The study also differentiated between synchronous and metachronous presentations of melanoma.

Statistical analysis was conducted using various methods to compare baseline characteristics and to estimate median survival times and the impact of the year of diagnosis on overall survival.

This involved descriptive statistics, Pearson’s chi-squared, and t-tests for categorical and continuous variables, respectively. Survival analysis was performed with the Kaplan-Meier method, and the Cox proportional hazards model was applied for multivariable analysis, considering several factors identified from previous research.

Statistical computations were performed using R software and several packages for data manipulation and analysis, ensuring a comprehensive and rigorous statistical examination of the collected data.

Study results

Between 2013 and 2021, the DMTR recorded 7,928 patients with advanced melanoma. After excluding cases of uveal and mucosal melanoma, 7,317 patients were included in the analysis.

Many of these patients received systemic treatment, increasing from 74% in 2013 to 86% in 2020 and slightly decreasing to 83% in 2021.

Out of those treated, 6,260 patients were included after further exclusions for uveal and mucosal melanoma. Among these, 428 had received neoadjuvant or adjuvant treatment before their systemic treatment for advanced melanoma.

The study observed a median follow-up of 50.9 months, with the longest follow-up for the 2013 cohort at 106.0 months and the shortest for the 2021 cohort at 14.1 months.

The median age of patients diagnosed with advanced melanoma increased over the years, and there was a noticeable rise in the number of patients with poor performance status and brain metastases. Interestingly, the prevalence of synchronous metastatic disease also increased, particularly in 2020 and 2021.

Treatment modalities evolved from BRAF inhibitors and ipilimumab monotherapy to BRAF/MEK inhibitors, anti-PD-1 antibodies, and combination therapies. The study also noted changes in the duration of these treatments over time.

The median OS for systemically treated advanced melanoma patients improved from 11.2 months in 2013 to 32.0 months in 2019.

However, a decline was observed in patients diagnosed in 2020 and 2021, with median OS dropping to 26.6 and 24.0 months, respectively, although these decreases were not statistically significant.

This trend was mirrored in the melanoma-specific survival (MSS) data, with improvements seen until 2019, followed by a decrease for the cohorts of 2020 and 2021.

Furthermore, the study found that neoadjuvant and adjuvant treatments did not significantly affect survival outcomes for advanced melanoma. Patients with synchronous metastases had shorter survival than those with metachronous metastases.

Despite treatments improving survival post-2013, a concerning trend of increased mortality risk was noted for diagnoses in 2020 and 2021, underscoring the urgency for ongoing research and treatment adaptation.

[ad_2]

Source link

February 14, 2024
CDC releases new syphilis testing guidelines to combat rising cases
[ad_1]
In a recent report published in the Morbidity and Mortality Weekly Report (MMWR), the United States (US) Centers for Disease Control and Prevention (CDC) shares its recommendations for the tests and protocols required to diagnose syphilis in the US. The recommendations build upon existing conventional serologic algorithms and involve the combined use of nontreponemal and treponemal tests to identify if the patient’s immune response indicates a current untreated infection or a past-treated one. Additionally, recommendations for the direct microscopic detection of Treponema pallidum, the causative pathogen of syphilis, are included. These recommendations will help clinical laboratory directors, clinicians, laboratory staff, disease control personnel, and patients combat this dreadful disease.

CDC Laboratory Recommendations for Syphilis Testing, United States, 2024. Image Credit: Peddalanka Ramesh Babu / Shutterstock

Why do we need these recommendations?

Syphilis is a bacterial sexually transmitted infection (STI) that progresses in stages from a painless sore (stage 1) to a severe disease that may attack the brain, liver, nerves, eyes, or cardiovascular system (stage 3). Caused by the bacterium Treponema pallidum subspecies pallidum, the disease has been further associated with congenital complications such as stillbirths, spontaneous abortions, and miscarriages.

Alarmingly, the global burden of syphilis is rising rapidly, especially in wealthy and developed countries, with approximately 6 million new cases in 2021 alone. Reports from the United States of America (US) observe an increase of 2,140% in syphilis incidence rates between 2000 (n = 5,979) and 2020 (n = 133,945), suggesting a local epidemic within the country. Research has characterized this epidemic as displaying significant health disparities, with gender and sexual minorities being the worst affected.

The laboratory diagnosis of syphilis represents a crucial effort in the war against the disease. Timely diagnoses, especially before the onset of stage 3 syphilis, are critical for positive disease outcomes. Public health reporting by laboratories provides the Centers for Disease Control and Prevention (CDC) and other government agencies the information needed to enact policies to attenuate local outbreaks and monitor epidemic trends.

About the report

The current report details the CDC’s first-ever recommendations for syphilis testing and includes optimal methods for point-of-care (POC) tests, laboratory-based tests, sample processing, and reporting. These recommendations were formulated by CDC scientists in collaboration with the Association of Public Health Laboratories (APHL) after reviewing up-to-date peer-reviewed literature, especially publications published by the US Food and Drug Administration (FDA).

Serologic Laboratory Testing

The first section of the report summarises progress in syphilis serological testing since the invention of the Wassermann test through to current nontreponemal (lipoidal antigen) and treponemal tests. In brief, when patients display symptoms or signs of syphilis or have had known sexual contact with a diagnosed syphilis patient, nontreponemal (lipoidal antigen) tests are recommended for laboratory screening. These tests are also recommended when assessing reinfections or reporting outcomes during clinical trials.

“Nontreponemal (lipoidal antigen) tests might be less sensitive than treponemal tests in early primary syphilis and tend to wane with time regardless of treatment. Before testing, test and specimen type should be carefully considered because serum and plasma cannot always be used interchangeably, and certain nontreponemal (lipoidal antigen) tests require heat treatment of specimens. One caveat of nontreponemal (lipoidal antigen) tests is that a reactive result could be a false positive because of recent conditions (e.g., infections, vaccinations or injection drug use, or underlying autoimmune or other chronic conditions).”

Nontreponemal tests are usually carried out manually, but some test versions (e.g., the rapid plasma reagin [RPR] test) may be automated to increase throughput. In the latter (automated) case especially, care must be taken to ensure that samples are maintained at optimal conditions and coinfections are accounted for to ensure diagnostic performance and prevent false positives. Treatment outcomes are best reported by comparing nontreponemal antibody titers at baseline and 12 months following treatment, at which time titers are expected to reduce fourfold.

Treponemal tests are used to validate nontreponemal test results and to diagnose early syphilis infections that cannot (yet) be detected by nontreponemal tests. Most of these tests are conducted manually, but some can be automated for high throughput. In most patients, treponemal antibodies are detectable for life and are helpful to indicate a past, successfully treated syphilis infection. All donations to blood banks must undergo treponemal screening to ensure that volunteered blood is free of syphilis antibodies.

Syphilis screening algorithms

The traditional algorithm for syphilis screening involved nontreponemal tests followed by treponemal tests to confirm any dubious or contentious nontreponemal results. This is because the former is comparatively inexpensive and rapid, while the latter is manually labor-intensive, expensive, and limited in number. However, recent advancements in automated treponemal immunoassays have bridged the time and monetary gap between these techniques, resulting in the more recent ‘reverse’ algorithm for syphilis screening, wherein nontreponemal tests are used to validate the results of treponemal tests further.

Building upon these methodologies, the report provides recommendations for the optimal screening, clinical care, and recording of patients suffering from neurosyphilis, ocular syphilis, otosyphilis, and congenital syphilis. Pregnancy status, in particular, is noted as a condition that should not influence the standard interpretation of nontreponemal and treponemal test results due to scientific evidence that their functioning is not altered during pregnancy.

Direct detection tests

Immunohistochemistry and microscopy techniques for detecting syphilis from biopsies and other preserved samples are outlined with a particular focus on darkfield microscopy (the most widely used method for direct syphilis detection) and silver staining. Darkfield microscopy has been found to outperform antibody screening approaches, especially in the early stages of infection, thereby presenting itself as an ideal tool for early disease detection.

While Nucleic Acid Amplification Tests (NAATs) have shown great potential in accurately diagnosing syphilis infection, no FDA-approved NAATs currently exist. These recommendations are expected to be updated once FDA-approved NAATs enter the market.
Journal reference:

Papp JR, Park IU, Fakile Y, Pereira L, Pillay A, Bolan GA. CDC Laboratory Recommendations for Syphilis Testing, United States, 2024. MMWR Recomm Rep 2024;73(No. RR-1):1–32, DOI: 10.15585/mmwr.rr7301a1, https://www.cdc.gov/mmwr/volumes/73/rr/rr7301a1.htm
[ad_2]

Source link
February 12, 2024
Monash-led study unveils potential long-term treatment for lupus

[ad_1]

In a recent study published in Nature Communications, a group of researchers assessed Smith (Sm)-specific regulatory T cells (Tregs) efficacy in halting lupus nephritis (LN) by engineering and testing epitope-targeted Tregs for systemic lupus erythematosus (SLE) treatment.

Study: Smith-specific regulatory T cells halt the progression of lupus nephritis. Image Credit: megaflopp/Shutterstock.com

Background

Tregs play a crucial role in immune balance, with their dysfunction linked to autoimmune conditions like SLE. Treg therapies, especially those targeting specific antigens, have shown promise in controlling autoimmune responses. LN, a critical SLE manifestation, is often associated with the Sm autoantigen and specific human leukocyte antigen (HLA) haplotypes, suggesting a targeted therapeutic approach might be effective.

Further research is needed to optimize Sm-specific Treg therapy for broader clinical application and to understand its long-term efficacy and safety in diverse SLE patient populations.

About the study

The present study utilized a biophysical affinity binding assay. Researchers screened peptides derived from Sm proteins against HLA-DR15, identifying those with the highest affinity. This thorough approach enabled the calculation of binding affinities and half-life estimations, crucial for selecting epitopes with the potential to evoke a strong T-cell response.

Ethical adherence was paramount, with all procedures conforming to the Declaration of Helsinki and receiving approval from relevant ethics committees. The study’s rigorous inclusion criteria ensured that only suitable participants, informed and consenting, contributed to the findings.

Further investigations into the immunogenicity of top-ranking Sm epitopes utilized whole blood from an HLA-DR15 homozygous donor. This approach allowed for the differentiation of monocytes into dendritic cells and the subsequent activation of Cluster of Differentiation 4 (CD4)+ T cells, providing a robust platform for assessing T-cell responses to Sm epitopes.

The process extended to detailed methodologies for expressing and purifying HLA-DR15, crucial for understanding the intricate interactions between Sm epitopes and the immune system. Protein crystallization and structural determination further illuminated the binding mechanisms at play, offering insights that could pave the way for novel therapeutic strategies.

This comprehensive study not only identified potential targets for autoimmune therapy but also set a high standard for methodological rigor and ethical compliance, promising future research in this critical area of medicine.

Study results

The researchers explored the potential of Tregs, particularly in SLE and its severe manifestation, LN. Tregs, known for their role in maintaining immune equilibrium, become a focus due to their decreased numbers or malfunction in autoimmune diseases. Targeted therapies using Tregs, especially those engineered to be antigen-specific, offer a promising approach to suppress the pathogenic autoactivity inherent in these conditions.

The study embarked on identifying immunodominant Sm protein epitopes, given their association with LN and specific HLA haplotypes. Through a thorough screening process involving 145 overlapping peptides from Sm proteins, researchers identified a set of epitopes with strong binding affinity to HLA-DR15, with SmB/B’_58-72standing out for its binding stability and capacity to induce T-cell proliferation, marking it as a prime candidate for further exploration.

Diving deeper, the team elucidated the crystal structure of the SmB/B’_58-72epitope in complex with HLA-DR15, revealing key amino acid residues pivotal for T-cell activation. This structural insight laid the groundwork for identifying high-affinity T-cell receptors (TCRs) specific to the SmB/B’_58-72 epitope. Leveraging high-throughput sequencing and binding assays, they isolated TCRs with potent affinity, notably TCR1, which demonstrated significant clonal expansion and functional activity indicative of its therapeutic potential.

The translational leap involved engineering Tregs with the identified Sm-specific TCRs using lentiviral vectors. These engineered Tregs not only retained their regulatory phenotype but also showcased enhanced specificity and suppressive capacity against Sm epitope-induced pro-inflammatory responses, both in vitro and in a humanized mouse model of LN. This specificity was further evidenced by their ability to form immune synapses upon encountering their target antigen, leading to effective T-cell activation and suppression of autoimmunity.

Moreover, the study highlighted the therapeutic efficacy of these Sm-specific Tregs in suppressing SLE patient-derived autoreactivity, as demonstrated through in vitro cytokine profiling and in vivo models of LN. Mice treated with Sm-Tregs exhibited significantly less renal injury and proteinuria compared to those receiving polyclonal Tregs or no treatment, underscoring the potential of antigen-specific Tregs in restoring immune tolerance and halting disease progression.

This research opens new avenues for targeted immunotherapy in autoimmune diseases, emphasizing the power of precision medicine in addressing complex disorders like SLE and LN. Harnessing the specificity and regulatory capabilities of Tregs presents a promising strategy for developing more effective and personalized treatments, marking a significant step forward in the battle against autoimmune diseases.

[ad_2]

Source link

February 8, 2024
CAR T cells target senescent cells, improve healthspan in mice

[ad_1]

Chimeric antigen receptor (CAR) T cells have transformed the treatment of blood cancers in recent years. And there have been positive signs the “living drugs” can be harnessed against other diseases, like autoimmune disorders.

Now laboratory research led by Memorial Sloan Kettering Cancer Center (MSK) and Cold Spring Harbor Laboratory suggests these engineered immune cells hold promise for treating some diseases related to aging, as well -; specifically, those caused by the accumulation of senescent cells (cells that stop dividing due to age or damage).

An infusion of CAR T cells designed to target senescent cells was not only able to improve metabolic function in older mice and mice prematurely aged by a high-fat diet, but a single dose given to young, healthy mice also helped prevent metabolic decline later in life, according to findings the research team published in Nature Aging.

When you hear ‘CAR T cell therapy,’ you think ‘cancer’ -; and it makes sense that it was pioneered at a place like MSK. But what we’re learning is that this approach of engineering immune cells to target disease has much broader possibilities.”

Scott Lowe, PhD, senior study author, Chair of the Cancer Biology and Genetics Program in MSK’s Sloan Kettering Institute

CAR T treatment improves metabolic function in mice

In the study, younger mice were fed a high-fat diet for two months, which made them obese and caused metabolic stress. After an infusion of the experimental CAR T cells, the mice had lower body weight, better fasting blood glucose levels, and improved glucose and insulin tolerance, despite continuing the high-fat diet. They also had fewer senescent cells in the pancreas, liver, and fatty tissues than mice in a control group. Similar results were seen in older mice where metabolic function had decreased due to natural aging.

Older mice that received the treatment even took longer to become exhausted when exercising. And the approach didn’t appear to cause any significant side effects.

Further research is needed to see if the approach could extend the life span of the mice in addition to improving their “healthspan” -; that is, how long they stay healthy and free of disease, the scientists note.

“We’re continuing to learn new things about senescence on a biological level,” Dr. Lowe says. “It will take time, but we’re interested in working with industry partners to move the laboratory findings into clinical trials.”

There are a number of diseases associated with aging and chronic inflammation that potentially might be helped, Dr. Lowe says, such as chronic obstructive pulmonary disease (COPD), nonalcoholic steatohepatitis (NASH), osteoarthritis, metabolic syndrome, and even certain neurodegenerative diseases.

Along with Dr. Lowe’s lab, immunologist Michel Sadelain, MD, PhD, and members of his lab were key collaborators in the research. Dr. Sadelain is a pioneer in the development of CAR T cell therapy, for which he was recently awarded the 2024 Breakthrough Prize in Life Sciences.

The study was co-led by Inés Fernández-Maestre, a graduate student in the lab of MSK physician-scientist Ross Levine, MD, and by Corina Amor Vegas, MD, PhD, a former graduate student in the Lowe Lab who now heads her own lab at Cold Spring Harbor and is the corresponding author of the paper.

Targeting senescent cells with CAR T

A microscope image of an aged mouse liver showing signs of chronic inflammation (clusters of dark purple cells).

Senescent cells are damaged cells that have gone into a protective, shutdown mode, where they stop dividing and actively send “help me” signals to the immune system. This can have some short-term benefits in contexts like wound healing and preventing the runaway cell division that happens in cancer, but it also can lead to chronic inflammation as senescent cells accumulate as people age.

In 2020, researchers at MSK identified a molecule on the surface of senescent cells that was largely absent on other types of cells. This allowed them to design CAR T cells that could recognize and attack that specific molecule, called urokinase plasminogen activator receptor (uPAR). The team successfully tested the approach in several different mouse models of senescence-related diseases, including cancer and liver fibrosis, according to findings they published in Nature.

The new research goes further in demonstrating that senolytic (senescence-targeting) cell therapies can improve symptoms associated with aging.

The uPAR-targeting CAR T cells provide an alternative to the more traditional small-molecule drugs currently being investigated to clear senescent cells, notes Dr. Lowe, who is also a Howard Hughes Medical Institute Investigator.

“One of the challenges with the current small-molecule drugs is that many don’t have a well-understood mechanism of action as it pertains to senescence. And a lot of them are repurposed cancer drugs with substantial toxicities.”

Such drugs also must be given repeatedly.

“T cells, however, have the ability to develop memory and persist in your body for really long periods, which is very different from a chemical drug,” notes Dr. Amor Vegas, who was also a co-first author on the earlier study. “With CAR T cells, you have the potential of getting this one treatment, and then that’s it. For chronic pathologies, that’s a huge advantage. Think about patients who need treatment multiple times per day versus you get an infusion, and then you’re good to go for multiple years.”

Furthermore, with a cellular therapy, it’s possible to engineer in safety features to mitigate side effects as well as simultaneously to target multiple molecules on the surface of cells -; reducing the chances of them attacking healthy cells.

Different challenges than using CAR T cell against cancer

Through these experiments, the research team was able to show: uPAR-positive cells increase with age and significantly contribute to aging-related disfunction in tissues; uPAR-targeting CAR T cells can effectively eliminate the senescent cells without major side effects in mice; and that administering the treatment improved metabolism health in both normal aging and diet-related metabolic disease.

Mice normally live about two years, and research found the uPAR-targeting CAR T cells persisted and expanded for more than 15 months in mice as they grew from youth into older age.

“In some ways, using CAR T cells to treat age-associated diseases presents distinct challenges from using these therapies in cancer,” Dr. Lowe says. “If only a few cancer cells survive treatment, they may keep dividing to enable the tumor to relapse. Since senescent cells don’t divide, clearing most but not all of them should still produce substantial health benefits.”

Still, there is a high safety bar for developing therapies for diseases that are less lethal than cancer.

“We continue to develop new strategies to engineer cell therapies to be less toxic and less expensive,” Dr. Sadelain says. “These efforts will undoubtedly expand the list of diseases that can be treated by CAR T cell therapies in the coming years.”

Source:

Memorial Sloan Kettering Cancer Center

Journal reference:

Amor, C., et al. (2024). Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction. Nature Aging. doi.org/10.1038/s43587-023-00560-5.

[ad_2]

Source link

February 3, 2024