Acute myeloid leukemia (AML) is a deadly blood cancer that originates in the bone marrow and kills most of its victims within five years. Chemotherapy has been the standard AML treatment for over 40 years, and while it often causes the cancer to go into remission, it rarely completely eliminates the cancerous cells, which then lead to disease recurrence in nearly half of treated patients. Aggressive post-remission treatments, like high-dose chemotherapy or bone marrow transplants, can reduce the chance of recurrence, but many AML patients are not healthy enough to tolerate them.
Now, a new study presents an alternative treatment that has the potential to eliminate AML cells completely: an injectable, biomaterial-based vaccine that, when combined with standard chemotherapy, caused complete and lasting recovery from and immunity against AML in mice. The study was conducted by researchers from Harvard's Wyss Institute for Biologically Inspired Engineering, John A. Paulson School of Engineering and Applied Sciences (SEAS), and Stem Cell Institute (SCI), and is published in Nature Biomedical Engineering .
We have previously developed cancer vaccines against solid tumors, and we were curious to see if this technology would also be effective at treating a blood cancer like AML. The promising outcomes of the combination of this vaccine with chemotherapy may translate to human vaccines that can be personalized yet offer off-the-shelf convenience. Co-first author Nisarg Shah, Ph.D., a former Postdoctoral Fellow in the lab of Wyss Core Faculty member David Mooney, Ph.D. who is now an Assistant Professor at the University of California, San Diego A crafty cryogel
Like other vaccines, the AML vaccine "teaches" the body's immune system to recognize a foreign invader (in this case, AML cancer cells) so that it can mount an effective attack when that invader appears. While traditional vaccines are typically liquid, this vaccine is a tiny, disk-shaped "cryogel" scaffold made primarily of two materials - polyethylene glycol and alginate - that have been cross-linked together to form a matrix. Two chemicals (GM-CSF and CpG-ODN) are embedded in the scaffold to attract the body's dendritic cells and activate them, along with antigens specific to AML cells (either contents from dead AML cells or a peptide from the protein WT-1). The activated dendritic cells take up the antigens from the vaccine site and present them to T cells, triggering them to seek and destroy AML cells and, hopefully, patrol the body long-term to destroy any disease recurrence.
To test whether their cryogel vaccine effectively primed the immune system to attack AML cells, the team injected it under the skin of healthy mice, and saw that it resulted in a much higher number of activated T cells when either AML cell contents or WT-1 was used as the antigen, compared with mice that received the activating chemicals via a traditional vaccine injection or a "blank" scaffold without any chemicals. They then "challenged" the mice by injecting them with WT-1-expressing AML cells to mimic the initial onset of the disease. The mice that received either the traditional vaccine or a blank scaffold succumbed to the disease within 60 days, while those that received the cryogel vaccine survived. The survivors were then re-challenged with a second dose of AML cells after 100 days and displayed no signs of disease, demonstrating that the vaccine successfully protected them against recurrence.
Because AML originates in the bone marrow and cancerous cells can "hide" there to escape chemotherapy treatment, the team analyzed the mice's bone marrow. They found large numbers of active T cells and no trace of AML cells in the cryogel-vaccinated mice's marrow. When they transplanted bone marrow from those mice into healthy mice that were then challenged with AML cells, all of the transplant recipients survived while a control group of mice succumbed to AML within 30 days, indicating that the immune protection against AML was sustained and transferable. Unexpected results, better-than-expected outcomes
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