Stem Cell Transplantation
Unfortunately, patients with a blood cancer that is considered "high-risk" of being non-responsive to standard therapies or who have already relapsed are unlikely to realize long-lasting remissions with additional standard treatments. As I have discussed here before, their best option may be stem cell transplantation in which patients receive blood stem cells (and some mature blood cells) to rebuild healthy immune systems after more aggressive, potentially curative therapies.
In "autologous stem cell transplantation," a patient's own stem cells are used to restore their blood systems after a "preparative" or "conditioning" regimen with high doses of chemo- and/or radiation. Recently, an LLS-funded physician scientist, Steven Gore M.D. of Johns Hopkins University School of Medicine, and his colleagues showed that a drug (called 4-HC for short) can be an important part of autologous transplants for patients with low-grade, transformed, or mantle cell lymphomas. In a Phase 2 clinical trial for 80 patients, the doctors used 4-HC to help "purge" patients' own stem cells of any residual cancer cells. Patients who were less than 50 years of age, had less than three prior chemotherapies, and received transplants before relapsing did especially well - 15 patients were disease-free more than 15 years after transplantation.
Over the last decade, autologous stem cell transplantation has become a standard treatment for patients with multiple myeloma - high doses of the drug, melphalan, are typically used as the preparative treatment. Unfortunately, despite good response rates, most patients eventually relapse. A team that includes LLS grantee Jonathan Serody M.D. of University of North Carolina School of Medicine hypothesized that the drug, mitoxantrone, could further improve myeloma patient outcomes, especially when administered by prolonged infusion. The results of their early phase trial show that infusional mitoxantrone can be safely used with melphalan and indeed seems to substantially prolong remissions. Larger trials are now planned, including trials that will also include the targeted drug, Revlimid®, in the preparative regimen.
In "allogeneic stem cell transplantation," a patient receives blood stem cells from a genetically "matched" stem cell donor. Here, high-dose conditioning chemotherapy (with or without radiation) is used not only to treat the blood cancer but also to inactivate the patient's immune system so that the donor stem cells will not be rejected. Allogeneic transplants are especially recommended for patients with myeloid cancers that carry high-risk features.
For example, acute myeloid leukemia (AML) patients "FLT3/ITD" gene mutations in their cancer cells are very likely to relapse after standard two-drug therapies. Doctors at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, including Mark Levis M.D./Ph.D., Richard Jones M.D. and Dr. Gore (from above) have now reported that FLT3-mutated patients can do as well as other AML patients when they undergo allogeneic transplants while in first complete remission. Although this was a single institution experience, the findings were for 133 patients, including 31 who carried FLT3 mutations. As I mentioned here before, Dr. Levis also recently reported promising results for a FLT3 inhibitor drug that may further improve outcomes for these patients.
Importantly, allogeneic transplants can produce cures not just because of the high-dose therapies, but also because mature donor immune cells come along with the blood stem cells in the donor "graft." Some of these immune cells, including certain types of "T cells," can fight infections while the blood stem cells divide to produce the new immune system. And, T cells can kill any cancer cells that remain after therapy, preventing early relapse. This is called the graft versus leukemia (GvL) effect because it was first proven for leukemia patients, but grafted immune cells can fight other blood cancers as well. Unfortunately, other types of donor T cells can attack a patient's normal tissues (the "host") and produce a serious condition known as graft-versus-host disease (GvHD).
I've talked here before about GvHD. It can affect a patient's gastrointestinal tract, liver, skin and/or lungs, and can be very serious, even lethal. There is currently no completely effective treatment for GvHD and conquering GvHD would almost certainly make cures possible for more patients.
Now, LLS-funded Andrea Velardi M.D. and her colleagues at the University of Perugia and University of L'Aquila have developed a strategy that seems to reduce GvHD risk and also promote faster immune reconstitution. For 28 patients with high risk blood cancers who underwent allogeneic transplantation, they recently showed that early infusion of special T cells called T-regs prevented GvHD, improved immunity to infectious agents, without weakening the GvL effect.
Dr. Velardi and her colleagues are among those that are learning how to help immune cells do a better job in preventing relapse after transplantation. They are working with another type of immune cells called natural killer (NK) cells that can stimulate immune responses. As with immune T cells, there are subsets of NK cells - the Italian team has now shown that larger numbers of a particular NK subset (lacking the CD56 marker) are found in recipients of T cell-depleted transplants and may contribute to GvL and relapse prevention. This is good news as researchers around the world are learning how to make more of these cells in the laboratory.
Stay tuned!
