A recent study published in Cancer Discovery has highlighted yet another example of how a combination of chemotherapy and immunotherapy could be a way to treat acute myeloid leukemia.
Acute myeloid leukemia is a type of cancer that originates in bone marrow, the site for the formation of blood cells in the body. The cancer occurs due to aberrant transformation within myeloid cells. In normal cases, myeloid cells act as progenitors for white blood cells. However, in acute myeloid leukemia, there is an aggressive and unrestricted proliferation of the myeloid cells. Cancer can then spread into distant organs such as lymph nodes, spleen, and central nervous system.
Based on how fast the cells proliferate, different types of leukemias can be classified as acute myeloid leukemia (AML) or chronic myeloid leukemia (CML). Although AML is relatively rare in comparison to other forms of cancers, more than 19,000 people are diagnosed with AML in the United States.
Although chemotherapy can lead to remission of AML in certain patients, cancer can return after initial remission in a subset of AML patients – leading to relapsed or refractory AML.
Combining Chemotherapy and Immunotherapy
Researchers from The University of Texas MD Anderson Cancer Center in the United States recently showed that a combination of Nivolumab (immunotherapy) and Azacytidine (chemotherapy) resulted in a 33% overall response in AML patients. They published results of their study in Cancer Discovery. The reported phase-2 clinical trial enrolled 70 patients who were treated with this combination.
Immunotherapy: Nivolumab is a monoclonal antibody-based immunotherapy targeting programmed cell death-ligand 1. In normal cases, T cells within our body act as astute sentinels clearing cancer cells before they can get a chance to proliferate. However certain cancer cells can overexpress a gene called PD-L1 and bind to a protein (PD-1) present on the surface of T cells. This, in turn, puts a brake on the T cell activity, allowing the tumor cells to escape the immune response and grow rampantly in the body.
Chemotherapy: Azacytidine, on the other hand, is a chemotherapeutic agent that was approved in 2004 and is frequently used as an anti-cancer agent for myelodysplastic syndromes. This epigenetic drug acts by reactivating tumor suppressors and exhibiting direct cytotoxic activity against cancer cells. Tumor suppressors are genes that act as inherent breaks in dividing cells, preventing uncontrolled proliferation of cells. However, in cancer cells, these genes get silenced by methylation that is brought about by DNA methyltransferases.
Azacytidine acts as an inhibitor of the protein DNA methyl transferase, allowing the methylation to be lifted from segments of this DNA – in effect reactivating the useful brake proteins. Other studies shave shown that Azacytidine can also complement immunotherapy inducing higher expression of PD-1 and PD-L1.
Impressive response rate of 55%
Among the subset of patients who received the combination, patients with no prior exposure to Azacytidine fared better in comparison to patients that had received this treatment before. The overall response rate for this patient subset was a staggering 55%. What was particularly impressive was the finding that 22% of patients exhibited complete remission with the combination. The overall survival in all patients was 6.3 months. In patients with relapsed AML, the overall survival was 10.6 months.
This is impressive considering that the survival in patients that treated with Azacytidine alone is much lower in comparison in relapsed AML. A dampener on the positive results of this was finding that 11% of patients suffered from life-threatening complications. However, a diagnostically relevant finding revealed that patients that exhibiting higher CD3 and CD8 expression prior to the treatment seemed to respond better to this combination. Based on the encouraging results from this study, a phase-3 trial has been approved and the results will be eagerly awaited.
Reference: Daver, N., Garcia-Manero, G., Basu, S., Boddu, P. C., Alfayez, M., Cortes, J. E., . . . Kantarjian, H. (2018).Efficacy, Safety, and Biomarkers of Response to Azacitidine and Nivolumab in Relapsed/Refractory Acute Myeloid Leukemia: A Non-randomized, Open-label, Phase 2 Study. Cancer Discovery. doi:10.1158/2159-8290.cd-18-0774