New Therapies for Blood Cancers Hold Promise
Blood cancer is actually a term applied to three different types of cancer – leukemia, lymphoma and myeloma. For centuries, these cancers had virtually no possibility of survival. Even as recently as the 1960s, the five-year survival rate for leukemia was 14%. By 2010, it had increased to 61%. Similar gains have been made in the survival rates for lymphoma and myeloma, with Hodgkin lymphoma reaching a five-year survival rate of 88% in that year. The story of the science behind the gains in survival rates and the development of ever-more effective therapies is the story of advances in the field of immunotherapy and personalized medicine taking place at centers such as Abramson at UPENN and Dana-Farber in Boston.
Bone Marrow Transplants
The first significant increases in survival rates occurred in the early 1980s, with the introduction of chemotherapy and bone marrow transplants. In a UPENN CureTalks interview in 2017, Dr. Carl June of UPENN described the two-step process. First, the patient’s immune system received super-lethal doses of chemotherapy. Then, bone marrow from a sibling was transplanted into the patient. When the result was a better survival rate, the increase in survival was attributed to the super-lethal dose of chemotherapy administered prior to the transplant. When the procedure was performed on identical twins and researchers discovered that increased survival did not occur, researchers had to rethink their premise. They realized that the source of the survival increase lay in the differences in the marrow of the non-identical sibling rather than in the process of destroying the patient’s immune system before the introduction of new bone marrow.
This better understanding of the cause of increased survival rates from bone marrow transplant therapy, combined with the significant downside arising from graft vs host disease, led June to explore the possibility that patients could receive the benefits of a bone marrow transplant without an actual transplant. He studied the possibility that a patient’s own immune system could be used as a weapon. The outcome of this work was the development of CAR-T cells, approved for use by the FDA in 2017.
CAR-T therapy is the first personalized cancer therapy to be approved by the FDA. The process has been licensed by Novartis. They have manufactured CAR-T cells for patients in their FDA-approved facility. With CAR-T, a patient’s own T-cells are filtered, along with white blood cells, through the leukapheresis process. A viral vector is used to recognize the targeted cells – cells with cancer and other cells expressing a specified antigen. These “reprogrammed” cells are then introduced back into the patient’s blood.
According to June, it is not at all uncommon for a high fever to occur during the time when the CAR-T cells are annihilating the cancer cells. This fever has shown no lasting effect. It is a side effect that indicates that the process is working. For two of the first three participants in the clinical trials held at Penn in 2010, the survival rate for chronic lymphocytic leukemia (CLL) was eight years as of 2018.
Immune Checkpoint Inhibitors
Another FDA-approved immunotherapy agent is used in patients with recurring Hodgkin lymphoma (HL). The FDA approval occurred in 2016, but a study underway in 2019 at Dana-Farber by Dr. Margaret Shipp’s team is investigating the mechanism that causes two proteins, PD-L1 and PD-L2, to overproduce on HL cells. They’ve found that the proteins work with a protein on the T-cells that keeps the T-cells from attacking the HL. By blocking PD-1, it is possible to expose the HL to the T-cells. The use of these checkpoint inhibitors holds promise for those with HL that has reoccurred or not responded to the first therapy.
Until recently, a patient’s immune system was reprogrammed to fight a single target – an antigen. Dr. Daniel D’Angelo of Dana-Farber describes BiTEs (bispecific antibodies) as a way to cut out the middle step. Rather than attack first one, and then the other, the BiTE attaches to both a T-cell and a tumor cell at the same time. This FDA-approved therapy is being used to treat acute lymphoblastic leukemia (ALL) but shows potential for the treatment of other cancers.
The potential advantage of BiTEs over CAR-T cell therapy lies in the fact that BiTEs are not patient-specific: There is not the need to remove and reprogram T-cells for reintroduction into the patient’s blood. Currently, BiTE is being used with patients who have multiple myeloma (MM) and have relapsed. Early results are promising. In one clinical trial, some patients showed no trace at all of cancer after treatment. The next step is to see how long this remains the case, as well as whether or not different delivery times or the use of BiTE in conjunction with CAR-T will make a difference in the outcome.
At the ASH Annual meeting held at Abramson Cancer Center, two new studies were described.
One study is designed to determine the best time to introduce CAR-T therapy in multiple myeloma (MM). It will identify T-cell biomarkers that help to predict the outcome from CART-BCMA therapy (Abstract #1974 and Abstract #1886). The other explores the combination of CAR-T cells and the tyrosine kinase inhibitor ibrutinib in chronic lymphocytic leukemia (CLL). Initial results show that the use of both in combination will lead to deep and sustained remission (Abstract #298).
The current work is already leading to new avenues of investigation. Improved blood cancer therapies are one part of the advances being made in targeted, personalized therapies.
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