Treatment of relapsed myeloma with novel targeted and immune therapies
Dr Kenneth Anderson - Dana–Farber Cancer Institute, Boston, USA
This year’s AACR is an extraordinary meeting, it’s clearly the best one yet. At this meeting there are very seminal advances in genomics, in epigenomics and especially in the immunotherapy of cancer. The plenary session really talks about how these advances are now being translated to patients with cancers of all kinds. I specialise on a cancer called multiple myeloma and we will have a session here which will talk about the science and genomics, epigenomics in multiple myeloma and the immunotherapeutic approaches in multiple myeloma that have and will translate to the initial management of this disease, the management of relapsed disease and also in the future targeted therapies.
I think the history of treatment of myeloma has been very remarkable in the last 10-15 years. We have sixteen new approved, FDA approved, therapies in the last dozen years and we had seven new approved therapies in 2015 alone. As a consequence, as a direct consequence, of these advances there has been a three- to fourfold increase in the survival of patients with myeloma.
Now, on the level of the genomics of myeloma in terms of profiling, understanding the disease, prognosis and potential therapies, it’s a very genetically complex disease. There are many abnormalities, thousands of mutations at presentation. There is underlying genomic instability that ultimately leads to drug resistance and relapse. Nonetheless there are attempts now to identify those pathways that are essential for growth, survival and drug resistance and to target them with combinations of targeted therapies. On the genomic side there’s also the real possibility of targeting the consequences of this genomic instability. So, for example, cells that are multiplying very fast because they have amplification of the Myc oncogene have high levels of replicative stress and it’s now possible to block that stress response and induce those cells into apoptosis. In a similar way cells that have ongoing DNA damage should die given the genetic instability and damage but we and others are now strategizing on how to turn on the natural death pathways in these cells with all of the DNA damage so that they can, in fact, die as they should.
In the area of immune therapies that’s particularly exciting because the immune system is potent, it is adaptable and it is selective. It, in my view, is the most likely way that we will be able to overcome the continued different strategies that myeloma cells do to resist our therapy. In myeloma there are many members of what I call the immune team. There are the immunomodulatory drugs – lenalidomide, thalidomide, pomalidomide – that upregulate the immune system; there are monoclonal antibodies that bind – elotuzumab and daratumumab – and mediate ADCC, CDC and block agonistic or trigger death pathways. Those two, the first two members of the team, the immunomodulatory drugs are now being used with antibodies to enhance their activity and that is how elotuzumab was FDA approved together with lenalidomide. The third member of the immune team in myeloma is the checkpoint inhibitors and the interest there is that PD-L1 is expressed not only on the myeloma tumour cell and PD-1 on the immune effector NKT and NKT cells but PD-L1 is also expressed on accessory cells, the myeloid derived suppressor cells and plasmacytoid dendritic cells that promote tumour cell growth survival and drug resistance and further inhibit the immune system. So checkpoint blockade with PD-L1 should not only release the brake on the immune effector cells but also block these accessory cells’ phenotype.
In addition to these three members, the immunomodulatory drugs, the antibodies and the checkpoint inhibitors, there are two other members, actually three other members, of the immune team. Histone deacetylase inhibitors, in particular the HDAC-6 selective HDAC inhibitors, have the ability as single agents to stimulate in patients autologous immune response against their myeloma but they can also be combined with the immunomodulatory drugs or the antibodies. Interestingly, they can shift the immune response towards a memory phenotype. For that reason vaccines, which are the next member of the immune team, have now been re-explored in myeloma. We can vaccinate with a peptide based vaccine, for example, and get an immune response. And we can amplify that response with the addition of lenalidomide. We’re now testing whether a checkpoint inhibitor, anti PD-L1, or the HDAC inhibitor can not only amplify this response but switch it to a memory phenotype. And long-term memory immunity in patients against their own myeloma, especially if we can achieve this early on, is a really major advance.
Finally we have cellular therapies that are part of our immune team and that would be CAR T-cells, for example, which, as you know, the T-cells are harvested from patients, transfected so that they react against a particular target, the most promising target in myeloma is BCMA or B-cell maturation antigen. Those cells are expanded and then transfused back to patients as their own immune army.
So featured here in the myeloma session will be combinations of these immune team members to achieve a selective response and to amplify it. Just to summarise, we’re particularly excited, given the genetic heterogeneity, ongoing DNA damage, that a combination immune approach may just be selective, potent and adaptable enough to overcome any mechanisms of drug resistance