Cancer Moonshot - inmunoterapia

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Mié, 18 Ene 2017, 04:17

Combination therapy melanoma
Of 10 study participants:

three experienced disease progression
three had their disease stabilize
two had a partial response before the disease progressed and metastasized
two experienced complete remission
Five of the 10 were still alive three to five years after starting the treatment. In 2011, when the study began, patients with metastatic melanoma faced an average survival time that could be measured in months.
With only 10 patients in the trial, definitive conclusions cannot be reached. But one of the patients -- whose case study was recently published in the Journal of Experimental Medicine -- had previously received a checkpoint inhibitor and an earlier version of T-cell therapy. Neither treatment had worked independently, but the combination approach -- which included newer T-cell technology -- apparently drove the cancer into remission.

"This suggests that you can probably 'rescue' patients who do not respond to one form of treatment by doing combinations," says Dr. Aude Chapuis, first author, a medical oncologist and an adult hematopoietic stem cell transplant (HCT) physician with a strong background in immunology and adoptive T-cell transfer studies in humans.
https://www.sciencedaily.com/releases/2 ... ign=buffer
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Mié, 18 Ene 2017, 04:18

TNRF2
blockage of TNFR2 may have the effect of killing two birds with one stone: boosting anti-tumor immune responses and directly killing tumor cells." The MGH study, they conclude, "clearly shows that TNFR2 antagonists have promise as cancer therapies by simultaneously blocking both an immune checkpoint molecule in T cells and an oncoprotein in tumor cells. . . . TNFR2 antagonists have the capacity to eliminate Treg activity and thus may further enhance the efficacy of current immunotherapeutics. In addition, suppression of tumor cell survival by the TNFR2 antagonist may improve the outcome of chemo- or radiotherapy in cancer patients.
https://scienmag.com/massachusetts-gene ... notherapy/
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Jue, 19 Ene 2017, 23:37

No es el gen, ni el microambiente, sino la respuesta sistémica
•System-wide models reveal coordinated anti-tumor immunity across the organism
•Tumor eradication requires immune activation in the periphery
•Network analysis identifies CD4 T cells sufficient to initiate immune responses
•PD-L1 upregulation early post-therapy protects distal tumors from systemic immunity

Summary

Immune responses involve coordination across cell types and tissues. However, studies in cancer immunotherapy have focused heavily on local immune responses in the tumor microenvironment. To investigate immune activity more broadly, we performed an organism-wide study in genetically engineered cancer models using mass cytometry. We analyzed immune responses in several tissues after immunotherapy by developing intuitive models for visualizing single-cell data with statistical inference. Immune activation was evident in the tumor and systemically shortly after effective therapy was administered. However, during tumor rejection, only peripheral immune cells sustained their proliferation. This systemic response was coordinated across tissues and required for tumor eradication in several immunotherapy models. An emergent population of peripheral CD4 T cells conferred protection against new tumors and was significantly expanded in patients responding to immunotherapy. These studies demonstrate the critical impact of systemic immune responses that drive tumor rejection.
cell.com/cell/abstract/S0092-8674(16)31738-X?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS009286741631738X%3Fshowall%3Dtrue
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Jue, 19 Ene 2017, 23:48

Aneuploidia como marcador de respuesta a inmunoterapia

Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy

http://science.sciencemag.org/content/355/6322/eaaf8399
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Lun, 23 Ene 2017, 14:36

Microbioma predice respuesta a la inmunoterapia. ¿Podría manipularse con antibióticos, probióticos o transplante fecal para mejorar el tratamiento? (y también cabe preguntarse si esto interesa lo más mínimo...).
By comparing the gut bacteria of melanoma patients who responded to immunotherapy and those who did not, researchers found a stark contrast in the balance of bacterial species in the faecal samples of responding and non-responding patients.

Lead researcher, Associate Professor Jennifer Wargo from MD Anderson Cancer Center, who presented at the 2016 Australasian Melanoma Conference, says, "Not all patients respond to immunotherapy drugs and it's hard to know who will benefit from the treatment prior to it being given. Our research shows a really interesting link that may mean the immune system is aided by gut bacteria when responding to these drugs.”
https://www.melanoma.org.au/research/re ... ign=buffer
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Mar, 24 Ene 2017, 19:57

Muy interesante sobre el estudio de Cell de más arriba, las personas que no responden a inmunoterapia es porque no logran una respuesta inmune sistémica
Successful cancer immunotherapy appears to depend on whether the treatment can trigger a system-wide immune response, rather than just a local response within the tumor itself. “Profiling the immune response across the organism allowed us to see that successful immunotherapy involves widespread activation of the immune system in places far from the tumor itself: in the lymph nodes, the bone marrow, in the blood,”
Most patients simply don’t respond. Some forms of immunotherapy, such as anti-PD1 “checkpoint blockade” therapy, are frequently effective against melanoma, but fail to trigger a successful immune response against most carcinomas, which are the most common forms of cancer.
while the ineffective anti-PD1 therapy triggered a short-lived immune response in the tumor itself, the effective experimental treatment triggered a coordinated immune response across many different tissues, even as the immune response within the tumor itself began to die down
successful immunotherapy activated a population of immune cells called CD4+ T cells, which appear to be key to “remembering” the tumor and coordinating a long-lasting immunity to cancer throughout the body. When the researchers extracted CD4+ T cells from successfully treated mice and transplanted them into other mice, these memory cells alone proved to be sufficient to trigger an immune response against the other animals’ tumors.
https://www.ucsf.edu/news/2017/01/40558 ... e-response
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Mié, 25 Ene 2017, 06:07

Me preguntaba cuantas proteinas diferentes expresa un tumor... llegamos a proteómica. Lo interesante no es solo el numero de proteinas codificadas por un gen, sino la cantidad de modificaciones post transcripcionales que hacen que sea distinta.
Proteomics: High-protein research

The human body contains roughly 20,000 genes that are capable of producing proteins. Each gene can produce multiple forms of a protein, and these in turn can be decorated with several post-translational modifications: they can have phosphate or methyl groups attached, or be joined to lipids or carbohydrates, all of which affect their function. “The number of potential molecules you can make from one gene is huge,” says Bernhard Küster, who studies proteomics at the Technical University of Munich in Germany. “It's very hard to estimate, but I wouldn't be surprised to have in one cell type 100,000 or more different proteins.”
http://www.nature.com/nature/journal/v5 ... 27S6a.html
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Mié, 25 Ene 2017, 06:25

Radioterapia para aumentar la eficacia de la inmunoterapia haciendo las células tumorales más inmunogénicas estimulando la presentación de antígenos via expresión de MHC
Drugs that inhibit immune checkpoints—CTLA-4 (cytotoxic
T lymphocyte antigen 4), PD-1 (programmed cell death protein 1), or PD-L1 (the PD-1 ligand)—can elicit impressive responses in some cancer patients, even in those with metastatic disease. However, immunotherapy eliminates distant disease in perhaps only 20% of patients with metastatic cancer; Dr. Welsh hopes to use radiation to push that rate to 30% or even 40%.

Radiation can stimulate immunogenic cell death and sensitize cancer cells to immunotherapy by promoting the expression of major histocompatibility complex (MHC) class I molecules and other apoptosis-mediating proteins.

Radiation can cause the cells to release tumor antigens that prime T cells to attack other tumor cells in the body, including those at distant, non-irradiated sites.
https://www.mdanderson.org/publications ... dk.twitter
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Jue, 26 Ene 2017, 18:02

¿Cómo elegir un antígeno?
It’s an idea as dangerous as it is powerful. The reason is that few antigens appear exclusively in cancer cells. In 2009, a woman given T cells engineered to recognize colon cancer suddenly went into respiratory distress; she died five days later. Doctors at the National Cancer Institute quickly canceled the study, concluding that the T cells had encountered their antigen in her lungs and attacked.
Leucemia, antígeno ideal
one ideal antigen, called CD19. It appears nowhere in the body except on B cells, the same kind that go awry in lymphoma and in the leukemia that afflicted Wright. And it turns out that wiping out a person’s B cells isn’t life-threatening. With shots of immunoglobulin, you can live without any for years.

By 2010, doctors at Memorial Sloan Kettering, Penn, and the National Cancer Institute had begun trying to treat leukemia patients with T cells bearing a doctored receptor for CD19. To the inside of the receptor, they’d added another snippet of DNA that stimulates the cells to divide. No one is sure how the stimulation works, but without it, the modified T cells don’t do much. Early case reports eventually multiplied into trials that have treated about 350 leukemia and lymphoma patients. The results are remarkable, partly because they’re so consistent, even though each lab uses slightly different DNA designs.

The big question mark is whether T cells will work in cancers other than those of the blood. The goal is to find the next CD19. But that’s not easily done. Since few antigens appear only on tumor cells, any targeted T cell runs the risk of wiping out vital organs, as happened to the colon cancer patient in 2009.

https://www.technologyreview.com/s/5384 ... edium=post
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Vie, 27 Ene 2017, 22:03

CART, dos bebés en remisión de leucemia. En 28 días.

http://stm.sciencemag.org/content/9/374/eaaj2013


Esto es de cojones.

- Va a haber que cambiar muchas cosas para poder trasladar todo esto a los sistemas de salud. Pero muchas cosas.
- Y los oncólogos van a tener que hacer formación continuada fin de semana sí, y otro también. Porque controlar todo esto...
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