EMN 2021 | BiTEs for the treatment of multiple myeloma

So, bispecific antibody constructs tackle two main problems in anticancer immunotherapy with autologous T-cells. First of all, that there are very few anti-tumor reactive T-cells in a patient with a tumor, as with multiple myeloma, and that often these few anti-tumor reactive T-cells are dysfunctional and anergic. And so the strategy we need is to use activated, fully activated T-cells that have a different specificity. For example, addressing, cells infected by cytomegalovirus, or by influenza virus, and retarget these T-cells to become tumor-reactive.

And so, the bi-specific antibodies are binding to a surface antigen on the T-cells, mainly CD3, and with the other binding domain to a surface antigen on the tumor cell, which is mainly, in myeloma, BCMA. And by this, you can actually force a T-cell that is specific for a virus infected cell to target and lyse the tumor cell. And this allows to have a lot of T-cells that are functionally active. You’ll make the T-cell activation independent of MHC class one and class two expression, which is important because often tumor cells, like myeloma cells, are down-regulating MHC class one and class two, and you can induce an efficient lysis of the myeloma cell.

So, there are different targets. I’ve already discussed BCMA, which is the main target for all these redirection strategies, like the bispecifics and CAR T-cells. But there are other targets like GPRC5D, or FcRH5, or CD38, or CD138, or CD19. So, there are quite a few targets, and the major target that has been addressed using bispecific antibodies is really BCMA, which is quite homogeneously expressed on myeloma cells, and up to now, there is only very few reports about the loss of BCMA expression on the myeloma cells. So, what typically happens if you infuse a bispecific antibody is that you get an expansion of these activated T-cells, or often effector memory T-cells more from the CD8 than from the CD4 compartment.

The first clinical trial that was done in multiple myeloma using a bispecific antibody, or what they are also called T-cell engaging antibodies, was the AMG 420. This was a study which was performed by several French and also some German centers, and in this trial patients with refractory/relapsed multiple myeloma having received at least two lines of prior therapy were included. They received up to five lines of therapy. It could be extended to 10 lines of therapy if they responded and had no major toxicity. And with not a lot of toxicity there the maximum tolerated dose was achieved with 400 micrograms per day.

Now the antibody had to be given as a continuous infusion like the first bispecific antibody that is approved for clinical use worldwide and that’s blinatumomab, a CD3, CD19 bispecific antibody for B-ALL in the situation of relapse/refractory disease or minimal residual disease-positive ALL. With this continuous infusion, we saw some issues. One was portal vein infections, and two, this continuous infusion of these T-cell engaging antibodies, there might have been some T-cell exhaustion, or some form of infectious disease or infectious pathogen-specific T-cell. So, we saw in two patients quite severe opportunistic infections, one of them an adenovirus infection one and the other one an Aspergillus infection. That, and that was really encouraging. The drug was very effective. So, even in these heavily pretreated patients, we had 70% overall response rate at the MTD and 50% complete remissions and also being MRD-negative, and we have ongoing remissions for more than one year.

Now, the further development of bispecific antibodies changed. They went away from this classical biomolecules, these very small molecules, that have to be used as continuous infusion, but half-life extended BiTEs, or other formats of bispecific antibodies were applied that allow weekly, or even bi-, or administration even every three weeks. So, which makes it much easier for patients to actually receive this treatment.

And one of these molecules was AMG 701, which was also used in heavily pretreated patients, median of six lines of prior therapy, and again, with a very low toxicity, very little cytokine release syndrome, very little severe neurotoxicity that was also seen in the AMG 420 study. This bispecific antibody was applied and 83% of the patients responded. And again, patients have been on the program now for more than one year and still responding. So this is very encouraging.

But there are a lot of other bispecific antibodies really targeting BCMA and CD3. And the one that is really probably most advanced at the clinical development is teclistamab, which is another format of a bispecific antibody, that can be given as also intravenously weekly, or by subcutaneous application. And again, quite well-tolerated, no severe cytokine release syndrome, no severe neurotoxicity and a high overall response rate of more than 70%. And again, ongoing responses for quite some time. And there are several other bispecific antibodies targeting BCMA and CD3 now in the clinic, in the clinical evaluation in patients with advanced multiple myeloma.

What we’ve also seen, and I think has been the first one that actually described this problem, is that in patients that receive redirected T-cell therapy, either by bispecific antibodies or CAR T-cells that are targeting exclusively BCMA, there can be a complete and irreversible loss of BCMA. So we had one patient who was treated with BCMA-specific CAR-T cells, and he had a very nice persistence on these CAR T-cells. He had a beautiful clearance of all the myeloma sites, and he also was shown to have also clearance in the bone marrow, clearance of the M-protein, clearance of the soluble BCMA. And then suddenly in spite of the persistence of the BCMA-directed CAR T-cells, the patient had a rapid rise in the M-protein, and in the PET-CT, we found, very early actually, before we found the M-protein increase, a small lesion and the lesion actually expanded very rapidly and then we found all the myeloma cells to have a complete loss, irreversible loss, of BCMA due to a biallelic lesion in the chromosome 16, where this gene segment that was lost is actually coding for BCMA as a clear explanation for this irreversible BCMA loss. So it’s important to have also other targets, and there are other targets like GPRC5D, or an antibody that is targeting the molecule FcRH5.

And both these bispecific antibodies, one called talquetamab which is targeting GPRC5D, and the other one cevostamab. They have been used in patients with advanced multiple myeloma and also a few patients that actually were failing BCMA targeting therapy. And again, with a very low rate of severe cytokine release syndrome, very low rate of severe neurotoxicity. They showed nice overall response rates ranging between 53 and 69%.

So, we have also targets for myeloma cells that are lacking BCMA expression, and if we look at the bispecific antibodies that are in clinical development, there are quite a few, they seem to be very well tolerated. And we know from the lymphoma field that patients actually beyond 80, even beyond 90 can be, yes, can be treated with a bispecific antibody because of the low toxicity of these bispecific antibodies. So, it’s something that can really be applied. And we don’t have a lot of patients in the very high dose levels, but at least the ones that received the highest dose that have showed very nice responses, and in a few patients with ongoing responses for more than one year.

So, it’s a great promise for patients with multiple myeloma. I think the future, in the future, we will see that these bispecific antibodies are moving to earlier lines of therapy in multiple myeloma, and maybe high-risk patients already in first-line, or patients that have relapsing multiple myeloma, definitely in the second line of treatment.