Immunotherapies in Multiple Myeloma

At the 2019 Lymphoma & Myeloma Congress, David E. Avigan, MD, Beth Israel Deaconess Medical Center, Boston, Massachusetts, discussed active immunotherapies for the treatment of multiple myeloma.

Transcript

I’m David Avigan. I'm the Chief of the Hematology and Hematologic Malignancy Division at Beth Israel Deaconess Medical Center. I'm a Professor of Medicine at Harvard Medical School, and I'm part of the Dana Farber Harvard Cancer Center.

My talk was related to cancer vaccines, and their potential use in blood cancers, specifically acute myeloid leukemia and multiple myeloma. Talked initially about the background to cancer vaccines, and the goal of trying to induce an immune response in patients with malignancy where the tumor has over time turned itself into a less immunogenic target, so that the tumor's not well-recognized by the immune systems.

The whole goal of cancer vaccines is to try and reverse that process and induce a productive immune response both by amplifying the response against the tumor, and also dealing with the microenvironment that helps protect the tumor from immune response as well.

I talked about the nature of how vaccines are constructed, and the fact that there are different ways to approach vaccine design that include the use of shared antigens as the target of the vaccine versus neoantigens that arise from mutational events that are truly tumor specific.

Gave a couple of different examples of peptide-based vaccines in that realm. Then focused the majority of the talk on our particular platform in which we take patient-derived tumor cells and create a hybridoma or effuse cell with the patient's own dendritic cells. This is a highly-personalized vaccine that captures the entire heterogeneity of the tumor cell clones and allows to produce an effective response both by CD4 and CD8 cells.

The initial results that were discussed had to do with acute myeloid leukemia, where we know in standard therapy patients may achieve remission after chemotherapy but most of those patients unfortunately go on to relapse, particularly in patients over the age of 50.

In our experience we conducted a trial where patients after achieving response and who are not transplant candidates underwent vaccine with our hybridoma of dendritic cell fusions, and we found that there was a very potent expansion of tumor-reactive lymphocytes both in the peripheral blood and in the bone marrow.

Most importantly what we saw was that over 70% of those patients stayed in remission more than five years out, which was really remarkably different than what we had expected based on the historical experience. We're now conducting a large randomized trial to further explore the potential role of that vaccine as a way of preventing relapse.

We talked about our experience in multiple myeloma, where we were vaccinating patients with this particular hybridoma, after autologous transplant, and we saw an initial phase 2 trial that the number of patience achieving complete response nearly doubled after the vaccination.

This led to really an exciting endeavor of a national trial that we're conducting through the CTN which is a cooperative group run by the NIH. This design is that patients after autologous transplant either receive standard maintenance therapy, or the combination of standard maintenance therapy and this vaccine.

This was a remarkable endeavor involving 17 sites around the country, where each site learned how to make the vaccine, and Beth Israel Deaconess ended up being the central sort of port where the vaccine was characterized and made sure that it met all release criteria.

We're now waiting for those results, but we had some exciting early results around immune response that was sort of described regarding patients undergoing vaccination in this setting.

We then talked about some combinatorial approaches of how this vaccine may integrate with other treatments that are now being explored. We think that we have a very powerful platform to expand tumor reactive lymphocytes, and now we want to focus on the microenvironment to try and make those responses stick, so to speak.

Talked about some preclinical experience showing that when the vaccine is given with the checkpoint inhibitor, there appears to be very powerful synergy while the checkpoint inhibitor by itself does not work very well in a hem malignancy model. That really mirrors what we've seen in the clinical setting. This idea of a synergistic effect of expanding t-cells and then activating them, is something that is now being explored in a clinical trial as well.

Finally, we talked about the potential integration between active vaccine strategies and CAR T-cells, or adoptive t-cell strategies. We reviewed some of the literature on multiple myeloma and CAR T-cells showing that we get very potent responses and very sort of exciting initial effect, but many of these patients go on to relapse. This has to do with the fact that the CARs both don't last forever, and also that there can be the emergence of antigen-negative variants.

The vaccine on the other hand, relies on the fact that there would be competent effector cells or t-cells which we don't always have, and the CARs provide that, but may be a better regulatory mechanism to create longer-term responses and a broader response. We've been looking with several investigators about integrating these 2 therapies and some data was presented pre-clinically about how vaccine in CARs may actually show some synergy together.

That was the focus of the talk, and ultimately thinking towards the future of how we might create rational design around combinatorial strategies that will both induce effective immunity, but also create more durable memory responses that will prevent relapse.