A group of scientists has unveiled a groundbreaking approach to supercharging CAR-T cell immunotherapy by blocking a metabolic mechanism, thus extending the cells’ ability to combat cancer. Their study has revealed that by halting this mechanism within CAR-T cells, these cells can transform into memory T lymphocytes, offering prolonged and robust immune defense against tumors.
In Western Switzerland, a team of researchers has unlocked the potential to amplify the tumor-fighting capabilities of CAR-T cells, which are artificial super-cells harnessed in the battle against blood cancers.
Among various immunotherapies, CAR-T cells, short for chimeric antigen receptor T cells, have demonstrated remarkable effectiveness in treating select blood cancers. However, this success has been limited to only half of the patients, largely due to the premature dysfunction of these modified immune cells produced in vitro.
A collaborative research initiative, drawing expertise from the Universities of Geneva (UNIGE) and Lausanne (UNIL), along with the Geneva University Hospitals (HUG) and the Vaud University Hospital (CHUV), all integral parts of the Swiss Cancer Center Léman (SCCL), has uncovered a means to extend the functionality of CAR-T cells. By inhibiting a specific metabolic mechanism, this team has succeeded in crafting CAR-T cells with fortified immune memory, significantly extending their capacity to combat tumor cells.
These highly promising findings have been recently published in the prestigious journal Nature.
CAR-T cell immunotherapy entails extracting immune cells, typically T lymphocytes, from a cancer patient, enhancing their tumor-targeting capabilities in the lab, and subsequently reintroducing them into the patient’s body. Nevertheless, similar to other forms of immunotherapy, a substantial number of patients either do not respond to the treatment or experience relapses.
Mathias Wenes, a research fellow who led this investigation in the laboratory of Professor Denis Migliorini, Department of Medicine at the UNIGE Faculty of Medicine and Department of Oncology at HUG, elaborated, “CAR-T cells must be massively multiplied before they can be administered. However, the patient’s disease history, combined with the amplification process, exhausts the cells, pushing them into a state of terminal differentiation that limits their lifespan and efficacy.”
A Shared Metabolic Mechanism
In the absence of oxygen, cancer cells resort to a specific survival mechanism: they metabolize the amino acid glutamine through a process known as ‘reductive carboxylation’ to generate alternative energy. Alison Jaccard, a Ph.D. student in Professor Ping-Chih Ho’s laboratory in the UNIL-CHUV Department of Oncology and the study’s lead author, explained, “Immune cells and cancer cells share a fairly similar metabolism, enabling them to proliferate rapidly. We have indeed discovered that T cells also employ this mechanism.”
To explore the role of reductive carboxylation, scientists inhibited this process in CAR-T cells within mouse models of leukemia and multiple myeloma, two prevalent blood cancers. Mathias Wenes summarized the results, stating, “Our modified CAR-T cells underwent normal multiplication and retained their ability to attack, indicating that reductive carboxylation is dispensable for them.”
Remarkable Results in Mice
Furthermore, mice treated in this manner showed near-complete recovery from cancer, surpassing the research team’s expectations. Wenes emphasized, “In the absence of reductive carboxylation, the cells do not differentiate as extensively and maintain their anti-tumor function for extended periods. Crucially, they also tend to transition into memory T lymphocytes, a type of immune cell that stores the memory of tumor elements to be targeted.”
Memory T lymphocytes play a pivotal role in secondary immune responses. They retain the memory of previously encountered pathogens and can re-activate when these threats reappear, whether viruses or, importantly, tumor-related pathogens. Wenes concluded, “The same principle applies to CAR-T cells: the greater the number of memory cells, the more potent the anti-tumor response, yielding superior clinical outcomes. The differentiation state of CAR-T cells emerges as a critical determinant of treatment success.”
A Nexus of Metabolism and Gene Expression
Unwound, the DNA contained in each of our cells would extend approximately two meters in length. To fit within the cell nucleus, it coils around histone proteins. For gene transcription to occur, specific DNA regions must unwind, a process facilitated by histone modifications.
Activated T cells undergo histone modifications that both condense DNA to preserve genes associated with longevity and open up DNA to activate genes responsible for inflammation and cell killing. Reductive carboxylation directly influences the generation of metabolites, small chemical entities that modify histones, thus impacting DNA packaging and accessibility to longevity genes. Inhibiting reductive carboxylation keeps these genes open and promotes their transformation into long-lasting memory CAR-T cells.
A Clinical Application on the Horizon?
The inhibitor employed by the researchers to block reductive carboxylation is already approved for treating certain cancers. Wenes concluded, “We propose repositioning it to extend its application and generate more potent CAR-T cells in vitro. Naturally, their efficacy and safety must undergo clinical trials, but our optimism is high.”
An Exemplar of the Swiss Cancer Center Léman’s Capabilities
This potentially translational work exemplifies the power of collaborative networks like the SCCL. The alliance of laboratories from four Lemanic institutes—UNIL, CHUV, UNIGE, and HUG—has facilitated the realization of this impactful project. Such inter-institutional cooperation fosters synergy across complementary fields, including tumor metabolism, oncoimmunology, and immune cell engineering.
Reference: “Reductive carboxylation epigenetically instructs T cell differentiation” by Alison Jaccard, Tania Wyss, Noelia Maldonado-Pérez, Jan A. Rath, Alessio Bevilacqua, Jhan-Jie Peng, Anouk Lepez, Christine Von Gunten, Fabien Franco, Kung-Chi Kao, Nicolas Camviel, Francisco Martín, Bart Ghesquière, Denis Migliorini, Caroline Arber, Pedro Romero, Ping-Chih Ho, and Mathias Wenes, 20 September 2023, Nature.
DOI: 10.1038/s41586-023-06546-y
Table of Contents
Frequently Asked Questions (FAQs) about Immunotherapy Advancements
Q: What is CAR-T cell immunotherapy, and how does it work?
A: CAR-T cell immunotherapy is a cutting-edge approach in cancer treatment. It involves extracting immune cells, typically T lymphocytes, from a cancer patient’s body. These cells are then modified in a laboratory to enhance their ability to recognize and target tumor cells. Finally, the modified CAR-T cells are reintroduced into the patient’s system, where they can actively seek out and attack cancer cells.
Q: What is the significance of inhibiting the metabolic mechanism in CAR-T cells mentioned in the text?
A: Inhibiting the metabolic mechanism in CAR-T cells is a groundbreaking discovery. This inhibition extends the functionality of CAR-T cells and transforms them into memory T lymphocytes. This transformation results in prolonged and more effective immune protection against tumors. It addresses a key issue in CAR-T cell therapy, which is the premature dysfunction of these cells, and holds the potential to improve the treatment’s success rate.
Q: How do memory T lymphocytes contribute to cancer treatment?
A: Memory T lymphocytes play a crucial role in cancer treatment. They store the memory of tumor elements that need to be targeted. When these elements reappear, such as in the case of a cancer relapse, memory T lymphocytes can re-activate and mount a robust immune response. This leads to longer-lasting immune protection and better clinical outcomes in CAR-T cell therapy.
Q: What is the connection between metabolism and gene expression discussed in the text?
A: The text highlights that metabolism and gene expression are interconnected in immune cells, particularly T cells. When T cells are activated, they undergo histone modifications that affect both DNA packaging and gene expression. Reductive carboxylation, a metabolic process, directly influences these modifications. Inhibiting reductive carboxylation keeps genes associated with longevity open, promoting the transformation of T cells into long-lived memory CAR-T cells.
Q: Are there potential clinical applications for this research, and what is the outlook for its implementation?
A: The text suggests promising clinical applications for this research. The inhibitor used to block reductive carboxylation is already approved for certain cancer treatments. Researchers propose repositioning it to enhance CAR-T cell therapy. However, before widespread implementation, the efficacy and safety of these enhanced CAR-T cells will need to undergo rigorous clinical trials. Despite this, the researchers are optimistic about the potential impact of their findings.
3 comments
The connection between metabolism and genes is fascinating. It’s like the body has its own secret code to fight cancer. Clinical trials? Let’s hope it’s a breakthrough!
The scientists are so smart! They take cells and do things in the lab, then put them back in the body to fight cancer. Mice cured of cancer? That’s great news! Hope this helps real people soon.
wow, this text is amazin a lot of sciency stuff about Cancer and cells and stuff. CAR-T cells sound cool, but what’s reductive carboxylating? This is some seriously promisin’ research!