Massachusetts Institute of Technology (MIT) scientists have devised a method that allows therapeutic cells used in fields such as cancer treatment to piggyback the adjuvants they need to maintain their viability and function. The researchers claim the technique not only effectively improves the activity and longevity of transplanted cells, but also means far less adjuvant is needed, circumventing the potentially life-threatening toxicity issues associated with the systemic delivery of adjuvants that traditionally accompanies therapeutic cell transplantation.
Initial studies by the MIT team in cancer-bearing mice found the approach significantly boosted tumor elimination in a model of adoptive T-cell therapy for cancer. They also found that attaching relevant adjuvants to immature bone marrow cells transplanted into mice significantly boosts blood cell maturation in vivo. Team leader, Darell Irvine, Ph.D., associate professor of biological engineering and materials science and engineering, hopes the technique could have applications beyond cancer therapy, and even enable the use of cells as targeted carriers of drug compounds.
Dr. Irvine projects the technology could be ready for clinical trials in cancer patients within two to three years. The MIT teams research to date is published in Nature Medicine, in a paper titled "Therapeutic Cell Engineering with Surface-Conjugated Synthetic Nanoparticles". “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,” remarks Dr. Irvine, who is also with MIT’s David H. Koch Institute for Integrative Cancer Research.
Cell-based therapies such as hematopoietic stem cell (HSC), islet cell, or hepatocyte transplants are already routinely used in clinical practice, and new strategies implementing adult, embryonic, or induced pluripotent stem cells are in various stages of development, Dr. Irvine and colleagues point out. However therapeutic cells often rely on the concurrent delivery of adjuvant drugs to maximize donor cell efficacy and in vivo persistence, or offset suppressive molecules at cell homing sites and promote the differentiation of transferred cells into a therapeutically optimal phenotype. To negate these issues, the MIT researchers devised a method for encasing adjuvant molecules in nanoparticles, and attaching these adjuvant-carrying sacs onto the surface of the therapeutic cells. They confirmed that the nanoparticles could be linked to cells without compromising key cellular functions. Once transplanted into the recipient, the nanoparticles gradually dissolved, and the released adjuvant molecules attached to the relevant cell-surface receptors.
For one in vivo experiment the researchers injected adjuvant-conjugated T cells into mice with lung and bone marrow tumors. Each T cell carried about 100 nanoparticle sacs loaded with IL-15 and IL-12. Within 16 days of therapy all the tumors in the treated mice disappeared and the animals all survived for the 100-day duration of the study. In contrast, animals treated using either T cells alone or T cells and injections of interleukins all died within 75 days.
“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,” the authors conclude.