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HIV-Aging/Senescence/CAR-T-Cells. Senolytic Agents or Senolytic Therapeutics
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Senolytic drugs are in research as a therapy against immunosenesence & aging.
Senescence causes aging in all people & HIV+ appear to develop this early, one study found i developed shortly after infection, this publication was years ago. Research in HIV showed ART slowed but did not stop or prevent immunosenescence, which might be & is speculated to be an important cause in aging among HIV+ either prematurely, accelerated or accentuated however you prefer to call it. Nonetheless at CROI 2020 Kaiser/Marcus reported a study finding comorbidities occur 10-20 earlier in HIV+ vs HIV- and mortality was 9 years earlier for HIV+ but mortality was the same as for HIV- if ART started with >500 cd4, still the same 10-20 earlier onset of comorbidities occurred regardless when one started ART. They looked at cancer, diabetes, heart disease, chronic liver disease, chronic kidney disease & chronic lung disease and found much earlier & premature onset for these comorbidities compared to HIV- of between 8 years to 24 years for chronic liver disease. Remember the CDC reports around 50% have detectable viral load in the USA and anyone with detectable viral load is at greater risk for developing comorbidities so the impact of aging & HIV has much more affect on out community & healthcare system than for those PLWH with undetectable viral load who are clearly at risk. Jules:
http://www.natap.org/2020/CROI/croi_36.htm
Senotherapeutics and HIV-1 Persistence & Aging/Senescence - (06/09/20)
Latently infected CD4+ T cells, the major source of HIV-1 persistence in patients on ART, are one potential candidate for targeting by senolytic/senomorphic intervention.
Treated HIV-1 infection results in a state of immune exhaustion, which may involve reprogramming of infected and bystander cells toward a state of cellular senescence....accumulation of senescent cells has been shown to contribute to age-related diseases.
The BCL-2 inhibitor venetoclax (ABT-199), FDA-approved for treatment of chronic lymphocytic leukemia and acute myeloid leukemia, has been shown to decrease reservoir size and proliferation in an in vitro latency model [66]. Venetoclax counteracted IL-7- and CD3/CD28-driven proliferation, viral reactivation, and new rounds of infection. Targeting the apoptosis threshold of latently infected cells with these senolytic agents holds promise but has yet to be tested clinically.....Recently, dasatinib, an FDA-approved TKI used in Philadelphia chromosome-positive chronic myeloid leukemia (CML), has been investigated for its anti-HIV effects. We and others have shown that this molecule prevents infection in major HIV-1 target cell types, and new evidence suggests it may also be useful in inhibiting cytokine-mediated homeostatic proliferation
Nature: Senolytic CAR T cells reverse senescence-associated pathologies
June 17 2020
see full text below
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Mechanisms of immunosenescence Short
report....http://www.natap.org/2010/HIV/062910_01.htm
Immunosenescence and aging in HIV
Immune senescence results in functional impairments of immunity and a reduced ability to adapt to metabolic stress. Understanding the factors driving the development of immune senescence is critical for the development of strategies to prevent early aging......Notwithstanding the association with an aging immune profile, definitive proof that T-cell immune senescence in those with HIV causes an accentuated development of comorbidities is still lacking".....Early aging in those with HIV appears to stem from persistent chronic inflammation and residual immune activation despite successful antiretroviral therapy......The association of HIV infection with early aging of the immune system is often made because of the persistence of inflammation and of residual chronic immune activation despite successful antiretroviral therapy. There is a pattern of abnormalities in T-cell-senescent phenotypes found in those with HIV that is similar to those of uninfected individuals several decades older......Immune senescence refers to a dynamic process of immune remodelling that occurs progressively over time.....There is mounting evidence of commonality in immune mechanisms underlying inflammatory disorders with respect to comorbidities of the elderly
Senolytic drugs reverse damage caused by senescent cells in mice
NIH-funded researchers see extended health span and lifespan in treated mice.
https://www.nih.gov/news-events/news-releases/senolytic-drugs-reverse-damage-caused-senescent-cells-mice
http://www.natap.org/2020/HIV/1-s2.0-S2352396419305912-main(1).pdf
Aging - New drugs: Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice
http://www.natap.org/2016/HIV/010816_05.htm
Senescent cells (SCs) accumulate with age and after genotoxic stress, such as total-body irradiation (TBI)1, 2, 3, 4, 5, 6. Clearance of SCs in a progeroid mouse model using a transgenic approach delays several age-associated disorders7, suggesting that SCs play a causative role in certain age-related pathologies. Thus, a 'senolytic' pharmacological agent that can selectively kill SCs holds promise for rejuvenating tissue stem cells and extending health span. To test this idea, we screened a collection of compounds and identified ABT263 (a specific inhibitor of the anti-apoptotic proteins BCL-2 and BCL-xL) as a potent senolytic drug. We show that ABT263 selectively kills SCs in culture in a cell type- and species-independent manner by inducing apoptosis. Oral administration of ABT263 to either sublethally irradiated or normally aged mice effectively depleted SCs, including senescent bone marrow hematopoietic stem cells (HSCs) and senescent muscle stem cells (MuSCs). Notably, this depletion mitigated TBI-induced premature aging of the hematopoietic system and rejuvenated the aged HSCs and MuSCs in normally aged mice. Our results demonstrate that selective clearance of SCs by a pharmacological agent is beneficial in part through its rejuvenation of aged tissue stem cells. Thus, senolytic drugs may represent a new class of radiation mitigators and anti-aging agents.
senolytics might become an entirely new path for alleviating currently untreatable chronic diseases and enhancing human health span. - (06/17/20)
Here, in an open-label Phase 1 pilot study, we show for the first time that senolytic drugs decrease senescent cell abundance in humans. A 3-day oral course of D + Q in subjects with diabetic kidney disease (DKD) reduced adipose tissue senescent cell burden 11 days later, as indicated by decreases in cells with markers of senescence: p16INK4A-and p21CIP1-expressing cells, cells with senescence-associated β-galactosidase (SAβgal) activity, and adipocyte progenitors with limited replicative potential.
In mouse models of age- and senescence-related chronic diseases, D + Q alleviated metabolic dysfunction in high fat diet-fed as well as genetically obese mice(in part by decreasing insulin resistance), DKD manifested by podocyte dysfunction and proteinuria, high fat diet-induced renal fibrosis, renal cortical hypo‑oxygenation, and increased creatinine, hepatic steatosis, neuropsychiatric dysfunction in high fat-fed and genetically obese mice, high fat diet-induced cardiac dysfunction and vascular hyporeactivity, Alzheimer's-like dementia in mice with brain tau or β-amyloid protein aggregates, failure of the arteriovenous fistulae used for vascular access during hemodialysis, bleomycin-induced pulmonary fibrosis (a mouse model of IPF), and hyperoxia-induced pulmonary dysfunction, among others [7,9,20,23,24,[32], [33], [34], [35], [36], [37]]. Thus, senolytic agents might have the potential to delay, prevent, or treat age-related diseases as a group, instead of one-at-a-time. To advance toward this goal, it is critical to focus on developing senolytic agents that are safe and effective when administered systemically (as opposed to locally by injection) in humans.
Senescent cells: an emerging target for diseases of ageing - Senotherapeutics for healthy ageing - (06/17/20)
It is established that senescent cells play a causative role in ageing and age-related disease. Therefore, the development of drugs that specifically kill senescent cells is envisioned to have significant therapeutic effects on slowing ageing phenotypes, treating age-related comorbidities and improving resiliency. However, not all senescent cells are the same, expressing different senescence markers, secreting different SASP factors and, more importantly, using different senescent cell anti-apoptotic pathways (SCAPs) to resist apoptosis. The elimination of senescent cells from multiple tissues or even a single tissue will probably require the combination of multiple senotherapeutic drugs2.
senolytics might become an entirely new path for alleviating currently untreatable chronic diseases and enhancing human health span. - (06/17/20)
If senolytic agents can be shown to be effective for several individual age-related conditions, they may prove to have a role beyond alleviating single diseases: they may be effective in reducing the multimorbidity common in elderly patients. In the first demonstration that healthspan can be improved by removing senescent cells from naturally-aged mice, we found that clearing senescent cells with D + Q improves cardiac function and vascular reactivity in old mice, alleviates frailty and increases intervertebral disc proteoglycans in progeroid mice, and enhances treadmill endurance in single-leg radiation-injured mice in early 2015 [32].
Senolytics decrease senescent cells in humans: Preliminary reportfrom a clinical trial of Dasatinib plus Quercetin in individuals withdiabetic kidney disease
http://www.natap.org/2020/HIV/1-s2.0-S2352396419305912-main(1).pdf
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Role of immune cells in the removal of deleterious senescent cells
June 3 2020 - Immunity & Ageing - Abhijit Kale1, Amit Sharma2, Alexandra Stolzing2,3, Pierre-Yves Desprez1,4 and Judith Campisi1,5*
https://immunityageing.biomedcentral.com/articles/10.1186/s12979-020-00187-9
Abstract
Cellular senescence is an essentially irreversible arrest of cell proliferation coupled to a complex senescence-associated secretory phenotype (SASP). The senescence arrest prevents the development of cancer, and the SASP can promote tissue repair. Recent data suggest that the prolonged presence of senescent cells, and especially the SASP, could be deleterious, and their beneficial effects early in life can become maladaptive such that they drive aging phenotypes and pathologies late in life. It is therefore important to develop strategies to eliminate senescent cells. There are currently under development or approved several immune cell-based therapies for cancer, which could be redesigned to target senescent cells. This review focuses on this possible use of immune cells and discusses how current cell-based therapies could be used for senescent cell removal.
Therapeutic use of CAR-T cells
Chimeric antigen receptor (CAR) T cell therapy has been successful in recent years for treating diseases such as cancer. CAR-T cell therapy uses autologous cells that are genetically modified ex vivo to encode a synthetic receptor that binds a known antigen [105]. The modified cells are then infused back into the patient to kill the target cells. A universal CAR-T cell product could eliminate many of the harvesting and manufacturing problems associated with autologous or HLA matched CAR-T cells. Advantages of CAR-T cells over other cell types include their capacity to induce durable responses and their ability to override tolerance to self-antigens [106]. CAR-T cell targeting moieties are not restricted to antibody targets, as non-antibody structures such as aptamers and polypeptides have been used [107]. However, a potential downside to this approach is that some antigens used to target cancer cells are also present in healthy tissues, albeit generally at much lower levels [108].
Evidence that there are senescent-specific surface markers is spotty [43], and specificity needs further validation. Nonetheless, once a good target has been identified, it can be used to create a CAR-T cell. Alternative CAR-T strategies are being developed to improve specificity or effectiveness that could be helpful in the context of senescent cells. One such alteration is the use of several antigens for improved recognition [107], allowing more specific recognition of senescent cells. The therapeutic potential of CAR-T cells in targeting senescent cells stems from their success in the treatment of solid tumors, as CAR-T cells are observed to reach deep into the parenchyma of many different organs in which senescent cells reside.
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CAR-T cells, better known as cancer drugs, show promise against aging in lab mice
June 17, 2020
https://www.statnews.com/2020/06/17/car-t-cells-show-promise-against-aging-in-mice/
Scientists are still trying to get CAR-T cells to work as well in solid tumors as they do in blood cancers, but the genetically engineered immune cells just might have a superpower beyond oncology. In mice, researchers reported on Wednesday in Nature, CAR-T cells can eliminate the senescent cells partly responsible for many diseases of aging.
If the results hold up, they could add another candidate to a growing list of "senolytics," experimental drugs that destroy senescent cells. A growing pile of mouse studies show that removing these decrepit and dysfunctional cells postpones or even reverses diseases of old age - and extends life span. The possibility that senolytics could do that in people has jump-started what analysts say could become a multibillion-dollar industry, with clinical trials already underway.
"I think their paper is incredibly exciting and adds to the senolytics armamentarium," said James Kirkland of the Mayo Clinic, who discovered that giving old mice compounds that destroy senescent cells makes the animals live longer and without the usual diseases of old age. "It could be another way to pharmacologically target senescent cells, but that will depend on safety, cost, and other factors."
Starting in the last decade, scientists discovered that senescent cells - old and no longer dividing - not only stop carrying out their jobs in the heart or liver or other organ. They also secrete a veritable Superfund site's worth of toxic molecules that cause inflammation, damage the DNA of nearby cells, and in general wreak havoc, causing osteoarthritis, atherosclerosis, diabetes, and other age-related diseases. Kirkland and other Mayo researchers showed that removing senescent cells from old mice extends both life span and health span, how long an animal lives without becoming sick and frail.
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Nature: Senolytic CAR T cells reverse senescence-associated pathologies
June 17 2020
https://www.nature.com/articles/s41586-020-2403-9
Abstract
Cellular senescence is characterized by stable cell-cycle arrest and a secretory program that modulates the tissue microenvironment1,2. Physiologically, senescence serves as a tumour-suppressive mechanism that prevents the expansion of premalignant cells3,4 and has a beneficial role in wound-healing responses5,6. Pathologically, the aberrant accumulation of senescent cells generates an inflammatory milieu that leads to chronic tissue damage and contributes to diseases such as liver and lung fibrosis, atherosclerosis, diabetes and osteoarthritis1,7. Accordingly, eliminating senescent cells from damaged tissues in mice ameliorates the symptoms of these pathologies and even promotes longevity1,2,8,9,10. Here we test the therapeutic concept that chimeric antigen receptor (CAR) T cells that target senescent cells can be effective senolytic agents. We identify the urokinase-type plasminogen activator receptor (uPAR)11 as a cell-surface protein that is broadly induced during senescence and show that uPAR-specific CAR T cells efficiently ablate senescent cells in vitro and in vivo. CAR T cells that target uPAR extend the survival of mice with lung adenocarcinoma that are treated with a senescence-inducing combination of drugs, and restore tissue homeostasis in mice in which liver fibrosis is induced chemically or by diet. These results establish the therapeutic potential of senolytic CAR T cells for senescence-associated diseases.
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That research inspired the formation of California-based Unity Biotechnology, Germany's Velabs Therapeutics, and other companies hot on the trail of senolytics, from small molecules to antibodies. CAR-Ts are latecomers to this gold rush, but have a potential advantage: In cancer, CAR-Ts become "living drugs," continuing to reproduce and (ideally) keep tumors in check. That suggests that, as senolytics, they might become "one and done" treatments, whereas other senolytics might require regular dosing to keep up with the production of senescent cells.
"The potential of using CAR-T cells to target senescent cells is very interesting and could potentially open up a path to a new class of senolytic drugs," said Unity CEO Anirvan Ghosh. "Identifying cell surface antigens that are specific to senescent cells would greatly expand the utility of these and other approaches."
CAR-Ts are a long way away from becoming human anti-aging drugs - aside from the scientific challenges ahead, they have dangerous side effects and are expensive to make. Even the new study's senior author, Scott Lowe of Memorial Sloan Kettering Cancer Center, is cautious.
"I view this as a very exciting proof of principle," he said, "and another way to think about possible senolytics. I was surprised it worked as well as it did." He and his colleagues finished the experiments just before his New York City lab shut down in response to the Covid-19 pandemic.
Graduate student Corina Amor, the study's first author, had just finished a stint in the lab of Michel Sadelain, one of the inventors of anti-cancer CAR-Ts, before moving to Lowe's, which has studied senescent cells in the context of cancer. She had an in idea: Why not merge the two labs' expertise and see if they could create CAR-Ts targeted against senescent cells?
The first step in making CAR-Ts that destroy senescent cells was to find an antigen on these old-timers, much like CD19 antigens on the cancer cells that Novartis' Kymriah and Gilead's Yescarta CAR-Ts target. Amor and her colleagues got a hit: Senescent cells in both mice and people (especially those with osteoarthritis, atherosclerosis, and diabetes) are as covered with molecules called uPAR as porcupines are with quills. They therefore used the standard CAR-T recipe to create T cells studded with receptors for uPAR.
They infused up to 3 million of the engineered cells into mice that had fibrotic livers filled with senescent cells. Within 10 days, the senescent cells were essentially gone. The fibrosis receded and the animals' previously terrible liver function bounced back toward normal. The senolytic CAR-Ts also worked in mice with the fatty liver disease NASH, which several biotechs are racing to cure. That supported the guiding principle of senolytics: Senescent cells cause a host of diseases, so a single agent might cure all of them.
The uPAR molecule is found on some immune cells, including macrophages and lymphocytes, whose destruction would probably not be a good idea. The mice, however, showed no such adverse effects.
The Sloan Kettering researchers have filed for a patent on their senolytic CAR-Ts. But both they and outside experts say it will take years of work to turn CAR-Ts into human senolytics.
For one thing, said Mayo's Kirkland, CAR-Ts are expensive to make, since they're manufactured for one cancer patient at a time (though several biotechs are trying to create off-the-shelf CAR-Ts for cancer, which might bring down the price). For another, they can be toxic. "I loved the paper and think it will have applications, but that will depend on making CAR-Ts cheaper, faster, simpler, and safer," Kirkland said.
"Faster" is happening; the original six-week manufacturing process for anti-cancer CAR-Ts has been whittled down to one week at Mayo, for instance. "Safer" is still an urgent goal, since in some cancer patients CAR-Ts trigger the life-threatening immune overreaction called cytokine storm (the same phenomenon that's killed many Covid-19 patients).
Using immune cells to eliminate senescent cells in order to treat diseases of old age and extend health span makes sense to longtime senolytics researchers.
"The use of CAR-T cells to target senescent cells has been, and still is being, discussed among scientists working on senescence," said Judith Campisi of the Buck Institute for Research on Aging, who discovered that senescent cells secrete hundreds of damaging molecules. In a review paper this month, she said that although more research is needed to show that antigens like uPAR aren't also found on cells whose destruction by senolytics would cause problems, "once a good target has been identified, it can be used to create a CAR-T cell."
One potential benefit of CAR-Ts compared to small-molecule senolytics, she said: They can "reach deep into the [functional tissue] of many different organs in which senescent cells reside."
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