Cancer Moonshot - inmunoterapia

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Mar, 31 Ene 2017, 21:36

Virus oncolíticos in the pipeline
Oncolytic virus therapy has recently been recognized as a promising new therapeutic approach for cancer treatment. An oncolytic virus is defined as a genetically engineered or naturally occurring virus that can selectively replicate in and kill cancer cells without harming the normal tissues. In contrast to gene therapy where a virus is used as a mere carrier for transgene delivery, oncolytic virus therapy uses the virus itself as an active drug reagent.
Historia de enfermedades víricas que encogían tumores al activar respuesta inmune
Tumor regression has often been observed during or after a naturally acquired, systemic viral infection.1, 2 In 1949, 22 patients with Hodgkin's disease were treated with sera or tissue extracts containing hepatitis virus.3 Between 1950 and 1980, many clinical trials were performed in attempts to treat cancer with wild type or naturally attenuated viruses, including hepatitis. West Nile fever, yellow fever, dengue fever and adenoviruses.4 However, these viruses were not deemed useful as therapeutics reagents because, in those days, there was no known method to control the virulence and yet retain viral replication in cancer cells
protection mechanisms against viral infection (e.g. interferon‐beta signal pathway) are impaired in the majority of cancer cells,5 that most viruses can replicate to a much greater extent in cancer cells than in normal cells
Oncolytic virus therapy is perhaps the next major breakthrough in cancer treatment following the success in immunotherapy using immune checkpoint inhibitors. Oncolytic viruses are defined as genetically engineered or naturally occurring viruses that selectively replicate in and kill cancer cells without harming the normal tissues. T‐Vec (talimogene laherparepvec), a second‐generation oncolytic herpes simplex virus type 1 (HSV‐1) armed with GM‐CSF, was recently approved as the first oncolytic virus drug in the USA and Europe. The phase III trial proved that local intralesional injections with T‐Vec in advanced malignant melanoma patients can not only suppress the growth of injected tumors but also act systemically and prolong overall survival. Other oncolytic viruses that are closing in on drug approval in North America and Europe include vaccinia virus JX‐594 (pexastimogene devacirepvec) for hepatocellular carcinoma, GM‐CSF‐expressing adenovirus CG0070 for bladder cancer, and Reolysin (pelareorep), a wild‐type variant of reovirus, for head and neck cancer. In Japan, a phase II clinical trial of G47∆, a third‐generation oncolytic HSV‐1, is ongoing in glioblastoma patients. G47∆ was recently designated as a “Sakigake” breakthrough therapy drug in Japan. This new system by the Japanese government should provide G47∆ with priority reviews and a fast‐track drug approval by the regulatory authorities. Whereas numerous oncolytic viruses have been subjected to clinical trials, the common feature that is expected to play a major role in prolonging the survival of cancer patients is an induction of specific antitumor immunity in the course of tumor‐specific viral replication. It appears that it will not be long before oncolytic virus therapy becomes a standard therapeutic option for all cancer patients.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5084676/
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Jue, 02 Feb 2017, 11:33

Linfangiogénesis, fármacos inhibidores del uso de ácidos grasos para el desarrollo de capilares linfáticos que el tumor utiliza para metastatizar
a shift to increased fat utilization is required for the development and growth of these 'roads', termed lymphatic vessels - a special kind of blood vessels. This discovery paves the way towards developing therapeutics to limit lymphatic vessel growth in cancer by targeting fat utilization.

In order for cancer cells to spread, they must find a pre-existing 'road', or build a new 'road' to travel on. Lymphatic vessels, a specialized kind of vessels transporting fluid rather than blood, are a primary route of cancer cell spread, and the formation of new lymphatic vessels, termed lymphangiogenesis, is a poorly understood process, which currently lacks clinically approved drugs to prevent their growth during disease.

Prof. Carmeliet sought to investigate the nutrient utilization (metabolism) of lymphatic vessels. The study began with a simple observation: lymphatics use more fat (fatty acids) compared to blood vessels. This is the first description of the nutrient utilization of lymphatic vessels. Using drugs to prevent fat utilization by lymphatics prevented lymphatic growth, an important step in translating this finding to the cancer setting and inhibition of metastasis.

The immediate next steps of this research are clear and two-fold. On one hand, inhibitors of fat usage will be tested on a large scale for their ability to reduce metastasis in different types of cancer. On the other hand, we will test whether dietary fat supplements (for instance in the form of ketone bodies, used by athletes) can heal faulty lymphatics, a major complication in cancer patients undergoing surgical cancer removal, which leads to the debilitating swelling and dysfunction of the arms and legs, termed lymphedema, for which no drug is available
https://www.eurekalert.org/pub_releases ... 122016.php
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Jue, 02 Feb 2017, 13:55

¿Una vacuna universal para el cancer? En teoría es factible, en la práctica no es tan sencillo.. a nuestro sistema inmune no le suele parecer buena idea atacar a nuestras propias células. Un enfoque de la vacunación contra el cáncer es separar las proteínas de las células cancerosas e inmunizar a los pacientes contra esas proteínas como antígenos que el sistema inmune reconoce.

Scientists have taken a “very positive step” towards creating a universal vaccine against cancer that makes the body’s immune system attack tumours as if they were a virus, experts have said. Writing in Nature, an international team of researchers described how they had taken pieces of cancer’s genetic RNA code, put them into tiny nanoparticles of fat and then injected the mixture into the bloodstreams of three patients in the advanced stages of the disease. The patients' immune systems responded by producing "killer" T-cells designed to attack cancer.
“[Such] vaccines are fast and inexpensive to produce, and virtually any tumour antigen [a protein attacked by the immune system] can be encoded by RNA," they wrote. “Thus, the nanoparticulate RNA immunotherapy approach introduced here may be regarded as a universally applicable novel vaccine class for cancer immunotherapy.”
The vaccine, which used a number of different pieces of RNA, activated dendritic cells that select targets for the body's immune system to attack. This was followed by a strong response from the "killer" T-cells that normally deal with infections.
http://www.independent.co.uk/news/scien ... 60181.html
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Jue, 02 Feb 2017, 14:46

Por qué las vacunas contra el cancer no funcionan (hasta ahora).
The widespread success of vaccines for the prevention of viral diseases provided a considerable base of immunologic information as well as a theoretical framework for immunization against cancer antigens, even though antiviral vaccines have not been effective for the treatment of patients with established viral disease
Cancer vaccines often result in low levels of circulating immune cells. Pox virus vaccines have been reported to increase circulating human antitumor antigen-reactive T cells from fewer than 1 in 200,000 to about 1 in 40,000. In some peptide vaccine trials, frequencies of over 1 in 200 antitumor cells can be generated, yet tumor regression is still not seen
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1435696/
A tumour can have many cell types of cells, each with different cell-surface antigens. Those cells are derived from each patient and display few if any antigens that are foreign to that individual. This makes it difficult for the immune system to distinguish cancer cells from normal cells. Some scientists believe that renal cancer and melanoma are the two cancers with most evidence of spontaneous and effective immune responses, possibly because they often display antigens that are evaluated as foreign. Many attempts at developing cancer vaccines are directed against these tumors. However, Provenge's success in prostate cancer, a disease that never spontaneously regresses, suggests that cancers other than melanoma and renal cancer may be equally amenable to immune attack.
Most vaccine clinical trials have failed or had modest according to the standard RECIST criteria.
Mecanismos que hacen que las vacunas no funcionen:
- Escape loss variants. The most effective vaccine is likely to raise an immune response against a broad range tumor antigens to minimise the chance of the tumor mutating and becoming resistant to the therapy
Pufff..
- Prior treatments may have modified tumors in ways that nullify the vaccine. (Numerous clinical trials treated patients following chemotherapy that may destroy the immune system. Patients who are immune suppressed are not good candidates for vaccines.)
Developing a mature immune response to a vaccine may require months, but some cancers (e.g. advanced pancreatic) can kill patients in less time.
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Jue, 02 Feb 2017, 14:54

1YR survival casi 30% vs 11% en cancer de estómago metastático que no tiene otras opciones.
Checkpoint inhibitor nivolumab (Opdivo ®) benefited patients with advanced stomach cancer who could not be helped by surgery or chemotherapy. Compared to the control group, nivolumab treatment was associated with a 37% decrease in risk of death, and 26.6% of patients who received it survived for at least one year, compared to just 10.9% of those who did not.

Nivolumab works by blocking the PD-1/PD-L1 pathway and preventing anti-cancer T cells from being de-activated by the tumor.
http://www.cancerresearch.org/news-publ ... ign=buffer


A ver si las combinaciones van aumentando el número de pacientes que alcanzan ese punto de corte, y sube el punto de corte.
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Jue, 02 Feb 2017, 16:24

Suprimir el sistema inmune que ayuda al tumor a protegerse
We have shown that we can turn a tumor that is resistant to checkpoint blockade into one that responds,” says Taha Merghoub, a cancer immunologist in the Ludwig Collaborative Laboratory at MSK and co-lead author on the study, published today in Nature.
the drug, called IPI-549, was effective at improving responses to checkpoint blockade therapy only in tumors that had an abundance of suppressive immune cells called tumor-associated myeloid cells. In tumors without these suppressive cells, the drug provided no benefit.
In mice with one type of suppressed tumor, checkpoint inhibitors administered alone resulted in complete remissions in only 20% of the mice; adding IPI-549 to the mix brought that number up to 80%
https://www.mskcc.org/blog/resistance-f ... 54079110=1
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Jue, 02 Feb 2017, 16:30

TAMCs
TAMCs group heterogeneous phagocytic populations stemming from a common myeloid progenitor (CMP), that orchestrate various aspects of cancer, including: diversion and skewing of adaptive responses; immunosuppression; cell growth; angiogenesis; matrix deposition and remodelling; construction of a metastatic niche and actual metastasis. Several evidence indicate that TAMCs show plasticity and/or functional heterogeneity, suggesting that tumour-derived factors promote their functional “reprogramming” towards protumoral activities

TAMCs include at least four different myeloid populations

1) tumor-associated macrophages (TAMs), considered crucial orchestrators of cancer-related inflammation, promoting angiogenesis, immunosuppression, tissue remodelling and metastasis

2) the angiogenic monocytes expressing the tunica internal endothelial kinase 2 (Tie2), the angiopoietin receptor, playing a key role in tumor angiogenesis

3) myeloid-derived suppressor cells (MDSCs) for their ability to suppress T cells functions, which accumulate mainly in blood and lymphoid organs during tumor progression, but may also be recruited to the tumor site

4) tumor-associated neutrophils (TANs) that, despite their short half-life, have been recently proven to participate in tumor promotion by the expression of crucial pro-angiogenic factors.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3399067/
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Jue, 02 Feb 2017, 16:43

Mecanismos de evasión
- Cancer cells may reduce the expression of tumor antigens on their surface, making it harder for the immune system to detect them.

- They may express proteins on their surface that lead to immune cell to be inactivated.

- Or they may lead cells surrounding the tumor to release substances that suppress immune responses.
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Jue, 02 Feb 2017, 16:49

Could Aspirin Be The Key To Supercharging Cancer Immunotherapy?
Skin, breast and bowel cancer cells often produce large amounts of prostaglandin E2 (PGE2).

Aspirin is part of a group of molecules called COX inhibitors, which stop the production of PGE2 and help reawaken the immune system. Combining immunotherapy with aspirin or other COX inhibitors substantially slowed bowel and melanoma skin cancer growth in mice, compared to immunotherapy alone.

cancers produce PGE2 as a way of escaping the immune system
http://reliawire.com/supercharging-immu ... ign=buffer
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Sab, 04 Feb 2017, 14:52

Using vaccines to fight cancer cells
One approach that we are studying at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute and in institutions across the globe is to develop single-shot vaccines that trigger the same processes.

The idea is that vaccination or immunization with carefully engineered synthetic proteins can train the immune system to recognize antigens on cancer cells, effectively inoculating a patient against a cancer for years at a time. And, the treatment should cost far less than $1,000 per patient.

There are several approaches in process, such as a HER-2 breast cancer vaccine, which we are evaluating in Phase II trials.

Such vaccines, if ultimately successful, could also be paired with checkpoint inhibitors to create an even more favorable environment for T cells to do their work.

The approach mimics the effect of monoclonal antibodies, but with a more direct, and much more cost-effective, technique. Instead of receiving antibodies, the patients themselves make the antibodies through the vaccination process.

In our trial, patients (who were all terminally ill) developed antibodies against their cancers via the vaccine. Ten patients out of 24 (41 percent) enrolled in the trial fought their cancer well enough to come back for a six-month booster. One patient has survived more than three years, and our hope is that by administering the vaccine earlier in a patient’s treatment, before the immune system is compromised by chemotherapy and radiation, the impacts will be even more profound.

To date, the treatment appears to show no toxicity and minimal side effects.
we are realizing that viruses can be trained to attack cancer, with a dual benefit. First these viruses, called oncolytic viruses, can directly assault tumor cells, and they can also massively replicate within the diseased cells, causing them to violently explode. The ensuing tumor destruction recruits the body’s immune cells, now enabled to recognize cancer cells, to attack the cancer cells with every tool in their arsenal.

Just as with immunotherapy vaccines, oncolytic viral therapy can create a long-term, robust defense that trains the immune system to attack cancer over months, or even years.

Current work at the OSUCCC-James using oncolytic viruses takes advantage of three categories of treatment – a virus, a cancer drug and an immunotherapy – to treat a deadly form of brain cancer called glioblastoma.
Glioblastoma cells in culture. Alex Gray. Wellcome Images, CC BY-NC-ND

We matched a modified oncolytic herpes simplex virus with a drug called bortezomib (which slows tumor growth and boosts the impact of radiation and chemotherapy) and an immunotherapy, which in this case is an infusion of immune cells.

In that study, bortezomib and the modified herpes virus tore apart tumor cells via a process called necroptosis. In turn this triggered the release of inflammatory molecules that redirected the efforts of cancer-killing immune cells to recognize and eradicate the cancer threat. In our animal model, the added infusion of natural killer cells helped eradicate tumor remnants
https://theconversation.com/immunothera ... ncer-71870
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