In the case of HIV/AIDS, this is the second patient treated with stem-cell transplantation from a donor whose macrophages (bone marrow and tissue scavengers) do not allow entry of the HIV virus. This means that there is no reservoir or storage of virus possible. Thus, after effective anti-retroviral treatment (ART), the virus is truly gone. The special macrophages are called CCR5Δ32/Δ32. The whole procedure, although fantastically effective, is a very difficult treatment and not something that can be considered on a large scale.
In the case of sickle cell anemia, the protocol being used by Dr. John Tisdale and Dr. Francis Collins (Director of the NIH) is a gene-therapy approach using the patients’ own stem cells. The sickle cell gene is replaced with the normal hemoglobin gene producing red blood cells that no longer have the sickle shape which causes the medical problems.
In both situations, stem-cell transplantation is involved, targeting the critical underlying molecular and cellular biology of the disease.
Are there targets like this in myeloma patients?
There are cases of myeloma in which the myeloma protein is directed against the HIV virus that has persisted in the macrophage reservoir. Thus, we know with this example and many others that persistent or poorly contained infections of different types, including viruses and bacteria, can function as potential triggers for myeloma. However, the infections are quite diverse, and the immune mechanisms involved are very complex, so eliminating reservoirs of infection would be no easy task. On the other hand, both in HIV and in myeloma there is reduced T-lymphocyte numbers and function that cause the immune dysfunction associated with the diseases. Thus, for myeloma, a key treatment is CAR T-cell therapies, which use engineered T cells to boost T cell numbers and activity to attack the myeloma cells. Right now, BCMA, which is highly expressed on myeloma cells, is the main target. Initial results with such BCMA-targeted therapies have been amazingly good (88 percent response rate in the LEGEND trial reported at ASH in 2018).
For myeloma, two main questions remain: can the anti-BCMA CAR T-cell approach eliminate all remaining myeloma cells? Are there mechanisms or hidden reservoirs which can lead to re-occurrence of myeloma? There is reasonable optimism that refinements and new understandings will bring patients close to cure with CAR T-cell therapies.
Single gene therapy for myeloma
Is there a single gene which can be replaced to treat myeloma, as in the case of sickle cell disease? At this time, no single gene has been shown to cause or trigger myeloma. In patients with active myeloma, the myeloma cells contain many mutations and abnormal genes. However, early in the disease evolution, at the stages of MGUS (monoclonal gammopathy of undetermined significance) and SMM (smoldering multiple myeloma), it is hoped that single-gene mutations can be identified that will emerge as candidates for gene-therapy strategies. The IMF-supported iStopMM project is central to this research approach, since all patients in the study have baseline and sequential genetic sequence information.
In the interim, one intriguing possibility is focusing on the p53 gene. Absence or mutation of this gene occurs in myeloma and is linked to high-risk disease. I have written in the past about how extra copies of the p53 genes in elephants can prevent cancer. In a new report, Dr. Robin Cristofari, a biologist at the University of Turku in Finland, has embarked on a project called “Genomic of Ageing in Elephants.” This work will further clarify the role of multiple copies of the p53 gene in reducing the development of cancer.
Using CRISPR gene-editing technology
So, could adding extra p53 copies to myeloma cells reverse the cancer? Maybe. If so, a gene therapy approach early in the disease evolution could be a useful strategy. This is truly intriguing for the future. It should be emphasized that the CRISPR gene-editing technology would be a treatment for adults with MGUS or SMM. This is different from the controversial approach in which gene editing is used to create CRISPR babies as occurred with the birth of two babies “Nana” and “Lulu” recently in China. This approach to create genetically modified children has been broadly condemned. It is proposed that there be a moratorium on such research or at least the establishment of an international governance framework. This is highly appropriate, and the genetic-editing techniques should also be pursued with due caution in the adult situation mentioned above. The ultimate opportunities for medical benefit are enormous.
The cures in HIV/AIDS and sickle cell anemia disease do not directly apply to myeloma. However, they do draw attention to several related opportunities which can contribute to dramatically improved outcomes and even cures in the near future.
Dr. Brian G.M. Durie serves as Chairman of the International Myeloma Foundation and serves on its Scientific Advisory Board. Additionally, he is Chairman of the IMF's International Myeloma Working Group, a consortium of nearly 200 myeloma experts from around the world. Dr. Durie also leads the IMF’s Black Swan Research Initiative®.