Cancer Moonshot - inmunoterapia

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

Moderador: Fisio

Cancer Moonshot - inmunoterapia

Notapor Fisio » Mar, 27 Dic 2016, 02:47

"Cáncer" son en realidad 100 o 200 tipos de enfermedades diferentes, cada uno con distintos mecanismos con los que logran evadirse y protegerse. La "guerra contra el cancer" que declaró Richard Nixon ha sido una guerra sin buenas comunicaciones (internet, proyectos coordinados internacionalmente), sin buenos mapas (conocimiento molecular, bioinformática, etc) y sin suficientes armas (solo citotoxicidad mediante química y radiación). Debido a que no todas las células cancerígenas están en división, la quimioterapia no afecta a todas ellas. Igualmente, durante el proceso de metástasis, las células cancerígenas se esconden en modo latente, indetectables también para el propio sistema inmune. Estamos en un momento interesante en la investigación del cáncer, porque a diferencia de la guerra contra el cancer de Nixon, ahora hay comunicaciones, grupos internacionales coordinados, un mapa con unas cuantas rutas a seguir (vascular, hormonal, inmune, etc), y distintas armas (oncovirus y bacterias, anticuerpos, vacunas, edición ex-vivo de inmunidad innata y adaptativa, incluso probióticos, etc). El cambio de paradigma es más que notable: de un tratamiento sobre las células cancerígenas se va a pasar a tratar a nuestro sistema inmune para que las reconozca y se encargue de ellas, inhibiendo rutas inmunosupresoras (la más común del momento es PD-L1) y/o estimulando vias agonistas activadoras. Incluso coger células de nuestro sistema inmune, reprogramarlas para que sean más letales e inyectarlas de nuevo en el organismo.

No es factible una cura de todos los tipos de cáncer con un mismo mecanismo, pero veremos como responden ciertos tipos de cancer (en realidad solo algunos subtipos de cada cancer, o incluso solo ciertas personas) hasta cronificarlo progresivamente con sucesivas líneas de tratamiento. El pronóstico no solo depende del tipo de tumor propiamente y su fenotipo (por ejemplo de la expresión de ciertas proteinas reconocidas por el sistema inmune llamadas neoantígenos), sino que también depende de las características de la respuesta inmune de la propia persona. Esto hará que no respondan todas las personas, incluso con el mismo tipo de cáncer.

Adoptive T-cell therapies:

- ex-vivo-expanded autologous T cells isolated from tumor tissue (TILs)
- autologous T cells engineered with therapeutic T-cell receptors (TCRs)
- chimeric antigen receptors (CARs) recognizing tumor-expressed antigens

- vaccination using tumor antigens or tumor antigen-presenting dendritic cells to stimulate the patient's immune system
- antibody-based therapies blocking immune checkpoints that would naturally elicit negative signals that hold back T cells to prevent autoimmune attack


El cancer se acaba haciendo resistente a casi cualquier fármaco (porque algunas células tienen una variante en algún tipo de proteina que las protege y sobreviven multiplicándose con esa proteina protectora). Tener distinto arsenal implica que cuando el cancer deje de responder a un fármaco, habrá otro disponible para atacar en segunda o tercera línea, o que un cáncer que no responda a un fármaco aislado porque encuentra mecanismos de escape alternativos, no tenga escapatoria al acorralarle mediante varios mecanismos que explota (de inmunosupresión, etc). También implica que pacientes refractarios a una terapia, tengan la oportunidad de responder a otra distinta. Parece difícil curar el cáncer definitivamente, pero es factible ir cronificándolo si existen distintas líneas terapéuticas con las que ir manteniéndolo a raya. A diferencia de la mayor parte de lo que se investiga y produce en medicina a día de hoy, esto es buena ciencia.

El gran problema de los nuevos tratamientos, además de la resistencia a los mismos con el tiempo, y el precio (aunque debería ir bajando con los años), y como implementar todo esto en hospitales, son los problemas autoinmunes que crean, frecuentes, y algunos graves. Por ejemplo algunos de los nuevos fármacos producen diabetes tipo I en cuestión de días, y hay personas que han muerto en ensayos clínicos. Problemas adicionales son la implementación tecnológica de todo esto, pues pasamos de farmacología a biotecnología. Probablemente haya unos cuantos centros donde se realicen estas terapias. Los propios oncólogos van a tener que especializarse mucho, no solo con las terapias, sino con los ensayos clínicos o el manejo de efectos secundarios que no están acostumbrados a identificar.

Lo más importante en este mismo momento es posiblemente entender la razón por la que solo un 20% de los pacientes están respondiendo a la inmunoterapia. Aunque se pensó que responderían principalmente aquellos tipos de cáncer inmunogénicos con una alta expresión de neoantígenos, se han documentado respuestas asociadas a la carga mutagénica, la expresión de PD-L1, el infiltrado linfocitario del tumor (hot vs cold), e incluso la microbiota de la persona. Nada predice por sí mismo la respuesta, y los candidatos a la inmunoterapia probablemente serán elegidos mediante un análisis complejo de distintos factores, desde las características del tumor, a las características del propio sistema inmune de la persona. También hay fármacos para intentar convertir un tumor frío en uno caliente (incluso la radioterapia podría servir, pero aquí entrarían oncovirus por ejemplo), o aumentar la expresión neoantigénica (con fármacos epigenéticos). Se están viendo respuestas duraderas con sólo un inhibidor de checkpoint, por lo que el siguiente paso lógico es la combinación de distintos fármacos. Esto no ha hecho nada más que comenzar. Hay cientos de ensayos clínicos programados en este momento, decenas de inhibidores de checkpoint siendo evaluados a nivel pre-clínico, vacunas, oncovirus, probióticos, fármacos epigenéticos, y los primeros ensayos clínicos con combinaciones. Más escéptico soy en cambio con los cribados detectando cáncer mediante análisis de sangre (buscando partículas de ARN y ADN).

Imagen

En este hilo hablaremos del cancer moonshot que han lanzado desde el congreso de los EEUU. Y la bienvenida a China que será la primera potencia económica el próximo año, y que se ha metido de lleno en la carrera del cáncer haciendo el primer ensayo clínico con CRISPR.


- CART/CRISPR

- Inhibidores de checkpoint, PD1, CTLA 4, VISTA, etc.

- Análisis genéticos, bioinformática

- Investigación con células dendríticas, NK, células T, plaquetas, macrófagos...

- Oncovirus

- Vacunas


Imagen



Revisión: inmunoterapia en tumores sólidos

http://www.mdpi.com/2072-6694/8/12/106/ ... s-08-00106


¿Debemos dejar de buscar genes y focalizarnos en reguladores maestros?

We must look to proteins rather than genes

analysed data from 20,000 tumour samples and generated maps for 36 types of tumour. All told, he has identified about 300 proteins that are probably master regulators in at least one sort of cancer. These are organised into groups of ten to 30 in each tumour type, and are probably, collectively, responsible for controlling most human cancers.


http://www.economist.com/news/science-a ... altcancers
Avatar de Usuario
Fisio
Administrador del Sitio
 
Mensajes: 6122
Registrado: Dom, 01 Sep 2013, 14:18

Re: Cancer Moonshot [hilo oficial]

Notapor Fisio » Mar, 27 Dic 2016, 15:33

Artículo en NY TIMES analizando problemas de la inmunoterapia

“We are playing with fire,” said Dr. John Timmerman, an oncologist and immunotherapy researcher at the University of California, Los Angeles, who recently lost a patient to side effects. The woman’s immunotherapy drugs had successfully “melted away” her cancer, he said, but some weeks later, she got cold and flulike symptoms and died in the emergency room from an inflammatory response


Despite the warnings, physicians like Dr. Timmerman remain hugely supportive of drugs that are saving the lives of people who would otherwise die. Far better to cope with diabetes, hepatitis or arthritis, the thinking goes, than to die. Most reactions are not nearly so bad and are treatable.

The rub, doctors and researchers say, is that the medical system — from front-line nurses to oncologists to emergency rooms — is too often caught off guard.


http://www.nytimes.com/2016/12/03/healt ... =1&referer


T-cell transfer therapy

https://www.nih.gov/news-events/news-re ... r-mutation

https://www.ncbi.nlm.nih.gov/pubmed/25838374

https://www.ncbi.nlm.nih.gov/pubmed/21498393
Avatar de Usuario
Fisio
Administrador del Sitio
 
Mensajes: 6122
Registrado: Dom, 01 Sep 2013, 14:18

Re: Cancer Moonshot

Notapor Fisio » Vie, 30 Dic 2016, 17:25

Como los macrófagos ayudan al cancer a crecer confundiendo a los linfocitos T y otras células de nuestro sistema inmune

Many different types of immune cells are found within tumors. For example, some types of T cells have the potential to attack tumors, while other immune cell populations seem to help cancers grow


In healthy tissues, macrophages are an essential first-line defense against infection, but tumor-associated macrophages (TAMs) appear to help cancers grow.

“Although several clinical studies show that patients with higher numbers of tumor-associated macrophages have a poorer prognosis, we do not know where these cells come from, what exactly they might be doing to promote tumor progression, or how to stop them,”


When the researchers knocked out a critical gene in this signaling pathway, the development of TAMs was inhibited, while the number of T cells within the tumors capable of killing cancer cells increased and tumor growth was suppressed. They propose that TAMs may aid tumor growth by turning off cancer-killing T cells that enter the tumor


immunotherapies that inhibit TAMs could be a powerful approach to unleash tumor-attacking T cells, particularly if used in combination with other T cell-directed immunotherapies.


https://www.mskcc.org/blog/how-co-opt-immune-defenses
Avatar de Usuario
Fisio
Administrador del Sitio
 
Mensajes: 6122
Registrado: Dom, 01 Sep 2013, 14:18

Re: Cancer Moonshot

Notapor Fisio » Lun, 02 Ene 2017, 18:35

NK en inmunidad innata y sus problemas/limitaciones

Poor antitumor efficacy has always been a possibility for NK cell–targeted therapies for several reasons, some of which are only now being revealed. NK cells are short lived and can be inactivated by tumors in several ways. Since NK cells don’t mount an effective immune response in isolation, many researchers doubt the ability of NK cell–targeted therapies to fully eliminate a tumor on their own and the development of rational combination therapy is likely to be key.

Another potential limitation of KIR blockade is that KIRs and their ligands play an important role in NK cell education, also known as licensing, the process through which immature NK cells achieve functional maturity. Although the process is still incompletely understood, essentially NK cells that express inhibitory KIRs that recognize MHC molecules found on normal tissues of the same individual are “educated” or “licensed” during their development. NK cells that don’t express inhibitory KIRs or express only KIRs that bind to non-self MHC ligands remain unlicensed.

Recent studies suggest that NK cell education is a dynamic process, maintained through constant KIR signaling. Thus, continual blockade of KIRs could impact this process and result in NK cells with reduced functionality. Ongoing clinical studies of lirilumab are investigating the effects of continuous and intermittent dosing to further tease out these effects.


http://www.onclive.com/publications/onc ... combos?p=2


Activación NK contra tumores sólidos

https://www.statnews.com/2016/12/14/nat ... n=stat:rss
Avatar de Usuario
Fisio
Administrador del Sitio
 
Mensajes: 6122
Registrado: Dom, 01 Sep 2013, 14:18

Re: Cancer Moonshot

Notapor Fisio » Mié, 04 Ene 2017, 23:46

Me estaba preguntando si una falta de actividad AMPK es la causa de muchos de nuestros cánceres debido a falta de autofagia por sedentarismo y alto consumo calórico.

Autophagic defects have been implicated in various diseases and health states, including neurodegeneration, aging, infection, myopathy, Crohn's disease and cancer


Y he llegado a un par de papers interesantes que discuten esto.

Basal autophagy plays a critical role in maintaining cellular homeostasis and genomic integrity by degrading aged or malfunctioning organelles and damaged or misfolded proteins. However, autophagy also plays a complicated role in tumorigenesis and treatment responsiveness. It can be tumor-suppressing during the early stages of tumorigenesis (i.e., it is an anti-tumor mechanism), as reduced autophagy is found in tumor cells and may be associated with malignant transformation. In this case, induction of autophagy would seem to be beneficial for cancer prevention.



No esperaba esto

In established tumors, however, autophagy can be tumor-promoting (i.e., it is a pro-tumor mechanism), and cancer cells can use enhanced autophagy to survive under metabolic and therapeutic stress. The pharmacological and/or genetic inhibition of autophagy was recently shown to sensitize cancer cells to the lethal effects of various cancer therapies, including chemotherapy, radiotherapy and targeted therapies, suggesting that suppression of the autophagic pathway may represent a valuable sensitizing strategy for cancer treatments.



Es decir, autofagia para prevenir, una vez establecido el tumor es más dudoso.


Deficiencies in autophagy lead to the accumulation of damaged macromolecules and organelles (particularly mitochondria), subsequently inducing oxidative stress, DNA damage and chromatin instability. Thus, autophagic defects are ultimately associated with the accumulation of oncogenic mutations and increased tumor susceptibility



Está bien encontrarse esto en un paper de Nature

Various dietary phytochemicals, including β-carotene, lycopene, lutein, quercetin, resveratrol, curcumin and epigallocatechin-3-gallate (EGCG) have demonstrated chemopreventive activities in many preclinical and clinical studies (Davis 2007; Pan and Ho, 2008). Their antioxidant, anti-inflammatory, and pro-apoptotic activities appear to be important for preventing, suppressing, or reversing the development of carcinogenesis (Tan et al., 2011). Both in vitro and animal studies have demonstrated that a number of phytochemicals (curcumin, resveratrol, EGCG, sulforaphane and silibinin) show preferential cytotoxicity to malignant cancer cells over normal cells, suggesting that they might safely be used for both cancer chemoprevention and cancer therapy (Nair et al., 2007; Mann et al., 2009).


Pero lo seguirán ignorando.

http://www.nature.com/emm/journal/v44/n ... 1215a.html
Avatar de Usuario
Fisio
Administrador del Sitio
 
Mensajes: 6122
Registrado: Dom, 01 Sep 2013, 14:18

Re: Cancer Moonshot

Notapor Fisio » Jue, 05 Ene 2017, 00:41

Quimioterapia, difícil combinar con inmunoterapia en aplicación sistémica vs local

local chemotherapy was particularly effective in combination with checkpoint inhibition, whereas systemic chemotherapy was too damaging to the immune system to make for useful combinations.


http://stm.sciencemag.org/content/8/370/370ra180
Avatar de Usuario
Fisio
Administrador del Sitio
 
Mensajes: 6122
Registrado: Dom, 01 Sep 2013, 14:18

Re: Cancer Moonshot

Notapor Fisio » Jue, 05 Ene 2017, 00:45

Inmunoterapia vs quimioterapia en cancer de cabeza y cuello avanzado

Advanced head and neck cancer has very poor survival rates.

In a trial of more than 350 patients, published in the New England Journal of Medicine, 36% treated with the immunotherapy drug nivolumab were alive after one year compared with 17% who received chemotherapy.

Patients also experienced fewer side effects from immunotherapy.


http://www.bbc.com/news/health-37588541
Avatar de Usuario
Fisio
Administrador del Sitio
 
Mensajes: 6122
Registrado: Dom, 01 Sep 2013, 14:18

Re: Cancer Moonshot

Notapor Fisio » Jue, 05 Ene 2017, 00:46

Inmunoterapia en glioblastoma. N = 1

The 50-year-old man with glioblastoma, a particularly aggressive type of brain tumor, had already been treated with surgery, radiation and anti-tumor drug therapies. Despite these treatments, his cancer had returned and also spread to other parts of his brain and spinal cord. Badie and his team extracted immune cells from him, then engineered them to express proteins on their surface that would recognize and destroy glioblastoma tumor cells. After surgery to remove the bulk of the brain tumor, Badie and his colleagues directly injected the site with the modified immune cells (called chimeric antigen receptor T cells, or CAR T cells) six times, and the remaining part of this tumor stopped growing.

Other smaller growths in the brain continued to grow, however, so the patient received 10 more doses of the CAR T cells injected into the cavities in the brain, called the ventricles. This is the first time that immune cells have been injected into these brain regions, because introducing anything into the ventricles can cause dangerous and possibly deadly inflammation. The man did not develop such serious complications, however, and after about four months, these tumors too started to shrink. By six months, almost all had disappeared.


http://time.com/4618566/brain-cancer-tr ... notherapy/
Avatar de Usuario
Fisio
Administrador del Sitio
 
Mensajes: 6122
Registrado: Dom, 01 Sep 2013, 14:18

Re: Cancer Moonshot

Notapor Fisio » Jue, 05 Ene 2017, 03:01

Están los cribados intoxicando los ensayos clínicos (para mal)? Extremadamente preocupante.

Perhaps clinical efficacy would be borne out by treating patients earlier in the disease spectrum (eg, chemotherapy-naive mCRPC) and improving patient selection (eg, exclusion of patients with visceral metastases).


De esto ya había hablado Vinay Prasad

Is prostate cancer screening responsible for the negative results of prostate cancer treatment trials?
Prasad V1.
Author information
Abstract

Clinical guidelines continue to move away from routine prostate specific antigen screening (PSA), once a widespread medical practice. A curious difference exists between early prostate cancer and early breast cancer. While randomized trials of therapy in early breast cancer continue to show overall survival benefit, this is not the case in prostate cancer, where prostatectomy was no better than observation in a recent trial, and where early androgen deprivation is no better than late androgen deprivation. Here, I make the case that prostate cancer screening contributes so greatly to over diagnosis that even treatment trials yield null results due to contamination with non-life threatening disease.


https://www.ncbi.nlm.nih.gov/pubmed/27372859
Avatar de Usuario
Fisio
Administrador del Sitio
 
Mensajes: 6122
Registrado: Dom, 01 Sep 2013, 14:18

Re: Cancer Moonshot

Notapor Fisio » Jue, 05 Ene 2017, 03:13

Cancer de colon metastático Kras + (N = 1)

A 50-year old woman who suffered from colon cancer that had spread to her lungs is now free from cancer following a clinical trial using her own white blood cells.

Her remarkable recovery was recently published in the New England Journal of Medicine. Before treatment, the patient had 7 tumors in her lungs. 40 days following treatment, all 7 of her lung metastases had shrunk. At a 9-month follow up, one of the tumors appeared to have started to develop resistance to the treatment, although it was successfully removed by surgery. The patient has since remained cancer free. No adverse side effects were reported.

Her cancer cells contained a mutation in a gene called KRAS, which is very common in cancers such as colorectal and pancreatic cancers. Cancers with this mutation generally have a poor prognosis, and previous attempts by scientists to target this mutation had been unsuccessful. This study marks the first successful attempt to target this KRAS mutation in a cancer.


http://biosky.co/clinical-trial-treatment-colon-cancer/
Avatar de Usuario
Fisio
Administrador del Sitio
 
Mensajes: 6122
Registrado: Dom, 01 Sep 2013, 14:18

Siguiente

Volver a Muscleblog

¿Quién está conectado?

Usuarios navegando por este Foro: No hay usuarios registrados visitando el Foro y 4 invitados