Cancer Moonshot - inmunoterapia

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Jue, 05 Ene 2017, 03:36

Vacuna en cancer de mama temprano (CDIS) HER2 +
clinical trial with 54 women all diagnosed with early-stage breast cancer. The other quality these women shared was that their breast cancer cells expressed HER2, a protein that is overexpressed in nearly a quarter of all breast cancers and which is unfortunately linked to cases of a particularly aggressive cancer and a poor prognosis. The vaccine helps the immune system relearn to recognize HER2, and researchers could extract dendritic cells from each breast cancer patient to cater a dendritic cell vaccine specifically to each person.

Results showed that the treatment was well received and women experienced only low-grade toxicity, if any. Remarkably, researchers saw a clear immune response to the vaccine in 80 percent of evaluable patients, and all of the responses were similar despite variation of vaccine administration location
https://www.labroots.com/trending/immun ... ign=buffer
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Jue, 05 Ene 2017, 03:50

Inmunoterapia en cancer de prostata resistente a la castración de andrógenos (MCRPC)
A randomized, placebo-controlled Phase 2 trial demonstrated the potential of PROSTVAC to extend the median overall survival by 8.5 months in patients with advanced prostate cancer. These results led to the initiation of the PROSPECT pivotal Phase 3 study.
http://www.bavarian-nordic.com/investor ... ?news=5117
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Jue, 05 Ene 2017, 15:26

Vejiga
“Until the first, recent approval of immune checkpoint therapy, patients with bladder cancer have not had new treatment options for over 30 years. We’re quickly moving from immune checkpoint monotherapy to immune checkpoint combination therapies to improve outcomes for patients with bladder cancer,”

Patients receiving the combination with the higher dose of ipilimumab had the highest objective response rate (38.5 percent), which is confirmed complete response (disappearance of tumors) plus confirmed partial response (at least a 30 percent shrinkage of tumors).
http://www.cancerfrontline.org/combinat ... er-cancer/
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Jue, 05 Ene 2017, 15:32

Como se desarrolla resistencia a la inmunoterapia (y a cualquier tratamiento en realidad).

Las células aberrantes producen proteinas aberrantes. Estas proteinas aberrantes son reconocidas por las células inmunes y es lo que permite conocer las células tumorales y destruirlas. Mientras más acumulación de daño en el ADN, más proteinas aberrantes y más sencillo que el sistema inmune sepa que algo va mal con esas células. Por eso responden a inmunoterapia canceres con mayor inmunogenicidad derivada de daño acumulado como pulmón y melanoma
Cancer cells may contain mutations in genes that code for antigens, producing misshapen or otherwise altered antigens that are known to scientists as neoantigens. Such neoantigens are foreign to the immune system, and thus, the cancer cell is flagged for destruction, usually with the help of immunotherapy drugs.
Si la inmunoterapia logra que las células T maten a las células cancerosas más aberrantes, sobreviven aquellas que no tienen estas mutaciones, y se irán expandiendo. Vamos, darwinismo.
The scientists found that after the patients developed resistance to immunotherapy, all of their tumors had shed between seven and 18 mutations in neoantigen-coding genes. By getting rid of those mutations, the tumor cells’ neoantigens look less foreign to the immune system and may go unrecognized, say the scientists.

The researchers found that the tumors had lost these mutations by various means, including immune-mediated elimination of cancer cells containing these mutations, leaving behind cancer cells without the mutations, or by deleting large regions of their chromosomes in all cancer cells.


http://www.hopkinsmedicine.org/news/med ... ewsRelease
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Vie, 06 Ene 2017, 00:18

Vinay Prasad, sobre cancer en general

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Sab, 07 Ene 2017, 03:14

Vienen más rutas a inhibir...
One reason why almost 70 percent of cancers do not respond to checkpoint inhibitors is that the cancer cells inhibit different pathways that affect T-cell function. Therapeutics targeting immune-evasion mechanisms other than the PD-1/PD-L1 checkpoint, such as IDO, CD40, OX40, TIM-3, LAG-3, and KIR, are already in early clinical development. We will see them progress to clinical testing, alone or in combination with PD-1/PD-L1 drugs, and some of them may be approved or may come close to approval this year
https://medium.com/@AACR/experts-foreca ... .vquubear9
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Sab, 07 Ene 2017, 15:32

La dura realidad de la oncología en las últimas décadas

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Vie, 13 Ene 2017, 18:13

Microambiente que engaña a nuestro sistema inmune reclutando macrófagos a favor del cancer
Cancer-associated fibroblasts promote an immunosuppressive microenvironment through the induction and accumulation of protumoral macrophages

Stromal cells in the tumor microenvironment (TME) closely interact with tumor cells and affect tumor cell behavior in diverse manners. We herein investigated the mechanisms by which cancer-associated fibroblasts (CAFs) affect the functional polarization of tumor-associated macrophages (TAMs) in oral squamous cell carcinoma (OSCC) in vitro and in human cancer samples. The expression of CD68, CD14, CD163, CD200R, CD206, HLA-G, CD80, and CD86 was higher in CD14-positive cells co-cultured with the culture supernatants of CAFs established from OSCC specimens (CAF-educated cells) than in control cells. The gene expression level of ARG1, IL10, and TGFB1 was increased in CAF-educated cells. CAF-educated cells suppressed T cell proliferation more strongly than control cells, and the neutralization of TGF-β IL-10, or arginase I significantly restored T cell proliferation. We then investigated the relationship between the infiltration of CAFs and TAMs using tissue samples obtained from patients with OSCC. The infiltration of CAFs was associated with the numbers of CD68-positive and CD163-positive macrophages. It also correlated with lymphatic invasion, vascular invasion, lymph node involvement, and the TNM stage. The infiltration of CAFs was identified as an independent prognostic factor in OSCC. Our results indicate that CAFs play important roles in shaping the tumor immunosuppressive microenvironment in OSCC by inducing the protumoral phenotype of TAMs. Therapeutic strategies to reverse CAF-mediated immunosuppression need to be considered.
http://www.impactjournals.com/oncotarge ... -linkout=1
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Vie, 13 Ene 2017, 18:37

Revisión CART
The first successful adoptive cell therapy of cancer took place over half a century ago3. In 1956 in New York, Dr E Donnall Thomas performed lethal irradiation on a patient with leukemia, followed by a bone-marrow transplant (BMT) from the patient's identical twin. The result was a complete regression of the leukemia via graft-versus-tumor (GVT) activity, a finding that earned Thomas a Nobel Prize in 1990. Attempts to transfer cells from non-related donors resulted in severe damage to the patient from graft-versus-host disease (GVHD), and often mortality of the patient, so these BMTs were limited to identical twin donors for another decade, until non-twin sibling donors were used to reduce potential HLA mismatch. It took another decade until BMT involving a partially HLA-matched non-related donor was able to treat a patient with leukemia in 1979 in Seattle, WA. The practice of non-related donor BMT continues today as the only curative option for many types of leukemia, but carries a heavy price, with many patients developing GVHD, which may be severe and lethal in some cases
Año 2002
National Cancer Institute (NCI) Surgery Branch used patient T cells extracted from tumor (or tumor-infiltrating lymphocytes, TIL), expanded ex vivo and re-infused to successfully treat metastatic melanoma. Though exciting news, this approach proved to have its own challenges. Not all patients have resectable tumor; of those with resectable disease, not all tumors grew lymphocytes; of those that grew lymphocytes, not all demonstrated anti-tumor activity; of those that demonstrated anti-tumor function, many patients would not survive the eight-plus weeks required to grow and expand their T cells to therapeutic levels for reinfusion.
need for a 'universal' T cell that could recognize tumors in different patients, without the costly and resource-heavy dependence on growing each patient's TIL.

First generation chimeric antigen receptors (CARs) — back in the day

CARs were originally conceptualized by Zelig Eshhar and colleagues in 1989. Their findings, published in Proceedings of the National Academy of Sciences, described the generation of an “immunoglobulin-T-cell receptor chimeric molecule” by splicing the heavy and light chain variable regions of a monoclonal antibody (mAb) followed by transfection of these two fragments along with the constant region of a TCR into a T lymphocyte cell line.
Efectos secundarios graves
Activated T cells produce high levels of inflammatory cytokines including tumor-necrosis factor (TNF)-α, multiple interleukins (ILs) such as IL-1, 2, 6, and 8, and interferon (IFN)-γ. (...) The generalized term for this has come to be called 'cytokine release syndrome' (CRS). The traditional way that clinicians would use to treat this presentation would be to deliver high doses of systemic corticosteroids; the problem in the context of CAR therapy is that steroids work by shutting down the immune system in general, and T cells in particular.
http://www.nature.com/cr/journal/v27/n1 ... 6154a.html
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Sab, 14 Ene 2017, 15:12

Pues lo de "shutear" el sistema inmune mal vamos. Es lo que hace el VIH xD.
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