Immunotherapy Activity Shown in Multiple Myeloma Trial

Ivan Borrello, MD

As part of our coverage of the American Society of Hematology or ASH annual conference being held December 3rd to December 6th in San Diego, California, we are speaking with Ivan Borrello, MD, associate professor of oncology who treats patients with hematological malignancies and who studies investigative immunotherapy approaches including adoptive T-cell therapy and vaccines for these tumor types. At the ASH meeting, Dr. Borrello gave a talk on adoptive T-cell and vaccine approaches for multiple myeloma.

-Interviewed by Anna Azvolinsky, PhD

OncoTherapy Network: First, there is evidence indicating that multiple myeloma may be amenable to immunotherapy? What do we know so far?

Dr. Borrello: There actually is. I think, for one thing, the role of allogeneic bone marrow transplantation clearly shows that there is a graft versus myeloma effect. And as has been just presented at this ASH meeting, there is data with CAR T cells, specifically looking at BCMA [B-cell maturation antigen] approaches, and certainly our work would seem to suggest that there is a significant antitumor effect mediated by the immune system.

OncoTherapy Network: Can you talk about some of the adoptive T-cell approaches that are currently in development for multiple myeloma?

Dr. Borrello: Sure. From a gene-modified perspective, I think, the thing that has gotten the most recognition and interest has been the use of a CAR T cell targeting a protein called BCMA, that stands for “B-cell maturation antigen” and there was data presented at the meeting on that. There are also modified T-cell receptors, specifically targeting another protein called NY-ESO-1 that was published several years ago and that work is ongoing.

Our approach, however, has been slightly different. To date, we have focused on nongene modifying T cells and a different compartment of T cells. Our work has focused on the development of MILs which stands for “marrow-infiltrating lymphocytes.” The concept is that the bone marrow, in addition to being the site of the tumor is also a very unique immune site where it is a reservoir of memory antigen experienced T cells and it is also a site, as in the case of hematological malignancies, and specifically in myeloma it is the site of the disease, so we have shown that when we take MILs out and compare them to peripheral blood lymphocytes or PBLs, that these T cells have a higher percentage of memory phenotype and are also significantly more tumor specific than are PBLs. So, what we have done so far are several clinical trials including one that has previously been reported, showing that in the context of a transplant, we were able to obtain, activate, and infuse these cells in all patients with a direct correlation between the extent of the tumor specificity of these MILs to the myeloma that correlated directly with a clinical response to the myeloma itself.

We are currently involved in a randomized trial of high-risk myeloma in the transplant setting of transplant with or without MILs. Another thing that we are using this with is following an allogeneic bone marrow transplantation where currently, when patients relapse, the standard of therapy is donor lymphocyte infusion, going back to the donor and obtaining peripheral T cells from them, and this is normally associated with a significant incidence of graft versus host disease and with somewhat marginal clinical benefit. We have shown that if we actually go into the patient following an allogeneic transplant and extract and expand the MILs that we can now impart a clinical meaningful antitumor effect and more importantly, can deliver this in the absence of any graft versus host disease.

OncoTherapy Network: Based on the data so far, where do you see these adoptive T-cell therapies being most useful? In what context or what patient subtypes?

Dr. Borrello: I think that a lot of the gene-modified approaches currently have been tested in the relapsed, refractory setting, one, because that is a setting where patients generally have fewer available therapeutic options. But another reason that can and tends to be underestimated is that there is significant toxicity associated with these gene-modified T cells. I think one of the benefits of MILs is that our overall toxicity profile is very, very low. We are currently using this as an adjuvant treatment, if you will, in the context of an autologous transplant. And as I mentioned, we are also doing this following relapse in the allogeneic transplant setting, but I think one could theoretically envision using this also in the context of earlier, upfront treatment or even in the nontransplant setting, and even in the elderly patients considering the favorable toxicity profile we are currently seeing with this therapy.

OncoTherapy Network: As far as the vaccine approaches, your lab has developed a vaccine that is in development. Could you talk about the design of the vaccine and some of the results so far?

Dr. Borrello: There are multiple different vaccines that are currently being used for the treatment of cancer. The approach we have taken has been using what is called GVAX, which is basically a whole-cell GM-CSF producing vaccine. I think the rationale for that is we want to try to prime an immune response to as many tumor-specific antigens as possible and not just go after one specific antigen. And, so our vaccine consists of three cell lines, two of them are unmodified myeloma cell lines and they are coupled to a cell that produces GM-CSF. And we have designed the vaccine so that the ratio of tumor cells to bystander cells is such that as to optimize the ability to generate tumor-specific immunity.

What we have reported at ASH is the fact that we are using in the context of minimal residual disease in patients that are on lenalidomide [Revlimid]. And I think this combines two important aspects that need to be considered when thinking about vaccine trial development. One is that it takes several weeks to months to actually prime specific vaccine responses. And so the ideal setting for this would be a setting where the disease burden is minimal which is why we picked the minimal residual disease setting, and the second thing is that you want an optimal host to effectively generate tumor-specific immunity. And work previously done by our group and also confirmed by other groups has shown that IMIDs [immunomodulatory drugs] can in fact augment tumor-specific immunity and that is the rationale for this combination.

So what we did in this trial is we took patients who were in a near complete remission from myeloma and that stayed that way for at least 6 months. This was defined as the absence of an M-spike [monoclonal spike], but the persistence of the immunofixation. And interestingly, of all the patients that we screened, half of them became ineligible and of those, half that became ineligible, half of those, so 50% of the ineligible patients were so because they relapsed during that 6-month window, but the other 50% became ineligible because they deepened their response and achieved a true complete remission. Those, what we would call the observation arm continued on all of their therapies and the median time to progression was roughly 15 months. In contrast, the patients that got vaccinated discontinued all of their therapies with the exception of Revlimid and then received the vaccine. So, theoretically, they were getting less therapy than were the observation arm and the vaccines were given at 1, 2, 3, and 6 months and single-agent Revlimid was continued until relapse. And of the 15 patients that we vaccinated, we are now out over 3.5 years and have not met our median progression-free survival and have had only three relapses.

So certainly from this small, preliminary phase I trial, it does appear that there is significant evidence of antidisease activity and this has prompted us to move forward with a randomized phase II trial.

OncoTherapy Network: Thank you so much for joining us today, Dr. Borrello.

Dr. Borrello: Thank you.