CAMBRIDGE, Mass.—While the field of medicine continues to wage war against tumors, researchers at the Massachusetts Institute of Technology (MIT) have a powerful new weapon in their arsenal: A new method of delivering immune-cell therapies directly to tumors by "smuggling" drugs on the backs of the cells sent in to fight the tumor. According to the researchers, who recently detailed the method in the journal Nature Medicine, their approach could dramatically improve the success rate of immune-cell therapies by helping drugs to reach only their intended targets while greatly reducing the toxic side effects inherent in this type of therapy.
The idea of using a patient's own immune system to attack cancer is not a new one, notes Darrell Irvine, associate professor of biological engineering and materials science and engineering and a member of MIT's David H. Koch Institute for Integrative Cancer Research. To perform immune-cell therapy, doctors remove a type of immune cell called T cells from the patient, engineer them to target the tumor, and inject them back into the patient. Those T cells then hunt down and destroy tumor cells.
But Irvine, who served as senior author of the paper, adds that despite advancements made in our understanding of immune cell biology in the past 10 years, this method of fighting tumors still has significant hurdles to overcome. Success of immune-cell therapy has been limited by difficulties in generating enough T cells that are specific to the cancer cells and getting those T cells to function properly in the patient, Irvine says. In addition, one class of drugs that has been tested in clinical trials, interleukins, help promote T-cell growth, but they also have severe side effects such as heart and lung failure when given in large doses.
"What we're looking for is the extra nudge that could take immune-cell therapy from working in a subset of people to working in nearly all patients, and to take us closer to cures of disease rather than slowing progression," he adds.
Noting that a major limitation of cell therapies is the rapid decline in viability and function of transplanted cells, the engineers at MIT devised a way to enhance cell therapy via the conjugation of adjuvant drug-loaded nanoparticles to the surfaces of therapeutic cells—in essence, "smuggling" drugs on the cells via "pouches" made of fatty membranes that can be attached to sulfur-containing molecules normally found on the T-cell surface.
Irvine and his colleagues injected T cells, each carrying about 100 pouches loaded with the interleukins IL-15 and IL-21, into mice with lung and bone marrow tumors. Once the cells reached the tumors, the pouches gradually degraded and released the drug over a week-long period. The drug molecules attached themselves to receptors on the surface of the same cells that carried them, stimulating them to grow and divide.
The team observed that within 16 days, all of the tumors in the mice treated with T cells carrying the drugs disappeared. Those mice survived until the end of the 100-day experiment, while mice that received no treatment died within 25 days, and mice that received either T cells alone or T cells with injections of interleukins died within 75 days.
Irvine and his colleagues also demonstrated that they could attach their "pouches" to the surface of immature blood cells found in the bone marrow, which are commonly used to treat leukemia. Patients who receive bone-marrow transplants must have their own bone marrow destroyed with radiation or chemotherapy before the transplant, which leaves them vulnerable to infection for about six months while the new bone marrow produces blood cells. Irvine suggests that delivering drugs that accelerate blood-cell production along with the bone-marrow transplant could shorten the period of immunosuppression, making the process safer for patients.
"We devised a facile and generalizable strategy to robustly augment the therapeutic potential of cytoreagents, while limiting the potential for side effects from adjuvant drugs," Irvine and his colleagues wrote in their paper. "We showed that adjuvant agent-releasing particles can be stably conjugated to cells without toxicity or interference with intrinsic cell functions, follow the characteristic in vivo migration patterns of their cellular vehicles and ultimately endow their carrier cells with substantially enhanced function using low drug doses that have no effect when given by traditional systemic routes. Prolonged retention of the particles on the surfaces of donor cells as shown here enables sustained drug release without concerns of premature degradation of the particle carrier or cargo due to internalization into degradative intracellular compartments."
In addition, these results suggest therapeutic cells are promising vectors for actively targeted drug delivery, Irvine says. The method could "open new venues, beyond existing cell therapies, for applications of cell products as actively targeting drug delivery pharmacytes or vaccine delivery tools," he adds.
"There are lots of people studying nanoparticles for drug delivery, especially in cancer therapy, but the vast majority of nanoparticles injected intravenously go into the liver or the spleen. Less than 5 percent reach the tumor," Irvine says.
What's more, Irvine notes that with a new way to carry drugs specifically to tumors, scientists may be able to give new life to promising drugs that failed in clinical trials because they were cleared from the bloodstream before they could reach their intended targets, for example.
"It may open up the possibility of resurrecting drugs that had severe side effects and got shelved–which is often the case for immunomodulatory drugs," he adds.
Irvine and his colleagues are now working on fine-tuning the manufacturing process to yield nanoparticles that are safe to test in humans. Once that is done, Irvine says the particles could be tested in human clinical trials within the next two or three years.
"We still have a long way to go, but the real test will be when it comes time to test in humans. A lot of drugs administered to animal models look good, but mice do not show the same levels of side effects that humans do," he says.
The MIT study, "Therapeutic cell engineering using surface-conjugated synthetic nanoparticles," was published in the Aug. 15 issue of Nature Medicine. The researchers' work was funded by the National Institutes of Health, the National Science Foundation, the National Cancer Institute and a gift to the Koch Institute.
The idea of using a patient's own immune system to attack cancer is not a new one, notes Darrell Irvine, associate professor of biological engineering and materials science and engineering and a member of MIT's David H. Koch Institute for Integrative Cancer Research. To perform immune-cell therapy, doctors remove a type of immune cell called T cells from the patient, engineer them to target the tumor, and inject them back into the patient. Those T cells then hunt down and destroy tumor cells.
But Irvine, who served as senior author of the paper, adds that despite advancements made in our understanding of immune cell biology in the past 10 years, this method of fighting tumors still has significant hurdles to overcome. Success of immune-cell therapy has been limited by difficulties in generating enough T cells that are specific to the cancer cells and getting those T cells to function properly in the patient, Irvine says. In addition, one class of drugs that has been tested in clinical trials, interleukins, help promote T-cell growth, but they also have severe side effects such as heart and lung failure when given in large doses.
"What we're looking for is the extra nudge that could take immune-cell therapy from working in a subset of people to working in nearly all patients, and to take us closer to cures of disease rather than slowing progression," he adds.
Noting that a major limitation of cell therapies is the rapid decline in viability and function of transplanted cells, the engineers at MIT devised a way to enhance cell therapy via the conjugation of adjuvant drug-loaded nanoparticles to the surfaces of therapeutic cells—in essence, "smuggling" drugs on the cells via "pouches" made of fatty membranes that can be attached to sulfur-containing molecules normally found on the T-cell surface.
Irvine and his colleagues injected T cells, each carrying about 100 pouches loaded with the interleukins IL-15 and IL-21, into mice with lung and bone marrow tumors. Once the cells reached the tumors, the pouches gradually degraded and released the drug over a week-long period. The drug molecules attached themselves to receptors on the surface of the same cells that carried them, stimulating them to grow and divide.
The team observed that within 16 days, all of the tumors in the mice treated with T cells carrying the drugs disappeared. Those mice survived until the end of the 100-day experiment, while mice that received no treatment died within 25 days, and mice that received either T cells alone or T cells with injections of interleukins died within 75 days.
Irvine and his colleagues also demonstrated that they could attach their "pouches" to the surface of immature blood cells found in the bone marrow, which are commonly used to treat leukemia. Patients who receive bone-marrow transplants must have their own bone marrow destroyed with radiation or chemotherapy before the transplant, which leaves them vulnerable to infection for about six months while the new bone marrow produces blood cells. Irvine suggests that delivering drugs that accelerate blood-cell production along with the bone-marrow transplant could shorten the period of immunosuppression, making the process safer for patients.
"We devised a facile and generalizable strategy to robustly augment the therapeutic potential of cytoreagents, while limiting the potential for side effects from adjuvant drugs," Irvine and his colleagues wrote in their paper. "We showed that adjuvant agent-releasing particles can be stably conjugated to cells without toxicity or interference with intrinsic cell functions, follow the characteristic in vivo migration patterns of their cellular vehicles and ultimately endow their carrier cells with substantially enhanced function using low drug doses that have no effect when given by traditional systemic routes. Prolonged retention of the particles on the surfaces of donor cells as shown here enables sustained drug release without concerns of premature degradation of the particle carrier or cargo due to internalization into degradative intracellular compartments."
In addition, these results suggest therapeutic cells are promising vectors for actively targeted drug delivery, Irvine says. The method could "open new venues, beyond existing cell therapies, for applications of cell products as actively targeting drug delivery pharmacytes or vaccine delivery tools," he adds.
"There are lots of people studying nanoparticles for drug delivery, especially in cancer therapy, but the vast majority of nanoparticles injected intravenously go into the liver or the spleen. Less than 5 percent reach the tumor," Irvine says.
What's more, Irvine notes that with a new way to carry drugs specifically to tumors, scientists may be able to give new life to promising drugs that failed in clinical trials because they were cleared from the bloodstream before they could reach their intended targets, for example.
"It may open up the possibility of resurrecting drugs that had severe side effects and got shelved–which is often the case for immunomodulatory drugs," he adds.
Irvine and his colleagues are now working on fine-tuning the manufacturing process to yield nanoparticles that are safe to test in humans. Once that is done, Irvine says the particles could be tested in human clinical trials within the next two or three years.
"We still have a long way to go, but the real test will be when it comes time to test in humans. A lot of drugs administered to animal models look good, but mice do not show the same levels of side effects that humans do," he says.
The MIT study, "Therapeutic cell engineering using surface-conjugated synthetic nanoparticles," was published in the Aug. 15 issue of Nature Medicine. The researchers' work was funded by the National Institutes of Health, the National Science Foundation, the National Cancer Institute and a gift to the Koch Institute.
