Cancer Moonshot - inmunoterapia

Foro general ciencia, medicina, nutrición, salud pública, política

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Fisio
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Mié, 15 Mar 2017, 03:02

CAR-NK

Poco explorado aún, pero algunas ventajas de partida
In contrast to donor T cells, natural killer (NK) cells are known to mediate anti-cancer effects without the risk of inducing graft-versus-host disease (GvHD).
http://journal.frontiersin.org/article/ ... 00021/full
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Jue, 16 Mar 2017, 02:30

1200 proyectos de vacunas contra el cancer en marcha. Las lesiones precancerosas posiblemente sean más fáciles de tratar. ¿Qué antígenos son los mejores candidatos? Un borrador con los primeros estará disponible pronto.
1,200 cancer vaccine projects in development, including both preventive ones and vaccines that act as therapies. Limburg's Cancer Prevention Network, for example, is testing a vaccine aimed at people with precancerous growths in the colon. Nora Disis's group at the University of Washington is just finishing up the first stage of a vaccine it hopes to use against breast cancer for women at high risk.

This new breed of cancer vaccines should be more effective than its failed precursors. Applying mathematical analysis to genome sequence data, researchers hope to predict which weird changes to tumor cells may be good targets for a vaccine, and bundle many of them together into a potent mix that can fire up the immune system.

The quest for the best of these "neoantigens" is underway in many groups; a project from Sean Parker's new cancer immunotherapy institute, announced in early December, is a collaboration/competition between some 30 research groups and companies to look for these targets in established cancers. Their first rough draft list is expected in the spring.

The longterm vision might be: A person at high risk because of genetics, or who has a premalignancy (maybe a former smoker with lesions of the lung picked up on CT) gets their tissue analyzed for suitable targets  —  mutations, or other misbehaving proteins. They'd get a vaccine, possibly aimed at their tumor type, or maybe custom built to hit those soft spots. They'd also get immunotherapy drugs that goose certain parts of the immune system and hold others back. If it worked, maybe they'd never really get cancer at all
http://www.businessinsider.com/scientis ... cer-2017-3
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Jue, 16 Mar 2017, 02:37

CD47, la proteína "no me comas".
CD47 is a kind of protein that is found on the surface of many cells in the body. It tells circulating immune cells called macrophages not to eat these cells. For instance, red blood cells start off with a lot of CD47 on their cell surface when young but slowly lose CD47 as they age. At some point, the amount of CD47 on the surface of an aging red blood cells is not enough to stave off the macrophages, and those older cells are devoured and destroyed, making way for new red blood cells. In this way, the supply of fresh blood cells is constantly replenished.

Unfortunately, some cells that should be destroyed are not. Researchers at Stanford have discovered that nearly every kind of cancer cell has a large amount of CD47 on the cell surface
https://med.stanford.edu/stemcell/CD47.html
macrophages and other myeloid immune cells offer much promise as effectors of cancer immunotherapy. The CD47/signal regulatory protein alpha (SIRPα) axis is a critical regulator of myeloid cell activation and serves a broader role as a myeloid-specific immune checkpoint. CD47 is highly expressed on many different types of cancer, and it transduces inhibitory signals through SIRPα on macrophages and other myeloid cells. In a diverse range of preclinical models, therapies that block the CD47/SIRPα axis stimulate phagocytosis of cancer cells in vitro and anti-tumour immune responses in vivo.
https://www.ncbi.nlm.nih.gov/pubmed/28286286
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Jue, 16 Mar 2017, 02:40

Estudio en 5 tipos de tumores pediátricos en ratones con anticuerpos contra CD47
When the antibodies were given to mice that had human tumor tissue implanted in their brains, macrophages engulfed and destroyed the brain tumor cells. And this happened without collateral damage to healthy brain cells nearby
Ya está en ensayos clínicos, en un año o dos comenzarán ensayos clínicos en niños
anti-CD47 antibodies are already being tested in a phase-1 clinical trial of adults with other forms of cancer, the researchers anticipate that the therapy will be tried in children with brain cancer fairly soon, probably within the next year or two


http://scopeblog.stanford.edu/2017/03/1 ... udy-shows/
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Jue, 16 Mar 2017, 02:43

Más inmunidad innata y TAMs, contra cáncer de mama. Inhibidores de histona deacetilasa clase II (HDAC)
TMP195 induces the recruitment and differentiation of highly phagocytic and stimulatory macrophages within tumours. Furthermore, combining TMP195 with chemotherapy regimens or T-cell checkpoint blockade in this model significantly enhances the durability of tumour reduction. These data introduce class IIa HDAC inhibition as a means to harness the anti-tumour potential of macrophages to enhance cancer therapy
http://www.nature.com/nature/journal/v5 ... 21409.html
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Jue, 16 Mar 2017, 02:55

La expresión de CD28 parece ser la pieza clave en la inhibición de PD-1. Supongo que hacer un perfil de marcadores de la expresión de ciertas proteínas, el número de neoantígenos, la mutación de JAK, y quien sabe si en un futuro la microbiota predecirán la terapia más apropiada.
when they chemically blocked CD28 activity, which is made by T cells, tumours kept growing in mice, even when the animals were treated with anti-PD-1 drugs. In patients with lung cancer whose T cells proliferated after receiving PD-1 therapy, those cells tended to express CD28.

In a separate study, Ronald Vale at the University of California, San Francisco, Ira Mellman at Genentech in South San Francisco and their colleagues found that PD-1 and CD28 are part of the same biochemical pathway. They report that PD-1 signalling suppresses T-cell function by inactivating CD28 activity.
http://www.nature.com/articles/n-12130106
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Vie, 17 Mar 2017, 06:04

PD-L1, no es un buen biomarcador, al menos en vejiga
the truth is, the response rate—even in PD-L1–negative tumors, is better than single-agent taxane. Those responses can also be durable. PD-L1 is a very dynamic biomarker; it can be upregulated in patients who have had chemotherapy, BCG given intravesically, or treatment with a PD-L1 inhibitor. That might be the reason why the data have been all over the board. We haven’t seen any definitive statements that you should not consider checkpoint inhibition when PD-L1 is low, because they still respond and may still benefit from treatment
http://www.onclive.com/web-exclusives/r ... cancer?p=1
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Dom, 19 Mar 2017, 14:41

Otra proteina inmunosupresora: moesina.
Cancer cells have learned to hijack this system of checks and balances to hide from the tumour-killing T cells. Many cancers produce TGF-beta that binds the receptors on the tumour-killing helper T cells so they can't be recruited to fight the tumour. The T cells convert instead to Tregs, which suppress the immune response against the cancer.

Inhibiting moesin could help prevent conversion of naïve T cells into Tregs, thereby restoring the anti-tumour immune response.

"Because moesin supports greater Treg production, we could design moesin inhibitors to halt or slow active TGF-beta signalling and slow down Treg conversion so that anti-tumour T cells can have a chance to see the cancer and eradicate it,"
https://scicasts.com/channels/cancer-re ... ic-target/
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Dom, 19 Mar 2017, 14:47

Uno de los estudios más interesantes que he leido: encontrar el donante adecuado para los neoantígenos expresados.
The study shows that adding mutated DNA from cancer cells into immune stimulating cells from healthy donors create an immune response in the healthy immune cells. Inserting the targeted components from the donor immune cells back into the immune cells of the cancer patients, the researchers were able to make cancer patients' own immune cells recognize cancer cells.
the cancer cells seemed to display a large number of different neo-antigens. But when the researchers tried to match these to the T cells derived from within the patient's tumors, most of these aberrant protein fragments on the tumor cells went unnoticed.

Next, they tested whether the same neo-antigens could be seen by T-cells derived from healthy volunteers. Strikingly, these donor-derived T cells could detect a significant number of neo-antigens that had not been seen by the patients' T cells.
Flipante. Si fuera millonario, estos tíos recibían una llamada de mi parte.

https://www.sciencedaily.com/releases/2 ... 144556.htm

http://science.sciencemag.org/content/352/6291/1337
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Lun, 20 Mar 2017, 08:12

Warburg: 'To stop cancer you have to stop lactate'
aberrant cell signaling due to exaggerated and continually high lactate levels yields an (inappropriate) positive feedback loop that increases glucose uptake and glycolysis, increases lactate production, accumulation and release, decreases mitochondrial function, upregulates monocarboxylate transporter expression thereby supporting angiogenesis, immune escape, cell migration and metastasis all of which encourage carcinogenesis and progression to cancer
https://academic.oup.com/carcin/article ... production
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