crispr immunotherapy

Collaborative Cancer Care: How CAR T-Cells and mRNA Vaccines Team Up

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Trimero

Introduction: Unlocking the Potential of CAR-T Therapy in Solid Tumors

Chimeric antigen receptor (CAR) T cells have successfully treated relapsed/refractory B-cell neoplasms and multiple myeloma but have limited efficacy in solid cancers. The main challenges in solid tumors are the absence of highly-specific cancer cell-surface targets, leading to on-target/off-tumor toxicity and issues with T cell expansion and persistence due to antigen inaccessibility and the immunosuppressive tumor microenvironment.

Messenger RNA (mRNA) vaccines, known for their success against infectious diseases, are now being explored in cancer research. These vaccines utilize mRNA technology to stimulate the immune system against cancer cells. In cancer immunotherapy, mRNA vaccines offer a novel approach, holding promise for more effective and targeted treatments.

Targeting Claudin 6 for Solid Tumor Treatment

The phase 1 BNT211-01 trial explored the use of Claudin 6 (CLDN6)-specific chimeric antigen receptor (CAR) T cells, along with an amplifying RNA vaccine (CARVac), in treating relapsed or refractory solid tumors. CLDN6, a primitive tight junction protein, is a promising target for immunotherapy due to its high and specific expression in many solid tumors. Yet, suppressed expression in healthy adult tissues makes it an ideal immunotherapy target.

The trial focused on the safety and feasibility of this approach. Manageable toxicity was observed, with some patients experiencing cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome. The efficacy of the treatment was also notable, with an unconfirmed objective response rate (ORR) of 33% and a disease control rate of 67% in the evaluable patients. Notably, patients with germ cell tumors (GCT) treated at higher dose levels showed a higher response rate.

The study highlighted the potential of CLDN6 expression as a predictive biomarker, suggesting that higher levels of CLDN6 expression predict better treatment outcomes. This is significant as it could guide selection of patients most likely to benefit from CLDN6-targeted therapies.

This trial represents a significant step in using CAR-T therapies for solid tumors, a field where these therapies have historically faced challenges such as lack of specific cell-surface targets and poor expansion and persistence in the tumor microenvironment.

Cut and paste wins the Nobel Prize

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Drawings by Maria Gonzalez Forero MD

Version en Español

An antiviral immune system

Today is a holiday in Spain. It is the day of the Virgin of Pilar, who appeared in Zaragoza to Santiago Apostle to encourage him to continue his journey. It’s not wrong to have a little (or a lot) of help to deal with problems better. In Madrid, we have been in a “State of Alarm” since last Friday due to the increase in coronavirus cases in the city. How can we defend ourselves from this virus?

Of course, the answer is through the immune system. Antibodies and T cells are the most suitable for the task, and at present, we expect that the clinical trials of SARS-Cov-2 vaccines will show good results in terms of safety and efficacy. For those interested in reading a nice update on the subject, I recommend this article by Florian Krammer.

Viruses are and will be a headache for living beings. For example, bacteria have been in a continuous war against different viral particles for more than two billion years. They have even developed several defense methods that include restriction enzymes (the basis of recombinant DNA technology) and something like an adaptive system (with memory). Two researchers received this year’s Nobel Prize in Chemistry for their “for the development of a method for genome editing” based on that antiviral system (CRISPR)

CTRL-F and CTRL-X

CRISPR (Clustered regularly interspaced short palindromic repeats) are viral DNA sequences that have been integrated into the genetic material of bacteria to “remember” previous infections, somewhat like a prehistoric vaccination system. CRISPR is like a poster with the “most wanted” face for those who enjoy crime stories (discovered by Francis Mojica)

This primitive immune system’s effector arm is composed of proteins that can cut DNA known as CRISPR associated nucleases or Cas for friends.

The process is roughly like this:

1. The CRISPR sequence is copied as RNA

2. RNA-CRISPR joins CAS

3. The CRISPR/Cas complex seeks the complement of the specific RNA

4. When Cas finds it, cuts off the DNA

In 2012, Doudna and Charpentier demonstrated that it is possible to use this bacterial defense system to edit any piece of DNA accurately. Easy, versatile, and cheap genetic editing. The applications are multiple and include silencing defective genes, increasing the expression of a gene, etc. A couple of months ago, the FDA approved a coronavirus detection system based on CRISPR technology.

To summarize, in terms of text editors, CRISPR is CTRL-F (search), and Cas is CTRL-X (cut)

Cancer immunotherapy applications

The CRISPR/Cas system has an infinite number of possible uses. In this section, I want to describe two exciting innovations.

1. T cell engineering: Carl June’s group (a pioneer in Chimeric Antigen Receptors) used CRISPR to knock out T cell and PD-1 receptor genes in lymphocytes that were then injected into cancer patients in a Phase 1 clinical trial.

2. Therapeutic targeting tool: Researchers at Dana Farber Cancer Institute conducted an experiment to remove all the genes from a tumor cell to determine which one(s) were needed to limit the activity of the immune system. The results of the study found that the ADAR1 protein is part of a novel T cell inhibition system.

The above applications are a sign of the future. Science is advancing by leaps and bounds.

As I have mentioned in other blog posts, I really like playing tennis. I’m left-handed, and I’m thrilled because Rafael Nadal (a left-handed man just to play tennis) won his thirteenth Roland Garros yesterday. Thirteen! It is said soon, but the effort and dedication behind it are beyond measure. This video about Nadal’s way of playing is remarkable. Especially the final part when his coach for many years (Toni Nadal) explains a very decent way of looking at life, “If you have inspiration, but you don’t work at all, you can’t get very far either. It’s much more formative to rely on effort than talent”

Trimero

Corta y pega genético gana el Premio Nobel

Un sistema inmune antiviral

Hoy es festivo en España. Día de la Virgen del Pilar que se apareció en Zaragoza a Santiago Apóstol para animarlo a continuar su camino. No esta mal tener un poco (o mucho) de ayuda para llevar mejor los problemas. En Madrid estamos desde el viernes pasado en “Estado de alarma” por el incremento en los casos de coronavirus en la ciudad. ¿Cómo podemos defendernos de este virus?

Desde luego, la respuesta es a través del sistema inmune. Anticuerpos y células T son los mas adecuados para la tarea y en la actualidad esperamos que los ensayos clínicos de vacunas contra SARS-Cov-2 arrojen buenos resultados en términos de seguridad y eficacia. Para los interesados en leer una buena actualización sobre el tema, este artículo de Florian Krammer es muy recomendable.

Los virus han sido y serán un dolor de cabeza para los seres vivos. Por ejemplo, las bacterias llevan en una guerra continúa frente a diferentes partículas virales durante mas de dos billones de años. Incluso han desarrollado varios métodos de defensa que incluyen enzimas de restricción (base de la tecnología del ADN recombinante) y algo parecido a un sistema adaptativo (con memoria) por el que dos investigadoras recibieron el Premio Nobel de Química 2020.

CTRL-F y CTRL-X

CRISPR (Clustered regularly interspaced short palindromic repeats) son secuencias de ADN viral que han sido integradas en el material genético de bacterias para “recordar” infecciones previas, algo así como un sistema de vacunación pre-histórico. Para aquellos que disfrutan de historias policiacas, CRISPR es como un cartel con el rostro de los “mas buscados”.

El brazo efector de este sistema inmune primitivo está compuesto por proteínas que pueden cortar el ADN conocidas como CRISPR associated nucleases o Cas para los amigos.

El proceso es a grandes rasgos así:

  1. La secuencia CRISPR es copiada como RNA
  2. RNA-CRISPR se une a CAS
  3. El conjunto CRISPR/Cas busca el complemento del RNA especifico
  4. Cuando lo encuentra Cas corta el ADN

En el año 2012 Doudna y Charpentier demostraron que es posible utilizar este sistema de defensa bacteriano para editar con precisión cualquier trozo de ADN. Edición genética fácil, versátil y barata. Las aplicaciones son múltiples e incluyen silenciar genes defectuosos, aumentar la expresión de un gen, etc. Hace un par de meses, la FDA aprobó un sistema de detección del coronavirus basado en tecnología CRISPR.

Para resumir, en términos de editores de texto, CRISPR es CTRL- F (buscar) y Cas es CTRL-X (cortar).

Aplicaciones en inmunoterapia del cáncer

El sistema CRISPR/Cas tiene infinidad de posibles usos. En este apartado quiero describir dos innovaciones interesantes

  1. Ingeniería de células T: El grupo de Carl June (pionero en Chimeric Antigen Receptors) utilizó CRISPR para eliminar genes del receptor de células T y de PD-1 en linfocitos que luego fueron inyectados a pacientes con cáncer en un ensayo clínico de Fase 1.
  2. Herramienta para buscar dianas terapéuticas: Investigadores de Dana Farber Cancer Institute realizaron un experimento para eliminar todos los genes de una célula tumoral y determinar de esta manera cual o cuales eran necesarios para limitar la actividad del sistema inmune. Los resultados del estudio encontraron que la proteína ADAR1 hace parte de un nuevo sistema de inhibición de las células T.

Las anteriores aplicaciones son una muestra del futuro. La ciencia avanza a pasos agigantados.

Como he contado en otras entradas al blog, me gusta mucho jugar tenis. Soy zurdo y estoy muy contento porque Rafael Nadal (un zurdo solo para jugar tenis) gano ayer su Roland Garros número trece. Trece! Se dice pronto, pero el esfuerzo y la dedicación que hay detrás no tiene medida. Este video sobre la forma de jugar de Nadal no tiene desperdicio. En especial la parte final cuando su entrenador por muchos años (Toni Nadal) explica una forma muy decente de ver la vida, “Si tienes inspiración, pero no trabajas nada tampoco es posible llegar muy arriba. Es mucho mas formativo basarse en el esfuerzo que en el talento”.