Immunotherapy & CAR T Cells: Part 1

How are CAR-T therapies designed and implemented? This video gives an overview of this exciting field.
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Transcript:
Our immune system has the ability to detect and fight infectious pathogens. It can also detect when normal cells become cancerous and kill those cells, preventing cancer progression. But over time, cancers can evolve and evade the immune response. Researchers have been investigating several potential avenues to counter tumor immunosuppresion and re-activate the immune system. One of these is CAR-T therapy, which is designed to harness the potent cytotoxicity of T cells by re-engineering their surface receptors to recognize and attack tumors.

Two CAR-T therapies for the treatment of malignant B-cell lymphomas were approved in 2017. More recently, solid tumors such as prostate cancer and glioblastoma have appeared on the radar as candidates for CAR-T immunotherapy.

This is Part One of a two-part video series. In this video, we'll cover the rationale and design of CAR-T cells. If you're already familiar with CAR-T cell technology, you can check out Part Two, which discusses potential future directions for this exciting field. Otherwise, keep it right here, and we'll get you up to speed on CAR-T immunotherapy. If you enjoy these kinds of videos, don't forget to hit the like and subscribe buttons, and share this video with your colleagues.

Okay, let's take a look at how CAR-T cells are engineered to understand how they can enhance anti-tumor immunity. Although there are many variations, the general theme behind the design of CARs is to combine two functions in one synthetic receptor. This is done by taking moieties, or pieces of different proteins, and combining them into a new recombinant protein, the chimaeric receptor.

First, the CAR ectodomain is derived from a recombinant single change variable fragment, or scFV, of a monoclonal antibody that targets a tumor-specific antigen. This provides the first function, target recognition. The intracellular domain is derived from a costimulatory receptor, or from other immune receptors. This facilitates the second function, T cell activation.

The recognition and activation functions are grafted together on either side of a spacer and transmembrane domain to create the synthetic CAR transgene. The receptor is engineered to specifically target surface tumor antigens, independent of MHC antigen presentation, which is often impaired in tumors. Activated CAR-T cells release cytotoxic compounds like perforin and granzyme B that kill the target cell and facilitate tumor eradication. Activation also facilitates other immune functions including proliferation and production of inflammatory cytokines.

So, how could CAR-T therapy be implemented? One paradigm is to reprogram the patient's own T cells to express the CAR transgene. In this scenario, blood is collected so that T cells can be isolated and activated in the clinic. The CAR transgene is inserted into the genome of these cells, using a replication-incompetent virus. Then, T cells that stably express the CAR are isolated and expanded before being transfused back into the patient's bloodstream.

Ensuring that the CAR-T cells are functional is critically important in preclinical development and beyond. Thus, the surface expression of the CAR needs to be monitored, as well as markers for T cell activation such as CD25 and CD69, and T cell exhaustion markers, such as TIM-3, LAG3 or PD-1.

Assays to characterize CAR-T cytokine release, proliferation, and cytotoxicity will also need to be routinely performed throughout the process. For example, xenograft mouse models have been employed in preclincal studies to assess tumor killing ability of CAR-T cells in vivo.

If you'd like to explore where CAR-T research is headed in the future, make sure to check out the second video in this series, Challenges for CAR-T research. You can also find relevant research tools, plus resources for studying the immune system on our website at https://cellsignal.com.

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#Immunotherapy #CART #Cancer #antibody

Видео Immunotherapy & CAR T Cells: Part 1 канала Cell Signaling Technology, Inc.