**Researchers Enhance CAR T-Cell Therapy to Prevent Premature Fading**:
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By Alvin Powel, Harvard Gazette |
Leading the research are Mohammad Rashidian, an assistant professor of cancer immunology at Dana-Farber and radiology at HMS, and postdoctoral fellow Taha Rakhshandehroo. Together with their team, they have created an enhancer protein that selectively boosts the efficacy of CAR T-cell therapy—a treatment that has revolutionized cancer care. This protein not only enhances the anticancer activity of CAR T-cells but also promotes the formation of memory CAR T-cells. These memory cells provide long-term immune protection against cancer, much like the immune response generated after a vaccination or an infection like chickenpox.
**The Promise and Challenge of CAR T-Cell Therapy**:
CAR T-cell therapy, approved by federal regulators in 2017, involves extracting T-cells from a patient’s immune system and reprogramming them with a “chimeric antigen receptor” (CAR) on their surface. This receptor acts as a lock and key with a specific protein marker on cancer cells, enabling the CAR T-cells to recognize and destroy these cancer cells once they are reintroduced into the patient’s body.
In recent years, CAR T-cell therapy has garnered significant attention for its success in treating patients where conventional therapies have failed. In some instances, this treatment has completely eradicated cancer cells in patients with the most severe cases.
However, a notable challenge has emerged: after CAR T-cells clear most of the cancer, their numbers gradually diminish, allowing any remaining cancer cells to multiply. For example, in multiple myeloma—a type of cancer affecting white blood cells—CAR T-cell therapy can extend patients' survival in the short term, but half of them relapse within one to two years. Within three years, most patients experience a recurrence of their cancer.
**A Breakthrough in Preclinical Studies**:
This new advancement, while still in the preclinical stage, was developed using mouse models of multiple myeloma. The research was supported by Dana-Farber’s Innovation Research Fund Award, the Parker Institute for Cancer Immunotherapy, and a Blavatnik Therapeutics Challenge Award.
The results, recently published in *Nature Biotechnology*, offer hope that this technique could be effective against other types of cancer as well. The researchers are already conducting studies to test the enhancer protein against leukemia and lymphoma, with the aim of extending the benefits of CAR T-cell therapy to a broader range of patients.
**A Revolutionary Approach to Cancer Care**:
CAR T-cell therapy is one of the most innovative cancer treatments in recent years, transforming the way we fight the disease. Unlike traditional methods like surgery, chemotherapy, and radiation, this therapy harnesses the body’s own immune system, turning it into a potent weapon against cancer.
Now, a new breakthrough by researchers Mohammad Rashidian and Taha Rakhshandehroo is set to take CAR T-cell therapy to the next level. They have developed an enhancer protein that selectively targets and energizes CAR T-cells, significantly boosting their activity and longevity. This advancement could ensure that the therapy remains effective long enough to eliminate all cancer cells.
**The Quest for Enhanced CAR T-Cell Longevity**:
The issue of CAR T-cell longevity has been a significant challenge for over a decade. Most approaches have focused on re-engineering the CAR T-cells themselves to extend their lifespan in the body, but these efforts have often fallen short. Rashidian and Rakhshandehroo, however, took a different approach. Instead of altering the cells, they focused on stimulating them after they’ve been infused into the patient, and at the precise time needed.
To achieve this, they designed an innovative enhancer protein. This protein works by fusing a cancer-specific marker to a molecule called IL-2, which naturally enhances T-cell activity and persistence. Importantly, the IL-2 in their design is engineered to be weak, minimizing any potential impact on normal T-cells and avoiding toxic side effects. However, when this enhancer protein is in proximity to CAR T-cells, even the weak IL-2 is sufficient to significantly boost their activity.
**A Game-Changing Discovery**:
“For us, it was like night and day,” Rakhshandehroo said, describing the dramatic impact of the enhancer protein on CAR T-cell activity. Unlike the marginal differences often seen in scientific research, the results of this study were immediately apparent and robust. The researchers conducted further experiments to explore the underlying biology, and the results continued to impress. The response of the CAR T-cells remained strong even as they adjusted various experimental variables.
“This discovery opens the door for others to explore the biology behind this enhancement,” Rakhshandehroo added.
**Precision Control for Future Treatments**:
One of the key features of this enhancer protein is its short circulatory half-life of just two hours. This brief duration allows for precise control of CAR T-cell stimulation, preventing overstimulation while still providing a robust immune response. As Rashidian explained, this also means that dosing can be more easily adjusted during human trials, ensuring the treatment is both safe and effective.
The researchers are now seeking funding for a Phase 1 clinical trial to test the efficacy and safety of this approach in humans. “I’m very excited about it,” Rashidian said. “The results have exceeded our expectations. It’s incredibly robust, and I’m hopeful that this will save patients’ lives.”
This groundbreaking work represents a significant step forward in cancer treatment, offering new hope to patients and paving the way for more effective and lasting therapies.
CAR T-cell therapy is one of the most innovative cancer treatments in recent years, transforming the way we fight the disease. Unlike traditional methods like surgery, chemotherapy, and radiation, this therapy harnesses the body’s own immune system, turning it into a potent weapon against cancer.
Now, a new breakthrough by researchers Mohammad Rashidian and Taha Rakhshandehroo is set to take CAR T-cell therapy to the next level. They have developed an enhancer protein that selectively targets and energizes CAR T-cells, significantly boosting their activity and longevity. This advancement could ensure that the therapy remains effective long enough to eliminate all cancer cells.
**The Quest for Enhanced CAR T-Cell Longevity**:
The issue of CAR T-cell longevity has been a significant challenge for over a decade. Most approaches have focused on re-engineering the CAR T-cells themselves to extend their lifespan in the body, but these efforts have often fallen short. Rashidian and Rakhshandehroo, however, took a different approach. Instead of altering the cells, they focused on stimulating them after they’ve been infused into the patient, and at the precise time needed.
To achieve this, they designed an innovative enhancer protein. This protein works by fusing a cancer-specific marker to a molecule called IL-2, which naturally enhances T-cell activity and persistence. Importantly, the IL-2 in their design is engineered to be weak, minimizing any potential impact on normal T-cells and avoiding toxic side effects. However, when this enhancer protein is in proximity to CAR T-cells, even the weak IL-2 is sufficient to significantly boost their activity.
**A Game-Changing Discovery**:
“For us, it was like night and day,” Rakhshandehroo said, describing the dramatic impact of the enhancer protein on CAR T-cell activity. Unlike the marginal differences often seen in scientific research, the results of this study were immediately apparent and robust. The researchers conducted further experiments to explore the underlying biology, and the results continued to impress. The response of the CAR T-cells remained strong even as they adjusted various experimental variables.
“This discovery opens the door for others to explore the biology behind this enhancement,” Rakhshandehroo added.
**Precision Control for Future Treatments**:
One of the key features of this enhancer protein is its short circulatory half-life of just two hours. This brief duration allows for precise control of CAR T-cell stimulation, preventing overstimulation while still providing a robust immune response. As Rashidian explained, this also means that dosing can be more easily adjusted during human trials, ensuring the treatment is both safe and effective.
The researchers are now seeking funding for a Phase 1 clinical trial to test the efficacy and safety of this approach in humans. “I’m very excited about it,” Rashidian said. “The results have exceeded our expectations. It’s incredibly robust, and I’m hopeful that this will save patients’ lives.”
This groundbreaking work represents a significant step forward in cancer treatment, offering new hope to patients and paving the way for more effective and lasting therapies.
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