The Yin and Yang of Stem Cell Transplantation
For many patients with a high-risk or relapsed blood cancer, stem cell transplantation is the best chance for a cure. But, transplant complications can be dangerous. This month, I will share some exciting new advances in LLS-funded research aimed at reducing the main transplant complication, known as graft-versus-host disease (GvHD).
As many of you know, patients who undergo "allogeneic" transplantation receive blood stem cells (the "graft") from a healthy donor after receiving high-dose radiation and/or chemotherapy to kill the cancer cells. The donor stem cells are needed to replace the normal blood cells of the patient (the "host") that are unfortunately also killed.
Allogeneic transplants produce cures not just because of the high-dose therapies, but also because mature donor immune cells are in the graft and come along with the blood stem cells. These ?good' immune cells, including "T cells", can fight infections while the stem cells divide to produce the new immune system. And, they kill any cancer cells that remain after therapy, preventing early relapse. But, other ?bad' donor T cells can attack a patient's normal tissues - that's GvHD.
GvHD can affect a patient's gastrointestinal tract, liver, skin and/or lungs, and can be very serious, even lethal. There is currently no good treatment for GvHD - conquering GvHD would make cures possible for more patients.
In last November's commentary, I told you about a promising new approach to selectively incapacitate one type of donor T cells that can apparently cause GvHD - the bad guys. This novel procedure also activates a T cell subtype called "T-regs" that seem to prevent GvHD - T-regs are the good guys.
Now, an international team of researchers, including LLS grantees James Ferrara M.D. and Pavan Reddy M.D. of the University of Michigan, has measured the levels of Treg cells in patients who underwent allogeneic transplants. They found that Treg numbers were significantly lower in patients with GvHD, lowest in patients with the most severe GvHD. These findings suggest that Treg tests might be used to identify patients who need GvHD-blocking treatments, before they have GvHD. This study strongly supports selective T-reg stimulating strategies to prevent GvHD.
But, T-regs aren't the whole story. Another normal T cell subset, known as "naïve" is responsible for many desirable immune responses, but can apparently cause GvHD. Naïve T cells from the donor migrate after transplant to specialized lymph nodes within the patient. There they are taught by a totally different type of immune cells, known as "APC" cells, to find and kill the patient's normal cells. The now not-so-naïve T cells migrate again, especially to a patient's gut where they can cause GvHD. GvHD is overall an abnormal situation that comes from mixing patient and donor cells that haven't grown-up and been educated together.
LLS-funded researcher, Bruce Blazar M.D. of the University of Minnesota, and his colleagues just reported that naïve T cells use a molecule on their surfaces, called "CCR7", to find their way around. Blocking or removing CCR7 reduced GvHD in animal models, without increasing relapse, supporting short term T cell CCR7 targeting as a promising new anti-GvHD strategy.
And, there are subtypes of APC teacher cells too. Which APCs are involved in inducing GvHD and whether they are from the donor or the patient is not yet clear. Immune "B cells" can act as APC teachers, and may help induce GvHD. This idea is based on the fact that the antibody drug, Rituxan®, kills B cells and can reduce GvHD symptoms in patients.
Rituxan binds a B cell molecule called CD20 and thereby kills B cell subsets with high CD20 levels (yes, more subsets). Rituxan kills malignant B cells and is approved for B-cell lymphoma and leukemia patients.Rituxan also kills the abnormal B cells that cause rheumatoid arthritis and is approved for patients with this auto-immune disease.
Rituxan might reduce GvHD by killing normal B cells before they can teach T cells to cause GvHD. LLS grantee, Warren Shlomchik M.D., and his Yale University colleagues just showed in a mouse model that GvHD can occur without host B cells, strongly suggesting that Rituxan's relevant effects in GvHD reduction must be on donor B cells or on some other type of APC that is impacted indirectly. Research continues and the answer will almost certainly lead to better ways to use Rituxan to block GvHD.
The most potent type of APC immune teacher is the "dendritic cell" or DC. Recent findings suggest that host DCs can induce GvHD. But, as with T cells (and B cells) it seems there are balancing DC forces. Some DCs can teach T cells not to attack and Dr. Reddy, mentioned above, just showed that a particular type of host dendritic cells can be used to reduce GvHD, in a mouse model of transplantation.
It has taken more than twenty years of intensive research to catalogue the complexity of normal immune systems, to learn the immune alphabet. Now, we can distinguish various immune cell types and subtypes, and we know some of them teach others, to activate or block immune responses. The goal of this yin/yang complexity is balanced immune responses that fight infections and cancers, for example, but don't cause autoimmune disease or GvHD.
From the dark complexity, light is emerging. Researchers are beginning to learn how to use new understandings to develop promising GvHD treatments. They are learning how to activate good immune cells and inactivate bad cells. They are learning how to manipulate the donor graft so that the incoming cells can fight infection and prevent relapse without causing GvHD.
Not only are new insights likely to make stem cell transplantation safer and available to more patients, but they are also spearheading the development of new "immunotherapies" that can help a patient's own immune system fight cancer. Someday we hope immune cells can fight cancer without highly toxic chemotherapies being necessary.