T-cells artificially equipped with 2 cancer-seeking receptors aim to be an elite army of cancer killers

I laboratoriet: T-celler, der er kunstigt udstyret med 2 kræftsøgende receptorer, sigter mod at være en elitehær af kræftmordere2 Fragment Goat Anti-Mouse antibody. CD38-CCR expression was measured after binding of protein L. Surface expression of CD38 is shown on transduced T cells from a representative experiment. scFv, single chain variable fragment; LNGFR, low affinity nerve growth factor receptor; FSC-A, forward spreading range. Credit: DOI: 10.1126 / scitranslmed.abh1962 “width =” 542 “height =” 530 “/>

Figure S1. Design of chimeric antigen receptor (CAR) and chimeric costimulatory receptor (CCR) constructs and expression of CAR, CCR and CD38 on T cells. (A) Schematic diagrams of the vectors used for CARs and CCRs are shown. SP, signal peptide; P2A, “self-cleaving” 2A peptide; IC, intracellular domain; TM, transmembrane domain. (B) Surface expression of the B cell maturation antigen (BCMA) -CAR and CD38-CCR with different costimulatory designs is shown from a representative experiment. BCMA-CAR expression was measured with an F (ab ‘)2 Fragment goat anti-mouse antibody. CD38-CCR expression was measured after binding of protein L. Surface expression of CD38 is shown on transduced T cells from a representative experiment. scFv, single chain variable fragment; LNGFR, low affinity nerve growth factor receptor; FSC-A, forward spreading range. Credit: DOI: 10.1126 / scitranslmed.abh1962

Despite high remission rates for patients treated with T cells, which are left in laboratories to elite cancer fighters, there is still a significant population of patients who eventually relapse and their cancers inevitably return.

It is estimated that CAR T cell therapy – a pioneering form of cancer immunotherapy – has a success rate of 30 to 40 percent for lasting remission. This means that a significant number of patients are not quite so lucky. To improve the odds, medical researchers in laboratories around the world are looking for ways to make CAR T-cell cancer treatment work more effectively.

CAR T cells – chimeric antigen receptor T cells – start as the patient’s own T cells isolated from a blood sample, but the cells are primed in a laboratory using a genetic modification process that causes T cells to express a cancer-seeking and – destroy receptor on their surface.

The particular receptor is known as the chimeric antigen receptor or CAR, which is designed to bind to a specific target – the antigen of cancer – a molecular complex known as CD19. Cancer cell destruction can be rapid – in fact so much so that therapy has been known to quickly force some cancers into remission. CAR T-cell therapy is used to treat certain cancers in the blood, primarily acute lymphocytic leukemia, B-cell lymphoma, follicular lymphoma and multiple myeloma.

The population of CAR T cells expands into a formidable army before being transfused to the patient. A laboratory grows millions of altered T cells before sending them back to the patient’s hospital. Once returned, the modified T cells are stronger, bolder and cancerous. Carrying the chimeric antigen receptor allows these T cells to hunt and destroy cancer cells. Because they seek out and destroy malignant cells around the clock, some doctors have referred to CAR T cell therapy as “a living substance.”

“Immunotherapy with chimeric antigen receptor cells has emerged as a promising therapeutic tool against cancer,” claimed Dr. Afroditi Katsarou, who reported in Science translational medicine. Although the therapy works best for hematological cancers, it is not recommended for all types of these malignancies. The approach is still under investigation as a form of treatment for solid tumors that do not have as high a response rate on CAR T cells as blood cancer, although new clinical trials suggest a possible success.

Katsarou, lead author of the new research, is teaming up with a team of researchers in the Department of Hematology at Amsterdam University Medical Centers in the Netherlands, embarking on a new approach involving attaching not one but two engineered receptors to T cells. Researchers from across the Netherlands work with the Amsterdam-based team as well as with a collaborative team of international researchers, including U.S. researchers at the Memorial Sloan Kettering Cancer Center in New York and Harvard Medical School in Boston.

Their goal is to solve one of the biggest problems in CAR T-cell cancer therapy: It does not work for everyone. Cancers are rising in what researchers describe as a significant proportion of patients. The Amsterdam-led team theorizes that a dual-receptor strategy can increase the effectiveness of this type of immunotherapy and lower the number of treatment errors.

The researchers claim that T cells with two receptors can double the ability of CAR T cells to fight cancer. Using a dual strategy also increases the persistence of CAR T cells in the blood. It is therefore hoped that this new breed of CAR T cells can detect insidious malignant cells that evade traditional single-receptor CAR T cells. Having two receptors reduces the possibility of cancer cells sowing a recurrence, sending patients into a relapse, scientists say.

“Second-generation CARs that provide combined activation and co-stimulatory signals have been shown to induce impressive clinical responses,” Katsarou wrote in Science translational medicine.

Not long after the first CAR T cell therapies were approved nearly five years ago, doctors noticed that the treatment worked better for some patients with hematologic cancers than others. “CARs are highly dependent on target antigen density and, as a consequence, CAR T cells lose their functionality when antigen expression falls below a [certain] threshold, “Katsarou wrote.

Most relapses occur either because the CAR T cells do not last long enough after transfusion, according to the research team, or because the CAR T cells struggle to recognize cancer cells that contain fewer antigens to target. “T cell fatigue and reduced persistence are other important factors limiting the efficiency of CAR T cells,” the collaborative group reported.

In their study, Katsarou and colleagues tested dual-receptor T cells in laboratory dishes and in an animal model. The performance of the cells suggests that this type of modification could solve the dual challenges of poor CAR T cell life and inefficiency against low antigen density, preventing the altered cells from working for many patients. The key to the research was the two types of receptors that were introduced into T cells. One was the traditional chimeric antigen receptor and the other a chimeric costimulatory receptor or CCR.

Compared to traditional CAR T cells, the CAR-CCR T cell combination was more sensitive “to low-antigen multiple myeloma and leukemia cells in culture,” the researchers reported in their research. The new double-receptor T cells also expanded and lasted longer in mouse models of multiple antigen multiple myeloma and leukemia, prolonging survival time and delaying cancer progression, the researchers found.

CAR T cell therapy, also known as CAR T, was developed by medical researchers Isabelle Rivière, Michel Sadelain, and Renier Brentjens of the Memorial Sloan Kettering Cancer Center in New York. Their misleading simple hypothesis that T cells, if modified, could overcome cancer became the basis of a series of laboratory and clinical studies that took nearly 20 years. The first drugs capable of eliciting the expression of chimeric antigen receptors on T cells were approved in 2017.

This type of therapy is defined as individualized – or customized – because patients’ own cells are the key ingredients. Doctors send patients’ blood samples to the drug manufacturer’s laboratory, where the T cells are modified to recognize the cancer target, OK CD19. It can take up to three weeks for the supercharged cells to return to patients’ hospitals.

Currently, there are five CAR T-cell drugs that have been approved by the U.S. Food and Drug Administration: Abecma (idecabtagene vicleucel); Breyanzi (lisocabtagene maraleucel); Kymriah (tisaglenlecleucel); Tecartus (Brexucabtagene autoleucel) and Yescarta (Axicabtagene ciloleucel).

Side effects in patients transfused with the altered T cells have included fever, dizziness, lightheadedness, nausea, vomiting, and diarrhea. More serious side effects have also been documented, such as irregular heartbeats and difficulty breathing.

Researchers hope that early research involving dual receptor T cells will lay the groundwork for a new way of delivering therapy. “The application of this strategy can improve clinical outcomes and accelerate the progress of CAR T cell therapy for various malignancies,” concluded Katsarou and the team.

CAR-T immunotherapy could be improved to kill solid tumors

More information:
Afroditi Katsarou et al., Combining a CAR and a Chimeric Costimulatory Receptor Increases T Cell Sensitivity to Low Antigen Density and Promotes Persistence, Science translational medicine (2021). DOI: 10.1126 / scitranslmed.abh1962

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Citation: In the laboratory: T cells artificially equipped with 2 cancer-seeking receptors aim to be an elite army of cancer killers (2022, 14 January) retrieved 15 January 2022 from https://medicalxpress.com/news/2022- 01-lab -cells-artificially-endowed-cancer-seeking.html

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