In two separate studies, US researchers demonstrate how the synthetic biology to address a frequent complication in immunotherapy, one of the most innovative treatments against cancer, and to expand the efficacy of CAR-T cells in solid tumors, hitherto insensitive to this type of therapy.
The researchers explain in two studies published in “Science” that they have introduced new modifications into CAR-T cells through bioengineering to try to make them more powerful and safe in their antitumor capacity. These variations allow their activity to increase only in the vicinity of the tumor or can be regulated on demand.
Among the armamentarium of cancer immunotherapy treatments, CAR-T CAR-T therapies involve ex vivo genetic engineering of a patient’s cancer-killing T cells to express CAR-T cells that recognize specific molecules on the surface. of a tumor.
These cells are then injected back into patients to trigger an immune response against the cancer cells.
However, CAR T cell therapies are generally highly effective in short-term cellular responses (eg, tumor cell killing) and may not achieve long-term systemic eradication of tumor.
What these groups have now done is propose strategies to allow better control over immunotherapy by using synthetic gene circuits by which antitumor cell functions can be activated on demand, or only when CAR T cells are in direct contact with cells. tumor cells. “Rather than being limited by the ‘natural’ immune response (using leukocytes, antibodies and cytokines), these studies broaden the scope of immune responses elicited by CAR T cells against diseased tissues,” write Emmanuel Salazar-Cavazos and Grégoire Altan-Bonnet in a comment in “Science”.
Greg Allen’s University of California-San Francisco (UCSF) group has taken advantage of newly developed synthetic Notch receptors to engineer CAR-T cells enhanced with a second receptor; in this way they achieved precise control of the function of CAR-T cells over time.
“This second receptor can recognize a tumor antigen and, subsequently, cause the T cell to release a cytokine -interleukin-2-, only when the CAR-T cells are in direct contact with the tumor cells”, they explain in their work.
This approach, in a mouse model, was able to eradicate pancreatic tumors and melanoma with CART-T therapy.
The study signed by Greg M. Allen is more specific, defining that with this NOTCH system it is possible to reconstitute circuits of synthetic T cells for an antitumor response, he points out to Science Media Center Manel Juan, head of the Immunology Service at the Hospital Clínic de Barcelona. “The option of use is clear, but the most complex path still remains to be covered, demonstrating this activity in humans. In the end, clinical trials are the ones that will allow us to know if proposals like these are effective or not”.
For their part, Hui-Shan Li’s team at Boston University developed a toolkit of 11 programmable synthetic transcription factors that could be activated on demand with the scheduled administration of approved small molecule inducers.
Using these tools, the authors engineered human immune cells that activate specific cellular programs, such as proliferation and antitumor activity, on demand. This allows gradual and controlled therapeutic responses over time, they write in their article.
The therapy succeeded, in a mouse model, in eradicating pancreatic tumors and melanoma with CART-T therapy
“These studies will make it possible to expand the efficacy of CAR-T cells in solid tumors, hitherto insensitive to this type of therapy, as well as improve the toxicity profile of these treatments,” Luis Álvarez-Vallina, head of the SMC, assures Mixed Cancer Immunotherapy Unit H12O/CNIO.
In addition, he adds, “they delve into a concept of the greatest interest in this field, the so-called “dynamic adjustment”, which aims to regulate the state of CAR-T cells (active vs. rest) to prevent “cellular exhaustion” and enhance the antitumor responses.
“The combination of the two technological advances will enable an unprecedented ability to accurately monitor the status of therapeutic cell populations not only at the time of injection -write Salazar-Cavazos and Altan-Bonnet-, but also while the immune response is developing within the patient».